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Xiaotan Sanjie Recipe Inhibits Gastric Cancer Metastasis by Regulating GnT-V-Mediated E-Cadherin Glycosylation
Nian Huang, Haiwei He, Yuyu He, Wei Gu, Mingjuan Xu, Long Liu
Journal of Integrative Medicine    2023, 21 (6): 561-574.   DOI: 10.1016-j.joim.2023.06.029
Accepted: 02 May 2023
Online available: 30 July 2023

Abstract84)      PDF(pc) (1367KB)(40)    PDF(mobile) (1367KB)(5)   
Objective: Xiaotan Sanjie recipe (XTSJ), a Chinese herbal compound, exerts a significant inhibitory effect on the GC metastasis. Nevertheless, the mechanism underlying the XTSJ-mediated inhibition of GC metastasis is unknown. Our study demonstrated the regulation of XTSJ on the GnT-V-mediated addition of β1,6 GlcNAc branches to E-cadherin and affected GC metastasis in vitro and in vivo.
Methods: The effect (and associated mechanism) of XTSJ on GC metastasis was evaluated in vitro (using GC cell lines) and in vivo (using a GC mouse model) by focusing on the expression of GnT-V (encoded by MGAT5).
Results: We demonstrated that the migration and invasion ability of GC cells decreased significantly after XTSJ administration, which confirmed the efficacy of XTSJ in treating GC in vitro. Moreover, we showed that XTSJ increased the accumulation of E-cadherins at junctions between GC cells, an effect which was reversed by MGAT5 overexpression. XTSJ administration and MGAT5 knockdown alleviated the structural abnormality of the cell-cell junctions, while MGAT5 overexpression had the opposite effect. MGAT5 knockdown and XTSJ treatment also significantly increased the accumulation of proteins associated with the E-cadherin-mediated adherens junction complex. Furthermore, the expression of MGAT5 was significantly lower in the lungs of BGC-823-MGAT5+XTSJ mice than in those of BGC-823-MGAT5+solvent mice, indicating that the ability of gastric tumors to metastasize to the lung was decreased in vivo following XTSJ treatment.
Conclusion: Our study confirmed that XTSJ prevented GC metastasis by inhibiting the GnT-V-mediated E-cadherin glycosylation and promoting E-cadherin accumulation at cell-cell junctions.
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Can acupuncture enhance therapeutic effectiveness of antidepressants and reduce adverse drug reactions in patients with depression? A systematic review and meta-analysis
Ming-min Xu, Pei Guo, Qing-yu Ma, Xuan Zhou, Yu-long Wei, Lu Wang, Yue Chen, Yu Guo
Journal of Integrative Medicine    2022, 20 (4): 305-320.   DOI: 10.1016/j.joim.2022.05.002
Online available: 14 July 2022

Abstract105)   HTML    PDF      
Background
Some depressed patients receive acupuncture as an adjunct to their conventional medications.

Objective
This review aims to provide evidence on whether acupuncture can enhance the therapeutic effectiveness of antidepressants for treating depression, and explore whether acupuncture can reduce the adverse reactions associated with antidepressants.

Search strategy
English and Chinese databases were searched for randomized controlled trials (RCTs) published until December 1, 2021.

Inclusion criteria
RCTs with a modified Jadad scale score ≥ 4 were included if they compared a group of participants with depression that received acupuncture combined with antidepressants with a control group that received antidepressants alone.

Data extraction and analysis
Meta-analysis was performed, and statistical heterogeneity was assessed based on Cochran’s Q statistic and its related P-value. Primary outcomes were the reduction in the severity of depression and adverse reactions associated with antidepressants, while secondary outcomes included remission rate, treatment response, social functioning, and change in antidepressant dose. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was used to evaluate the overall quality of evidence in the included studies.

Results
This review included 16 studies (with a total of 1958 participants). Most studies were at high risk of performance bias and at low or unclear risk of selection bias, detection bias, attrition bias, reporting bias, and other bias. Analysis of the 16 RCTs showed that, compared with antidepressants alone, acupuncture along with antidepressants reduced the Hamilton Depression Rating Scale-17 (HAMD-17) scores (standard mean difference [SMD] ?0.44, 95% confidence interval [CI] ?0.55 to ?0.33, P < 0.01; I2 = 14%), Self-rating Depression Scale (SDS) scores (SMD ?0.53, 95% CI ?0.84 to ?0.23, P < 0.01; I2 = 79%), and the Side Effect Rating Scale (SERS) scores (SMD ?1.11, 95% CI ?1.56 to ?0.66, P < 0.01; I2 = 89%). Compared with antidepressants alone, acupuncture along with antidepressants improved World Health Organization Quality of Life-BREF scores (SMD 0.31, 95% CI 0.18 to 0.44, P < 0.01; I2 = 15%), decreased the number of participants who increased their antidepressant dosages (relative risk [RR] 0.32, 95% CI 0.22 to 0.48, P < 0.01; I2 = 0%), and resulted in significantly higher remission rates (RR 1.52, 95% CI 1.26 to 1.83, P < 0.01; I2 = 0%) and treatment responses (RR 1.35, 95% CI 1.24 to 1.47, P < 0.01; I2 = 19%) in terms of HAMD-17 scores. The HAMD-17, SDS and SERS scores were assessed as low quality by GRADE and the other indices as being of moderate quality.

Conclusion
Acupuncture as an adjunct to antidepressants may enhance the therapeutic effectiveness and reduce the adverse drug reactions in patients receiving antidepressants. These findings must be interpreted with caution, as the evidence was of low or moderate quality and there was a lack of comparative data with a placebo control.

Systematic review registration: INPLASY202150008.
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Salvadora persica extract attenuates cyclophosphamide-induced hepatorenal damage by modulating oxidative stress, inflammation and apoptosis in rats
Talat Albukhari, Bassem Refaat, El-Sayed Bakr, Sameh Baz, Bodour Rajab, Hossam Gadalla, Mohamed El-Boshy
Journal of Integrative Medicine    2022, 20 (4): 348-354.   DOI: 10.1016/j.joim.2022.05.001
Accepted: 11 November 2021
Online available: 15 July 2022

Abstract104)   HTML    PDF      
Objective: Salvadora persica (SP) is used as a food additive and is a common ingredient in folk medicine. This study investigates the antioxidant, anti-inflammatory, and beneficial effects of SP against cyclophosphamide (CYP) toxicity in rats.
Methods: In a 10-day study, 32 male rats were equally allocated into 4 groups (8 rats/group) as follows: the normal control (NC group), normal rats that only received oral aqueous extract of SP (100 mg/[kg·d]; SP group), animals treated with intraperitoneal CYP injections (30 mg/[kg·d]; CYP group), and the CYP + SP group that concurrently received CYP with SP aqueous extract. Serum samples were collected to measure the liver and renal biochemical profiles, as well as antioxidant and oxidative stress markers and the concentrations of interleukin-1β (IL-1β), IL-6, IL-10, tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB) and adenosine 5’-monophosphate-activated protein kinase (AMPK). Hepatic and renal tissues were also harvested for histopathology and to measure apoptosis using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling technique, alongside tissue levels of oxidative stress markers.
Results: Liver enzymes, total bilirubin, creatinine and urea, as well as serum IL-1β, IL-6, TNF-α and NF-κB increased significantly, whilst total protein, albumin, calcium, IL-10 and AMPK declined in serum of the CYP group relative to the NC group. The hepatorenal concentrations of glutathione, glutathione peroxidase and catalase declined markedly in the CYP group, whereas malondialdehyde, protein adducts, and apoptosis index increased compared with the NC group. By contrast, the hepatorenal biochemistry and apoptosis index of the SP group were comparable to the NC group. Interestingly, the CYP + SP group had significant improvements in the liver and renal biochemical parameters, enhanced anti-oxidative and anti-inflammatory effects, and marked declines in hepatic and renal apoptosis relative to the CYP group. Moreover, all monitored parameters were statistically indistinguishable between the CYP + SP group and the NC group.
Conclusion: This study suggests that the aqueous extract of SP could be a potential remedy against CYP-induced hepatorenal damage and may act by modulating the AMPK/NF-κB signaling pathway and promoting anti-oxidative and anti-inflammatory activities.
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Filiform needle acupuncture for allergic rhinitis: A systematic review and meta-analysis
Shi-Hao Du, Wei Guo, Chao Yang, Sheng Chen, Sheng-Nan Guo, Shuo Du, Zhong-Ming Du, Yu-Tong Fei, Ji-Ping Zhao
Journal of Integrative Medicine    2022, 20 (6): 497-513.   DOI: 10.1016/j.joim.2022.08.004
Accepted: 07 May 2022
Online available: 05 August 2022

Abstract209)   HTML    PDF      

Background

Filiform needle acupuncture (FNA), the most classical and widely applied acupuncture method based on traditional Chinese medicine theory, has shown a promising effect in the treatment of allergic rhinitis (AR).

Objective

We aim to comprehensively evaluate the efficacy, safety, cost-effectiveness, and patient preference of FNA in the treatment of AR by comparing FNA with sham acupuncture, no treatment, and conventional medication.

Search strategy

Eight electronic databases were systematically searched from inception to October 14, 2021. Additional studies were acquired from clinical trial registration platforms and reference lists.

Inclusion criteria

RCTs were included if they compared FNA with either sham acupuncture, no treatment, or conventional medications for AR.

Data extraction and analysis

Two researchers extracted data independently of each other using a predesigned data acquisition form, and results were cross-checked after completion. The primary outcome was symptom score (Total Nasal Symptom Score or Visual Analog Scale), and the secondary outcomes were the AR control questionnaire, quality of life (QoL) score (Different versions of Rhinoconjunctivitis Quality of Life Questionnaires), medication score (use of rescue medication), mental health score, total IgE, adverse event rate, clinical economic indicators, and patient satisfaction score. Standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CIs) was used to calculate the effect size for continuous data, while risk ratio with 95% Cis was used for dichotomous data.

Results

Thirty studies were included in this review. Compared with sham acupuncture, FNA significantly reduced the symptom score (SMD: –0.29 [–0.43, –0.15]), AR’s impact on QoL (SMD: –0.23 [–0.37, –0.08]) and medication score (SMD: –0.3 [–0.49, –0.11]). Compared with no treatment, FNA dramatically reduced the symptom score (SMD: –0.8 [–1.2, –0.39]) and AR’s impact on QoL (SMD: –0.82 [–1.13, –0.52]). There were no increased rates of adverse event with FNA compared to sham acupuncture and no treatment. FNA increased patient satisfaction and may be cost-effective. Most pieces of evidence from the above two comparisons were of high confidence. Moreover, FNA significantly outperformed conventional medication in reducing the symptom score (SMD: –0.48 [–0.85, –0.1]) and displayed a lower rate of adverse events, but the quality of evidence was very low.

Conclusion

FNA is an effective and safe intervention for AR and can help with symptom relief, QoL improvement, reducing medication usage, and increasing patient satisfaction. Further studies are needed to verify its cost-effectiveness and superiority over conventional medication and the best therapeutic strategies.

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Functional connectivity changes during migraine treatment with electroacupuncture at Shuaigu (GB8)
Xiang-yu Wei, Shi-lei Luo, HuiChen, Shan-shan Liu, Zhi-gang Gong, Song-hua Zhan
Journal of Integrative Medicine    2022, 20 (3): 237-243.   DOI: 10.1016/j.joim.2022.01.009
Accepted: 06 January 2022
Online available: 31 January 2022

Abstract200)   HTML    PDF      
Objective
To investigate the changes in the functional connectivity (FC) in the right insula between migraine without aura (MWoA) and healthy controls by using resting-state functional magnetic resonance imaging (rs-fMRI), and to observe the instant alteration of FC in MWoA during electroacupuncture (EA) stimulation at Shuaigu (GB8).

Methods
A total of 30 patients with MWoA (PM group) and 30 healthy controls (HC group) underwent rs-fMRI scans. The PM group underwent a second rs-fMRI scan while receiving EA at GB8. The right insula subregions, including the ventral anterior insula (vAI), dorsal anterior insula (dAI) and posterior insula (PI), were selected as the seed points for FC analysis.

Results
Aberrant FC, including dAI with right postcentral gyrus, PI with left precuneus, was found among PM before EA (PMa), PM during EA (PMb) and HC. Meanwhile, decreased FC between dAI and the right postcentral gyrus was found in the PMa compared to the HC and PMb. Increased FC between the PI and left precuneus was found in the PMa compared to the HC and PMb. Correlation analysis showed that the FC value of the right postcentral gyrus in PMa was negatively correlated with the scores of Hamilton Rating Scale for Depression and Hamilton Rating Scale for Anxiety. The FC value of the left precuneus in PMa was positively correlated with the visual analogue scale score.

Conclusion
The alteration of FC between the right insula subregions and multiple brain regions may be an important index for MWoA. EA at GB8 was able to adjust the FC between the right insula subregions and parietal lobe, namely, the right dAI and right postcentral gyrus, and the right PI and left precuneus, thereby rendering an instant effect in the management of MWoA.
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Improving the health and treatment success rates of in vitro fertilization patients with traditional chinese medicine: need for more robust evidence and innovative approaches
Marisa Casal
Journal of Integrative Medicine    2022, 20 (3): 187-192.   DOI: 10.1016/j.joim.2022.02.004
Online available: 21 February 2022

Abstract174)   HTML    PDF      
Maximising access to and the success of fertility treatments should be a priority for global reproductive health, as should overall patient well-being. The demand for in vitro fertilization (IVF) and other assisted fertility treatments has increased over the past decade and is likely to further increase in years to come. Nevertheless, there is still considerable unmet demand for infertility support worldwide. Moreover, the high emotional, physical and financial burden experienced by individuals undergoing IVF cycles can be a risk for their mental and physical health, which in turn can influence treatment continuation and the likelihood of IVF success. Studies from various parts of the world show that most individuals undergoing IVF also use adjunct alternative medicines and procedures, the most common being traditional Chinese medicine (TCM). The complementary and synergistic role of TCM for individuals undergoing IVF is an area that merits further attention and research, both for its potential positive effects on IVF success rates and for its broader physical and mental health benefits. However, much of the existing evidence is not sufficiently robust or consistent for findings to be adopted with confidence. This commentary argues that much work must be done to understand the efficacy and clinical best practices for these integrated approaches. This can be achieved in part by developing more robust and clinically relevant randomized controlled trial protocols, collecting and triangulating evidence through a variety of study designs and methods, and strengthening the collection and pooling of clinic-level data.
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Qili Qiangxin, a compound herbal medicine formula, alleviates hypoxia-reoxygenation-induced apoptotic and autophagic cell death via suppression of ROS/AMPK/mTOR pathway in vitro
Cai-lian Fana, Wan-jun Caib, Meng-nan Ye, Miao Chen, Yi Dai
Journal of Integrative Medicine    2022, 20 (4): 365-375.   DOI: 10.1016/j.joim.2022.04.005
Accepted: 07 February 2022
Online available: 15 July 2022

Abstract114)   HTML    PDF      
Objective: Qili Qiangxin (QLQX), a compound herbal medicine formula, is used effectively to treat congestive heart failure in China. However, the molecular mechanisms of the cardioprotective effect are still unclear. This study explores the cardioprotective effect and mechanism of QLQX using the hypoxia-reoxygenation (H/R)-induced myocardial injury model.
Methods: The main chemical constituents of QLQX were analyzed using high-performance liquid chromatography-evaporative light-scattering detection. The model of H/R-induced myocardial injury in H9c2 cells was developed to simulate myocardial ischemia-reperfusion injury. Apoptosis, autophagy, and generation of reactive oxygen species (ROS) were measured to assess the protective effect of QLQX. Proteins related to autophagy, apoptosis and signalling pathways were detected using Western blotting.
Results: Apoptosis, autophagy and the excessive production of ROS induced by H/R were significantly reduced after treating the H9c2 cells with QLQX. QLQX treatment at concentrations of 50 and 250 μg/mL caused significant reduction in the levels of LC3II and p62 degradation (P < 0.05), and also suppressed the AMPK/mTOR signalling pathway. Furthermore, the AMPK inhibitor Compound C (at 0.5 μmol/L), and QLQX (250 μg/mL) significantly inhibited H/R-induced autophagy and apoptosis (P < 0.01), while AICAR (an AMPK activator, at 0.5 mmol/L) increased cardiomyocyte apoptosis and autophagy and abolished the anti-apoptotic effect of QLQX. Similar phenomena were also observed on the expressions of apoptotic and autophagic proteins, demonstrating that QLQX reduced the apoptosis and auotophagy in the H/R-induced injury model via inhibiting the AMPK/mTOR pathway. Moreover, ROS scavenger, N-Acetyl-L-cysteine (NAC, at 2.5 mmol/L), significantly reduced H/R-triggered cell apoptosis and autophagy (P < 0.01). Meanwhile, NAC treatment down-regulated the ratio of phosphorylation of AMPK/AMPK (P < 0.01), which showed a similar effect to QLQX.
Conclusion: QLQX plays a cardioprotective role by alleviating apoptotic and autophagic cell death through inhibition of the ROS/AMPK/mTOR signalling pathway.
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Reporting and methodological quality of meta-analyses of acupuncture for patients with migraine: A methodological investigation with evidence map
Ting-ting Lu, Cun-cun Lu, Mei-xuan Li, Li-xin Ke, Hui Cai, Ke-hu Yang
Journal of Integrative Medicine    2022, 20 (3): 213-220.   DOI: 10.1016/j.joim.2022.02.003
Accepted: 10 January 2022
Online available: 23 February 2022

Abstract184)   HTML    PDF      
Background

Acupuncture has been widely used to relieve migraine-related symptoms. However, the findings of previous systematic reviews (SRs) and meta-analyses (MAs) are still not completely consistent. Their quality is also unknown, so a comprehensive study is needed.

Objective
To evaluate the reporting and methodological quality of these MAs concerning acupuncture for migraine, and summarize evidence about the efficacy and safety of acupuncture for migraine.

Search strategy
PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Databases, Wanfang Data, and VIP databases were searched from inception to September 2020, with a comprehensive search strategy.

Inclusion criteria
The pairwise MAs of randomized controlled trials (RCTs) concerning migraine treated by acupuncture or acupuncture-based therapies, with a control group that received sham acupuncture, medication, no treatment, or acupuncture at different acupoints were included.

Data extraction and analysis
Two independent investigators screened studies, extracted relevant data, and assessed reporting and methodological quality using PRISMA 2009 and AMSTAR 2, then all results were cross-checked. Spearman correlation test was used to evaluate the correlation between reporting and methodological quality scores.

Results
A total of 20 MAs were included in this study. The included MAs indicated that acupuncture was efficacious and safe in preventing and treating migraine when compared with control intervention. There was a high correlation between reporting and methodological quality scores (rs = 0.87, P < 0.001). The quality of the included SRs needs to be improved mainly with regard to protocol and prospective registration, using a comprehensive search strategy, summarizing the strength of evidence body for key outcomes, a full list of excluded studies with reasons for exclusion, reporting of RCTs’ funding sources, and assessing the potential impact of risk of bias in RCTs on MA results.

Conclusion
Acupuncture is an effective and safe intervention for preventing and treating migraine, and could be considered as a good option for patients with migraine. However, the reporting and methodological quality of MAs included in this overview is suboptimal. In the future, AMSTAR 2 and PRISMA tools should be followed when making and reporting an SR with MA.
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Ziyin Huatan Recipe, a Chinese herbal compound, inhibits migration and invasion of gastric cancer by upregulating RUNX3 expression
Shang-jin Song, Xuan Liu, Qing Ji, Da-zhi Sun, Li-juan Xiu, Jing-yu Xu, Xiao-qiang Yue
Journal of Integrative Medicine    2022, 20 (4): 355-364.   DOI: 10.1016/j.joim.2022.02.006
Online available: 27 February 2022

Abstract182)   HTML    PDF      

Objectives

Ziyin Huatan recipe (ZYHT), a traditional Chinese medicine comprised of Lilii Bulbus, Pinelliae Rhizoma, and Hedyotis Diffusa, has shown promise in treating gastric cancer (GC) in the clinic. However, its potential mechanism in treating GC has not yet been clearly addressed. This study aimed to predict targets and molecular mechanisms of ZYHT by network pharmacology analysis and to explore the role of ZYHT in GC both in vitro and in vivo.

Methods

Targets and molecular mechanisms of ZYHT were predicted via network pharmacology analysis. The effects of ZYHT on the expression of metastasis-associated targets were further validated by western blot and quantitative real-time polymerase chain reaction. To explore the specific molecular mechanisms of ZYHT on migration and invasion, the runt-related transcription factor 3 (RUNX3) gene was knocked out by clustered regularly interspaced short palindromic repeats/Cas9, and lentiviral vectors were transfected into SGC-7901 cells. Then lung metastasis model of gastric cancer in nude mice was established to explore the anti-metastasis effect of ZYHT. Western blot and immunohistochemistry were used to explore the impact of ZYHT on the expression of metastasis-related proteins with or without RUNX3 gene.

Results

The network pharmacology analysis showed that ZYHT might inhibit focal adhesion, and migration, invasion and metastasis of GC. ZYHT inhibited the proliferation, migration and invasion of GC cells in vitro via regulating the expression of metastasis-associated targets. Knocking out RUNX3 almost completely reversed the cell phenotypes (migration and invasion) and protein expression levels elicited by ZYHT. In vivo studies showed that ZYHT inhibited the metastasis of GC cells to the lung and prolonged the survival time of nude mice. Knocking out RUNX3 partly reversed the metastasis of GC cells to the lung and the protein expression levels elicited by ZYHT.

Conclusion

ZYHT can e?ectively inhibit the invasion and migration of GC in vitro and in vivo, and its molecular mechanism may relate to the upregulation of RUNX3 expression.


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Successfully treated recalcitrant atopic eczema with acupoint autohemotherapy: A case report and hypothesized mechanism of the therapy
Bin Zhao, Yong Chen, Shi-min Liao, Jian-ying Zheng, Shi-hua Yan, Dong-shu Zhang
Journal of Integrative Medicine    2022, 20 (2): 182-186.   DOI: 10.1016/j.joim.2022.01.003
Accepted: 07 December 2021
Online available: 13 January 2022

Abstract134)   HTML    PDF      
Acupoint autohemotherapy at bilateral Zusanli (ST36) and Xuehai (SP10) was used to treat a 26-year-old female patient who had suffered from recalcitrant atopic eczema (AE) for five years. The treatment was applied at a frequency of once per week for the first month, followed by a three-month period of once every other week. At the end of treatment, the patient's AE symptoms were entirely resolved, and by the end of a six-month follow-up her immunoglobulin E level had returned to the normal range. Further, there was no relapse of AE symptoms during the six-month follow-up. Therefore, we hypothesized that after the repeated treatments the local inflammatory reaction induced by autologous blood injection triggered a local immune response, followed by a systemic immune response after the repeated treatment, finally leading to the anti-inflammation and immunomodulation effects. This case suggests that acupoint autohemotherapy could be used as an effective complementary treatment for recalcitrant AE, especially in cases where other treatments have failed. Further comparative studies are needed to corroborate the value and mechanisms of this therapy.
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Clinical evidence of three traditional Chinese medicine drugs and three herbal formulas for COVID-19: A systematic review and meta-analysis of the Chinese population
Liang-zhen You, Qian-qian Dai, Xiao-ying Zhong, Dong-dong Yu, He-rong Cui, Yi-fan Kong, Meng-zhu Zhao, Xin-yi Zhang, Qian-qian Xu, Zhi-yue Guan, Xu-xu Wei, Xue-cheng Zhang, Song-jie Han, Wen-jing Liu, Zhao Chen, Xiao-yu Zhang, Chen Zhao, Ying-hui Jin, Hong-cai Shang
Journal of Integrative Medicine    2023, 21 (5): 441-454.   DOI: 10.1016/j.joim.2023.08.001
Accepted: 21 February 2023
Online available: 05 August 2023

Abstract115)   HTML    PDF      
Background
The coronavirus disease 2019 (COVID-19) continues to spread worldwide. Integrated Chinese and Western medicine have had some successes in treating COVID-19.

Objective
This study aims to evaluate the efficacy and safety of three traditional Chinese medicine drugs and three herbal formulas (3-drugs-3-formulas) in patients with COVID-19.

Search strategy

Relevant studies were identified from 12 electronic databases searched from their establishment to April 7, 2022.


Inclusion criteria

Randomized controlled trials (RCTs), non-RCTs and cohort studies that evaluated the effects of 3-drugs-3-formulas for COVID-19. The treatment group was treated with one of the 3-drugs-3-formulas plus conventional treatment. The control group was treated with conventional treatment.


Data extraction and analysis

Two evaluators screened and selected literature independently, then extracted basic information and assessed risk of bias. The treatment outcome measures were duration of main symptoms, hospitalization time, aggravation rate and mortality. RevMan 5.4 was used to analyze the pooled results reported as mean difference (MD) with 95% confidence interval (CI) for continuous data and risk ratio (RR) with 95% CI for dichotomous data.


Results
Forty-one studies with a total of 13,260 participants were identified. Our analysis suggests that compared with conventional treatment, the combination of 3-drugs-3-formulas might shorten duration of fever (MD = –1.39; 95% CI: –2.19 to –0.59; P < 0.05), cough (MD = –1.57; 95% CI: –2.16 to –0.98; P < 0.05) and fatigue (MD = –1.36; 95% CI: –2.21 to –0.51; P < 0.05), decrease length of hospital stay (MD = –2.62; 95% CI –3.52 to –1.72; P < 0.05), the time for nucleic acid conversion (MD = –2.92; 95% CI: –4.26 to –1.59; P < 0.05), aggravation rate (RR = 0.49; 95% CI: 0.38 to 0.64; P < 0.05) and mortality (RR = 0.34; 95% CI: 0.19 to 0.62; P < 0.05), and increase the recovery rate of chest CT manifestations (RR = 1.22; 95% CI: 1.14 to 1.3; P < 0.05) and total effectiveness (RR = 1.24; 95% CI: 1.09 to 1.42; P < 0.05).

Conclusion
The 3-drugs-3-formulas can play an active role in treating all stages of COVID-19. No severe adverse events related to 3-drugs-3-formulas were observed. Hence, 3-drugs-3-formulas combined with conventional therapies have effective therapeutic value for COVID-19 patients. Further long-term high-quality studies are essential to demonstrate the clinical benefits of each formula.
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Homeopathy for COVID-19 in primary care: A randomized, double-blind, placebo-controlled trial (COVID-Simile study)
Ubiratan Cardinalli Adler, Maristela Schiabel Adler, Ana Elisa Madureira Padula, Livia Mitchiguian Hotta, Amarilysde Toledo Cesar, José Nelson Martins Diniz, Helen de Freitas Santos, Edson Zangiacomi Martinez
Journal of Integrative Medicine    2022, 20 (3): 221-229.   DOI: 10.1016/j.joim.2022.03.003
Accepted: 21 February 2022
Online available: 12 March 2022

Abstract155)   HTML    PDF      
Background
Different homeopathic approaches have been used as supportive care for coronavirus disease 2019 (COVID-19) cases, but none has been tested in a clinical trial.

Objectives
To investigate the effectiveness and safety of the homeopathic medicine, Natrum muriaticum LM2, for mild cases of COVID-19.

Design, setting, participants, and interventions
A randomized, double-blind, two‐armed, parallel, single-center, placebo-controlled clinical trial was conducted from June 2020 to April 2021 in S?o-Carlos, Brazil. Participants aged > 18 years, with influenza-like symptoms and positive result from a real-time polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 were recruited and randomized (1:1) into two groups that received different treatments during a period of at-home-isolation. One group received the homeopathic medicine Natrum muriaticum, prepared with the second degree of the fifty-millesimal dynamization (LM2; Natrum muriaticum LM2), while the other group received a placebo.

Outcome measures
The primary endpoint was time until recovery from COVID-19 influenza-like symptoms. Secondary measures included a survival analysis of the number and severity of COVID-19 symptoms (influenza-like symptoms plus anosmia and ageusia) from a symptom grading scale that was informed by the participant, hospital admissions, and adverse events. Kaplan-Meier curves were used to estimate time-to-event (survival) measures.

Results
Data from 86 participants were analyzed (homeopathy, n = 42; placebo, n = 44). There was no difference in time to recovery between two groups among participants who were reporting influenza-like symptoms at the beginning of monitoring (homeopathy, n = 41; placebo, n = 41; P = 0.56), nor in a sub-group that had at least 5 moderate to severe influenza-like symptoms at the beginning of monitoring (homeopathy, n = 15; placebo, n = 17; P = 0.06). Secondary outcomes indicated that a 50% reduction in symptom score was achieved significantly earlier in the homeopathy group (homeopathy, n = 24; placebo, n = 25; P = 0.04), among the participants with a basal symptom score ≥ 5. Moreover, values of restricted mean survival time indicated that patients receiving homeopathy might have improved 0.9 days faster during the first five days of follow-up (P = 0.022). Hospitalization rates were 2.4% in the homeopathy group and 6.8% in the placebo group (P = 0.62). Participants reported 3 adverse events in the homeopathy group and 6 in the placebo group.

Conclusion
Results showed that Natrum muriaticum LM2 was safe to use for COVID-19, but there was no statistically significant difference in the primary endpoints of Natrum muriaticum LM2 and placebo for mild COVID-19 cases. Although some secondary measures do not support the null hypothesis, the wide confidence intervals suggest that further studies with larger sample sizes and more symptomatic participants are needed to test the effectiveness of homeopathic Natrum muriaticum LM2 for COVID-19.

Trial registration
UMIN Clinical Trials Registry ID: JPRN-UMIN000040602.
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Low-level laser acupuncture reduces postoperative pain and morphine consumption in older patients with total knee arthroplasty: A randomized placebo-controlled trial
Chiung-Hui Huang, Mei-Ling Yeh, Fang-Pey Chen, Daphne Wu
Journal of Integrative Medicine    2022, 20 (4): 321-328.   DOI: 10.1016/j.joim.2022.04.002
Accepted: 24 January 2022
Online available: 09 April 2022

Abstract183)   HTML    PDF      
Background
Patients commonly develop postoperative pain after total knee arthroplasty (TKA). Acupuncture-related techniques and low-level laser therapy could be beneficial for pain management for older individuals.

Objective
To examine the effect of low-level laser acupuncture (LA) in reducing postoperative pain, pain-related interference in daily life, morphine consumption, and morphine-related side effects in older patients with knee osteoarthritis who underwent TKA.

Design, setting, participants and intervention
A single-blind randomized placebo-controlled trial was conducted. Patients (N = 82) were recruited and randomly assigned via a computer-generated list to the LA group or a placebo group. The LA group received low-level laser therapy at Sanyinjiao (SP6), Taixi (KI3), Kunlun (BL60), Fengshi (GB31), Futu (ST32) and Neiguan (PC6) after TKA, while the placebo acupuncture group received the same treatment procedure without laser energy output.

Main outcome measures
The primary outcome was postoperative pain intensity, and it was measured at baseline and hours 2, 6, 10, 24, 48 and 72 after TKA. The secondary outcomes, including relative pain, postoperative pain-related interference in daily life and morphine consumption, were measured at hours 24, 48 and 72 after TKA.

Results
Generalized estimating equations revealed significant between-group differences in pain intensity (P = 0.01), and trend differences in pain intensity for the LA group starting at hours 10 to 72 (P < 0.05) and morphine consumption at hours 48 and 72 (P < 0.05). The changes in pain-related interference in daily life were significant (P < 0.05) at 72 h, with the exception of the parameters for worst pain, mood, and sleep. Nausea and vomiting side effects from morphine had significant between-group differences at hours 10 and 24 (P < 0.05).

Conclusion

Low-level LA gradually reduced older patients’ postoperative pain intensity and morphine consumption within the first 72 h after their TKA for osteoarthritis. Low-level LA may have benefits as an adjuvant pain management technique for clinical care.


Trial registration

ClinicalTrials.gov registration number NCT03995446.

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Appraisal of treatment outcomes in integrative medicine using metabonomics: Taking non-alcoholic fatty liver disease with spleen deficiency syndrome as an example
Liang Dai, Jing-juan Xu, Wen-jun Zhou, Ai-ping Lü, Guang Ji
Journal of Integrative Medicine    2022, 20 (6): 524-533.   DOI: 10.1016/j.joim.2022.08.002
Accepted: 06 July 2022
Online available: 13 August 2022

Abstract86)   HTML    PDF      
Objective
Appraisal of treatment outcomes in integrative medicine is a challenge due to a gap between the concepts of Western medicine (WM) disease and traditional Chinese medicine (TCM) syndrome. This study presents an approach for the appraisal of integrative medicine that is based on targeted metabolomics. We use non-alcoholic fatty liver disease with spleen deficiency syndrome as a test case.

Methods
A patient-reported outcome (PRO) scale was developed based on literature review, Delphi consensus survey, and reliability and validity test, to quantitatively evaluate spleen deficiency syndrome. Then, a metabonomic foundation for the treatment of non-alcoholic fatty liver disease with spleen deficiency syndrome was identified via a longitudinal interventional trial and targeted metabolomics. Finally, an integrated appraisal model was established by identifying metabolites that responded in the treatment of WM disease and TCM syndrome as positive outcomes and using other aspects of the metabonomic foundation as independent variables.

Results
Ten symptoms and signs were included in the spleen deficiency PRO scale. The internal reliability, content validity, discriminative validity and structural validity of the scale were all qualified. Based on treatment responses to treatments for WM disease (homeostasis model assessment of insulin resistance) or TCM syndrome (spleen deficiency PRO scale score) from a previous randomized controlled trial, two cohorts comprised of 30 participants each were established for targeted metabolomics detection. Twenty-five metabolites were found to be involved in successful treatment outcomes to both WM and TCM, following quantitative comparison and multivariate analysis. Finally, the model of the integrated appraisal system was exploratively established using binary logistic regression; it included 9 core metabolites and had the prediction probability of 83.3%.

Conclusion
This study presented a new and comprehensive research route for integrative appraisal of treatment outcomes for WM disease and TCM syndrome. Critical research techniques used in this research included the development of a TCM syndrome assessment tool, a longitudinal interventional trial with verified TCM treatment, identification of homogeneous metabolites, and statistical modeling.
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Safety of acupotomy in a real-world setting: A prospective pilot and feasibility study
Sang-Hoon Yoon, Chan-Young Kwon, Hee-Geun Jo, Jae-Uk Sul, Hyangsook Lee, Jiyoon Won, Su Jin Jeong, Jun-Hwan Lee, Jungtae Leem
Journal of Integrative Medicine    2022, 20 (6): 514-523.   DOI: 10.1016/j.joim.2022.08.003
Accepted: 09 July 2021
Online available: 17 August 2022

Abstract138)   HTML    PDF      
Objective
Acupotomy is a modern acupuncture method that includes modern surgical methods. Since acupotomy is relatively more invasive than filiform acupuncture treatment, it is important to establish the safety profile of this practice. To justify further large-scale prospective observational studies, this preliminary study was performed to assess the feasibility of the approach and investigate the safety profile and factors potentially associated with adverse events (AEs).

Methods
This was a prospective pilot study that assessed the feasibility of a large-scale forthcoming safety study on acupotomy treatment in a real-world setting. The feasibility (call response rate, drop-out rate, response rate for each variable and recruitment per month) and safety profile (incidence, type, severity and causality of AEs, and factors potentially associated with AEs) were measured.

Results
A total of 28 participants joined the study from January to May 2018. A follow-up assessment was achieved in 258 (1185 treatment points) out of 261 sessions (1214 treatment points). The response rate via telephone on the day after treatment was 87.3%. There were 8 systemic AEs in all the sessions (8/258; 3.11%) and 27 local AEs on the total points treated (27/1185; 2.28%). Severe AEs did not occur. Total AE and local AE occurrence were associated with blade width and the number of needle stimulations per treatment point.

Conclusion
The findings suggest that it could be feasible to analyze the safety of acupotomy in a real-world setting. Moreover, the primary data on some relevant AEs could be determined. We are planning large-scale prospective studies based on these findings.
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Methodology of network pharmacology for research on Chinese herbal medicine against COVID-19: A review
Yi-xuan Wang, Zhen Yang, Wen-xiao Wang, Yu-xi Huang, Qiao Zhang, Jia-jia Li, Yu-ping Tang, Shi-jun Yue
Journal of Integrative Medicine    2022, 20 (6): 477-487.   DOI: 10.1016/j.joim.2022.09.004
Accepted: 15 August 2022
Online available: 22 September 2022

Abstract120)   HTML    PDF      
Traditional Chinese medicine, as a complementary and alternative medicine, has been practiced for thousands of years in China and possesses remarkable clinical efficacy. Thus, systematic analysis and examination of the mechanistic links between Chinese herbal medicine (CHM) and the complex human body can benefit contemporary understandings by carrying out qualitative and quantitative analysis. With increasing attention, the approach of network pharmacology has begun to unveil the mystery of CHM by constructing the heterogeneous network relationship of “herb-compound-target-pathway,” which corresponds to the holistic mechanisms of CHM. By integrating computational techniques into network pharmacology, the efficiency and accuracy of active compound screening and target fishing have been improved at an unprecedented pace. This review dissects the core innovations to the network pharmacology approach that were developed in the years since 2015 and highlights how this tool has been applied to understanding the coronavirus disease 2019 and refining the clinical use of CHM to combat it.
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Tanshinone IIA prevents acute lung injury by regulating macrophage polarization
Jia-yi Zhao, Jin Pu, Jian Fan, Xin-yu Feng, Jian-wen Xu, Rong Zhang, Yan Shang
Journal of Integrative Medicine    2022, 20 (3): 274-280.   DOI: 10.1016/j.joim.2022.01.006
Online available: 21 February 2022

Abstract213)   HTML    PDF      

Objective

Acute lung injury (ALI) is a serious respiratory dysfunction caused by pathogen or physical invasion. The strong induced inflammation often causes death. Tanshinone IIA (Tan-IIA) is the major constituent of Salvia miltiorrhiza Bunge and has been shown to display anti-inflammatory effects. The aim of the current study was to investigate the effects of Tan-IIA on ALI.

Methods

A murine model of lipopolysaccharide (LPS)-induced ALI was used. The lungs and serum samples of mice were extracted at 3 days after treatment. ALI-induced inflammatory damages were confirmed from cytokine detections and histomorphology observations. Effects of Tan-IIA were investigated using in vivo and in vitro ALI models. Tan-IIA mechanisms were investigated by performing Western blot and flow cytometry experiments. A wound-healing assay was performed to confirm the Tan-IIA function.

Results

The cytokine storm induced by LPS treatment was detected at 3 days after LPS treatment, and alveolar epithelial damage and lymphocyte aggregation were observed. Tan-IIA treatment attenuated the LPS-induced inflammation and reduced the levels of inflammatory cytokines released not only by inhibiting neutrophils, but also by macrophage. Moreover, we found that macrophage activation and polarization after LPS treatment were abrogated after applying the Tan-IIA treatment. An in vitro assay also confirmed that including the Tan-IIA supplement increased the relative amount of the M2 subtype and decreased that of M1. Rebalanced macrophages and Tan-IIA inhibited activations of the nuclear factor κB and hypoxia-inducible factor pathways. Including Tan-IIA and macrophages also improved alveolar epithelial repair by regulating macrophage polarization. 

Conclusion

This study found that while an LPS-induced cytokine storm exacerbated ALI, including Tan-IIA could prevent ALI-induced inflammation and improve the alveolar epithelial repair, and do so by regulating macrophage polarization.

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Local vibration therapy promotes the recovery of nerve function in rats with sciatic nerve injury
Lu Yin, Yun An, Xiao Chen, Hui-xin Yan, Tao Zhang, Xin-gang Lu, Jun-tao Yan
Journal of Integrative Medicine    2022, 20 (3): 265-273.   DOI: 10.1016/j.joim.2022.02.001
Online available: 21 February 2022

Abstract185)   HTML    PDF      
Objective
It has been reported that local vibration therapy can benefit recovery after peripheral nerve injury, but the optimized parameters and effective mechanism were unclear. In the present study, we investigated the effect of local vibration therapy of different amplitudes on the recovery of nerve function in rats with sciatic nerve injury (SNI).
Methods
Adult male Sprague-Dawley rats were subjected to SNI and then randomly divided into 5 groups: sham group, SNI group, SNI + A-1 mm group, SNI + A-2 mm group, and SNI + A-4 mm group (A refers to the amplitude; n = 10 per group). Starting on the 7th day after model initiation, local vibration therapy was given for 21 consecutive days with a frequency of 10 Hz and an amplitude of 1, 2 or 4 mm for 5 min. The sciatic function index (SFI) was assessed before surgery and on the 7th, 14th, 21st and 28th days after surgery. Tissues were harvested on the 28th day after surgery for morphological, immunofluorescence and Western blot analysis.
Results
Compared with the SNI group, on the 28th day after surgery, the SFIs of the treatment groups were increased; the difference in the SNI + A-2 mm group was the most obvious (95% confidence interval [CI]: [5.86, 27.09], P < 0.001), and the cross-sectional areas of myocytes in all of the treatment groups were improved. The G-ratios in the SNI + A-1 mm group and SNI + A-2 mm group were reduced significantly (95% CI: [?0.12, ?0.02], P = 0.007; 95% CI: [?0.15, ?0.06], P < 0.001). In addition, the expressions of S100 and nerve growth factor proteins in the treatment groups were increased; the phosphorylation expressions of ERK1/2 protein in the SNI + A-2 mm group and SNI + A-4 mm group were upregulated (95% CI: [0.03, 0.96], P = 0.038; 95% CI: [0.01, 0.94], P = 0.047, respectively), and the phosphorylation expression of Akt in the SNI + A-1 mm group was upregulated (95% CI: [0.11, 2.07], P = 0.031).
Conclusion
Local vibration therapy, especially with medium amplitude, was able to promote the recovery of nerve function in rats with SNI; this result was linked to the proliferation of Schwann cells and the activation of the ERK1/2 and Akt signaling pathways.
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Analysis of mechanisms of Shenhuang Granule in treating severe COVID-19 based on network pharmacology and molecular docking
Xiang-ru Xu, Wen Zhang, Xin-xin Wu, Hong-qiang Yang, Yu-ting Sun, Yu-ting Pu, Bei Wang, Wei Peng, Li-hua Sun, Quan Guo, Shuang Zhou, Bang-jiang Fang
Journal of Integrative Medicine    2022, 20 (6): 561-574.   DOI: 10.1016/j.joim.2022.07.005
Accepted: 15 June 2022
Online available: 05 August 2022

Abstract167)   HTML    PDF      
Objective: Severe cases of coronavirus disease 2019 (COVID-19) are expected to have a worse prognosis than mild cases. Shenhuang Granule (SHG) has been shown to be a safe and effective treatment for severe COVID-19 in a previous randomized clinical trial, but the active chemical constituents and underlying mechanisms of action remain unknown. The goal of this study is to explore the chemical basis and mechanisms of SHG in the treatment of severe COVID-19, using network pharmacology.
Methods: Ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry was employed to screen chemical constituents of SHG. Putative therapeutic targets were predicted by searching traditional Chinese medicine system pharmacology database and analysis platform, SwissTargetPrediction, and Gene Expression Omnibus (GEO) databases. The target protein-protein interaction network and enrichment analysis were performed to investigate the hub genes and presumptive mechanisms. Molecular docking and molecular dynamics simulations were used to verify the stability and interaction between the key chemical constituents of SHG and COVID-19 protein targets.
Results: Forty-five chemical constituents of SHG were identified along with 131 corresponding therapeutic targets, including hub genes such as HSP90AA1, MMP9, CXCL8, PTGS2, IFNG, DNMT1, TYMS, MDM2, HDAC3 and ABCB1. Functional enrichment analysis indicated that SHG mainly acted on the neuroactive ligand-receptor interaction, calcium signaling pathway and cAMP signaling pathway. Molecular docking showed that the key constituents had a good affinity with the severe acute respiratory syndrome coronavirus 2 protein targets. Molecular dynamics simulations indicated that ginsenoside Rg4 formed a stable protein-ligand complex with helicase.
Conclusion: Multiple components of SHG regulated multiple targets to inhibit virus invasion and cytokine storm through several signaling pathways; this provides a scientific basis for clinical applications and further experiments.
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Genome-wide analysis of AP2/ERF superfamily in Isatis indigotica
Liang Xiao, Jun-ze Ren, Qing Li, Bin Yang, Zhen-jiang Liu, Rui-bing Chen, Lei Zhang
Journal of Integrative Medicine    2023, 21 (1): 77-88.   DOI: 10.1016/j.joim.2022.09.003
Accepted: 09 May 2022
Online available: 01 March 2023

Abstract56)   HTML    PDF      

Objective

AP2/ERF (APETALA2/ethylene-responsive factor) superfamily is one of the largest gene families in plants and has been reported to participate in various biological processes, such as the regulation of biosynthesis of active lignan. However, few studies have investigated the genome-wide role of the AP2/ERF superfamily in Isatis indigotica. This study establishes a complete picture of the AP2/ERF superfamily in I. indigotica and contributes valuable information for further functional characterization of IiAP2/ERF genes and supports further metabolic engineering.

Methods

To identify the IiAP2/ERF superfamily genes, the AP2/ERF sequences from Arabidopsis thaliana and Brassica rapa were used as query sequences in the basic local alignment search tool. Bioinformatic analyses were conducted to investigate the protein structure, motif composition, chromosome location, phylogenetic relationship, and interaction network of the IiAP2/ERF superfamily genes. The accuracy of omics data was verified by quantitative polymerase chain reaction and heatmap analyses.

Results

One hundred and twenty-six putative IiAP2/ERF genes in total were identified from the I. indigotica genome database in this study. By sequence alignment and phylogenetic analysis, the IiAP2/ERF genes were classified into 5 groups including AP2ERFDREB (dehydration-responsive element-binding factor), Soloist and RAV (related to abscisic acid insensitive 3/viviparous 1) subfamilies. Among which, 122 members were unevenly distributed across seven chromosomes. Sequence alignment showed that I. indigotica and A. thaliana had 30 pairs of orthologous genes, and we constructed their interaction network. The comprehensive analysis of gene expression pattern in different tissues suggested that these genes may play a significant role in organ growth and development of I. indigotica. Members that may regulate lignan biosynthesis in roots were also preliminarily identified. Ribonucleic acid sequencing analysis revealed that the expression of 76 IiAP2/ERF genes were up- or down-regulated under salt or drought treatment, among which, 33 IiAP2/ERF genes were regulated by both stresses.

Conclusion

This study undertook a genome-wide characterization of the AP2/ERF superfamily in I. indigotica, providing valuable information for further functional characterization of IiAP2/ERF genes and discovery of genetic targets for metabolic engineering.

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Treatment duration of wrist-ankle acupuncture for relieving post-thyroidectomy pain: A randomized controlled trial
Xin-rui Han, Wei Yue, Hui-chao Chen, Wei He, Jiang-he Luo, Shan-xia Chen, Na Liu, Ming Yang
Journal of Integrative Medicine    2023, 21 (2): 168-175.   DOI: 10.1016/j.joim.2023.02.001
Accepted: 10 October 2022
Online available: 02 February 2023

Abstract118)   HTML    PDF      
Background
Treatment duration of wrist-ankle acupuncture (WAA) is uncertain for post-thyroidectomy pain relief.

Objective
This study evaluated the effect of different WAA treatment duration on post-operative pain relief and other discomforts associated with thyroidectomy.

Design, setting, participants and intervention
This randomized controlled trial was conducted at a single research site in Guangzhou, China. A total of 132 patients receiving thyroidectomy were randomly divided into the control group (sham WAA, 30 min) and three intervention groups (group 1: WAA, 30 min; group 2: WAA, 45 min; group 3: WAA, 60 min), with group allocation ratio of 1:1:1:1. Acupuncture was administered within 1 hour of leaving the operating room.

Outcomes and measures
Primary outcome was patients’ pain at the surgical site assessed by visual analogue scale (VAS) at the moment after acupuncture treatment (post-intervention). Secondary outcomes included the patients’ pain VAS scores at 6, 12, 24, 48 and 72 h after the thyroidectomy, the 40-item Quality of Recovery (QoR-40) score, the grade of post-operative nausea and vomiting (PONV), and the use of additional analgesic therapy.

Results
The adjusted mean difference (AMD) in VAS scores from baseline to post-intervention in group 1 was 0.89 (95% confidence interval [CI], 1.02 to 0.76). The decrease in VAS score at post-intervention was statistically significant in group 1 compared to the control group (AMD, 0.43; 95% CI, 0.58 to 0.28; P < 0.001), and in groups 2 and 3 compared to group 1 (group 2 vs group 1: AMD, 0.65; 95% CI, 0.81 to 0.48; P < 0.001; group 3 vs group 1: AMD, 0.66; 95% CI, 0.86 to 0.47; P < 0.001). The VAS scores in the four groups converged beyond 24 h after the operation. Fewer patients in group 2 and group 3 experienced PONV in the first 24 h after operation. No statistical differences were measured in QoR-40 score and the number of patients with additional analgesic therapy.

Conclusion
Compared with the 30 min intervention, WAA treatment with longer needle retention time (45 or 60 min) had an advantage in pain relief within 6 h after surgery. WAA’s analgesic effect lasted for 6–12 h post-operatively.
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A comprehensive overview on the role of phytocompounds in human immunodeficiency virus treatment
Chinmayee Priyadarsani Mandhata, Chita Ranjan Sahoo, Rabindra Nath Padhy
Journal of Integrative Medicine    2023, 21 (4): 332-353.   DOI: 10.1016/j.joim.2023.05.001
Accepted: 21 March 2023
Online available: 22 May 2023

Abstract195)   HTML    PDF      
Acquired immune deficiency syndrome (AIDS) is a worldwide epidemic caused by human immunodeficiency virus (HIV) infection. Newer medicines for eliminating the viral reservoir and eradicating the virus are urgently needed. Attempts to locate relatively safe and non-toxic medications from natural resources are ongoing now. Natural-product-based antiviral candidates have been exploited to a limited extent. However, antiviral research is inadequate to counteract for the resistant patterns. Plant-derived bioactive compounds hold promise as powerful pharmacophore scaffolds, which have shown anti-HIV potential. This review focuses on a consideration of the virus, various possible HIV-controlling methods and the recent progress in alternative natural compounds with anti-HIV activity, with a particular emphasis on recent results from natural sources of anti-HIV agents.
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Shanghai expert consensus on clinical protocol for traditional Chinese medicine treatment of COVID-19 among the elderly population (second edition)
Xuan Chen, Chou-ping Han, Wei Zhang on behalf of Writing Group of the Shanghai Expert Consensus on Clinical Protocol for Traditional Chinese Medicine Treatment of COVID- among the Elderly Population (Second Edition)
Journal of Integrative Medicine    2022, 20 (5): 427-431.   DOI: 10.1016/j.joim.2022.06.001
Online available: 10 June 2022

Abstract236)   HTML    PDF      
This document is the revised edition of the previously issued Shanghai Expert Consensus on Clinical Protocol for Traditional Chinese Medicine Treatment of COVID-19 among the Elderly Population. Based on the clinical experience and the Protocol for Diagnosis and Treatment of COVID-19 (Trial 9th Edition), this revised edition provides treatment approaches and recommendations to proactively cope with Omicron variant and increase the therapeutic efficacy for coronavirus disease 2019 among the elderly population in Shanghai, China.
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Efficacy of the herbal formula of Foeniculum vulgare and Rosa damascena on elderly patients with functional constipation: A double-blind randomized controlled tria
Maryam Azimi, Hanieh Niayesh, Mahboobeh Raeiszadeh, Sedigheh Khodabandeh-shahraki
Journal of Integrative Medicine    2022, 20 (3): 230-236.   DOI: 10.1016/j.joim.2022.03.001
Accepted: 21 January 2022
Online available: 10 March 2022

Abstract153)   HTML    PDF      
Background
Constipation is a common chronic bowel disorder with an incidence of more than 50% in the elderly population. Complementary and alternative medicine is a cost-effective and satisfactory treatment for constipation used widely by the elderly.

Objective
This study evaluates the efficacy of an herbal formula made from Foeniculum vulgare Mill. and Rosa damascena for the treatment of constipation in an elderly population and consequent changes to their quality of life.

Design, setting, participants and intervention
This double-blind randomized active controlled clinical trial, with parallel group allocation ratio of 1:1, was conducted in a referral clinic in Afzalipour Hospital, affiliated to Kerman University of Medical Sciences in Kerman, Southeastern Iran. Individuals over 60 years of age, diagnosed with functional constipation (based on the Rome IV criteria), were included in this study. Participants received a sachet of 10 g F. vulgare and R. damascena (herbal formula group) or polyethylene glycol 4000 (PEG 4000 group) with a glass of warm water two times a day for 4 weeks and were followed up for 4 additional weeks.

Main outcome measures
Constipation severity, stool consistency, and the quality of life were used as the primary outcomes. Drug side effects were used as a secondary outcome. The outcomes were assessed using the Constipation Assessment Scale, the Bristol Stool Form Scale, and the Patient Assessment of Constipation Quality of Life questionnaire.

Results
A total of 25 participants in each group completed the four-week treatment cycle and the eight-week follow-up. At the end of the four-week treatment cycle, all clinical outcomes had significant improvements in both groups (P < 0.05). The analysis of constipation severity (P < 0.001), stool consistency (P < 0.001), and the quality of life (P < 0.001) showed significant improvements with fewer side effects (mild diarrhea) and a longer duration of symptom relief in the herbal formula group compared to the PEG 4000 group.

Conclusion
Although both interventions significantly improved the treatment outcomes, constipation severity, stool consistency and the quality of life were improved more effectively by the herbal formula than by PEG 4000; however, the mechanism of action is not yet understood.

Trial registration
This trial was registered in the Iranian Registry of Clinical Trials (IRCTID: IRCT20200108046056N1).
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Examining patterns of traditional chinese medicine use in pediatric oncology: A systematic review, meta-analysis and data-mining study
Chun Sing Lam, Li Wen Peng, Lok Sum Yang, Ho Wing Janessa Chou, Chi-Kong Li, Zhong Zuo, Ho-Kee Koon, Yin Ting Cheung
Journal of Integrative Medicine    2022, 20 (5): 402-415.   DOI: 10.1016/j.joim.2022.06.003
Accepted: 05 May 2022
Online available: 10 June 2022

Abstract169)   HTML    PDF      
Background
Traditional Chinese medicine (TCM) is becoming a popular complementary approach in pediatric oncology. However, few or no meta-analyses have focused on clinical studies of the use of TCM in pediatric oncology.

Objective
We explored the patterns of TCM use and its efficacy in children with cancer, using a systematic review, meta-analysis and data mining study.

Search strategy
We conducted a search of five English (Allied and Complementary Medicine Database, Embase, PubMed, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov) and four Chinese databases (Wanfang Data, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and VIP Chinese Science and Technology Periodicals Database) for clinical studies published before October 2021, using keywords related to “pediatric,” “cancer,” and “TCM.”

Inclusion criteria
We included studies which were randomized controlled trials (RCTs) or observational clinical studies, focused on patients aged < 19 years old who had been diagnosed with cancer, and included at least one group of subjects receiving TCM treatment.

Data extraction and analysis
The methodological quality of RCTs and observational studies was assessed using the six-item Jadad scale and the Effective Public Healthcare Panacea Project Quality Assessment Tool, respectively. Meta-analysis was used to evaluate the efficacy of combining TCM with chemotherapy. Study outcomes included the treatment response rate and occurrence of cancer-related symptoms. Association rule mining (ARM) was used to investigate the associations among medicinal herbs and patient symptoms.

Results
The fifty-four studies included in this analysis were comprised of RCTs (63.0%) and observational studies (37.0%). Most RCTs focused on hematological malignancies (41.2%). The study outcomes included chemotherapy-induced toxicities (76.5%), infection rate (35.3%), and response, survival or relapse rate (23.5%). The methodological quality of most of the RCTs (82.4%) and observational studies (80.0%) was rated as “moderate.” In studies of leukemia patients, adding TCM to conventional treatment significantly improved the clinical response rate (odds ratio [OR] = 2.55; 95% confidence interval [CI] = 1.49–4.36), lowered infection rate (OR = 0.23; 95% CI = 0.13–0.40), and reduced nausea and vomiting (OR = 0.13; 95% CI = 0.08–0.23). ARM showed that Radix Astragali, the most commonly used medicinal herb (58.0%), was associated with treating myelosuppression, gastrointestinal complications, and infection.

Conclusion
There is growing evidence that TCM is an effective adjuvant therapy for children with cancer. We proposed a checklist to improve the quality of TCM trials in pediatric oncology. Future work will examine the use of ARM techniques on real-world data to evaluate the efficacy of medicinal herbs and drug-herb interactions in children receiving TCM as a part of integrated cancer therapy.
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Effects of turmeric (Curcuma longa) and its constituent (curcumin) on the metabolic syndrome: An updated review
Zeinab Vafaeipour, Bibi Marjan Razavi, Hossein Hosseinzadeh
Journal of Integrative Medicine    2022, 20 (3): 193-203.   DOI: 10.1016/j.joim.2022.02.008
Online available: 09 March 2022

Abstract251)   HTML    PDF      
Metabolic syndrome (MS) involves people with the following risk factors: obesity, hypertension, high glucose level and hyperlipidemia. It can increase the risk of heart disease, stroke and type 2 diabetes mellitus. The prevalence of MS in the world’s adult population is about 20%–25%. Today, there is much care to use medicinal plants. Turmeric (Curcuma longa) as well as curcumin which is derived from the rhizome of the plant, has been shown beneficial effects on different components of MS. Thus, the purpose of this manuscript was to introduce different in vitroin vivo and human studies regarding the effect of turmeric and its constituent on MS. Moreover, different mechanisms of action by which this plant overcomes MS have been introduced. Based on studies, turmeric and its bioactive component, curcumin, due to their anti-inflammatory and antioxidant properties, have antidiabetic effects through increasing insulin release, antihyperlipidemic effects by increasing fatty acid uptake, anti-obesity effects by decreasing lipogenesis, and antihypertensive effects by increasing nitric oxide. According to several in vivoin vitro and human studies, it can be concluded that turmeric or curcumin has important values as a complementary therapy in MS. However, more clinical trials should be done to confirm these effects. 
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Influence of electroacupuncture on ghrelin and the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthase signaling pathway in spontaneously hypertensive rats
Yue Zhang, Dong-ling Zhong, Ya-ling Zheng, Yu-xi Li, Yi-jie Huang, Yi-jing Jiang, Rong-jiang Jin, Juan Li
Journal of Integrative Medicine    2022, 20 (5): 432-441.   DOI: 10.1016/j.joim.2022.06.007
Abstract101)   HTML    PDF      
Objective
To investigate the influence of electroacupuncture (EA) on ghrelin and the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthase (PI3K/Akt/eNOS) signaling pathway in spontaneously hypertensive rats (SHRs).
Methods
Eight Wistar-Kyoto rats were used as the healthy blood pressure (BP) control (normal group), and 32 SHRs were randomized into model group, EA group, EA plus ghrelin group (EA + G group), and EA plus PF04628935 group (a potent ghrelin receptor blocker; EA + P group) using a random number table. Rats in the normal group and model group did not receive treatment, but were immobilized for 20 min per day, 5 times a week, for 4 continuous weeks. SHRs in the EA group, EA + G group and EA + P group were immobilized and given EA treatment in 20 min sessions, 5 times per week, for 4 weeks. Additionally, 1 h before EA, SHRs in the EA + G group and EA + P group were intraperitoneally injected with ghrelin or PF04628935, respectively, for 4 weeks. The tail-cuff method was used to measure BP. After the 4-week intervention, the rats were sacrificed by cervical dislocation, and pathological morphology of the abdominal aorta was observed using hematoxylin-eosin (HE) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of ghrelin, nitric oxide (NO), endothelin-1 (ET-1) and thromboxane A2 (TXA2) in the serum. Isolated thoracic aortic ring experiment was performed to evaluate vasorelaxation. Western blot was used to measure the expression of PI3K, Akt, phosphorylated Akt (p-Akt) and eNOS proteins in the abdominal aorta. Further, quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to measure the relative levels of mRNA expression for PI3K, Akt and eNOS in the abdominal aorta.
Results
EA significantly reduced the systolic BP (SBP) and diastolic BP (DBP) (P < 0.05). HE staining showed that EA improved the morphology of the vascular endothelium to some extent. Results of ELISA indicated that higher concentrations of ghrelin and NO, and lower concentrations of ET-1 and TXA2 were present in the EA group (P < 0.05). The isolated thoracic aortic ring experiment demonstrated that the vasodilation capacity of the thoracic aorta increased in the EA group. Results of Western blot and qRT-PCR showed that EA increased the abundance of PI3K, p-Akt/Akt and eNOS proteins, as well as expression levels of PI3K, Akt and eNOS mRNAs (P < 0.05). In the EA + G group, SBP and DBP decreased (P < 0.05), ghrelin concentrations increased (P < 0.05), and the concentrations of ET-1 and TXA2 decreased (P < 0.05), relative to the EA group. In addition, the levels of PI3K and eNOS proteins, the p-Akt/Akt ratio, and the expression of PI3K, Akt and eNOS mRNAs increased significantly in the EA + G group (P < 0.05), while PF04628935 reversed these effects.
Conclusion
EA effectively reduced BP and protected the vascular endothelium, and these effects may be linked to promoting the release of ghrelin and activation of the PI3K/Akt/eNOS signaling pathway.
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Effects of physical rehabilitation interventions in COVID-19 patients following discharge from hospital: A systematic review
Masoud Rahmati, Mahdieh Molanouri Shamsi, Wongi Woo, Ai Koyanagi, Seung Won Lee, Dong Keon Yon, Jae Il Shin, Lee Smith
Journal of Integrative Medicine    2023, 21 (2): 149-158.   DOI: 10.1016/j.joim.2023.01.003
Accepted: 25 September 2022
Online available: 20 January 2023

Abstract68)   HTML    PDF      
Background: Hospitalized patients recovering from coronavirus disease 2019 (COVID-19) may experience disability and suffer from significant physical and mental impairment requiring physical rehabilitation following their discharge. However, to date, no attempt has been made to collate and synthesize literature in this area.

Objective: This systematic review examines the outcomes of different physical rehabilitation interventions tested in COVID-19 patients who were discharged from hospital.

Search strategy: A systematic search of MEDLINE/PubMed, CINAHL, Scopus and medRxiv was conducted to identify articles published up to March 2022.

Inclusion criteria: This systematic review included studies of outpatient rehabilitation programs for people recovering from COVID-19 who received physical activity, exercise, or breathing training to enhance or restore functional capacity, pulmonary function, quality of life, and mental health or function.

Data extraction and analysis: Selection of included articles, data extraction, and methodological quality assessments were conducted by two review authors respectively, and consensus was reached through discussion and consultation with a third reviewer. Finally, we review the outcomes of studies based on four categories including: (1) functional capacity, (2) pulmonary function, (3) quality of life, and (4) mental health status.

Results: A total of 7534 titles and abstracts were screened; 10 cohort studies, 4 randomized controlled trials and 13 other prospective studies involving 1583 patients were included in our review. Early physical rehabilitation interventions applied in COVID-19 patients who were discharged from the hospital improved multiple parameters related to functional capacity, pulmonary function, quality of life and mental health status.

Conclusion: Physical rehabilitation interventions may be safe, feasible and effective in COVID-19 patients discharged from the hospital, and can improve a variety of clinically relevant outcomes. Further studies are warranted to determine the underlying mechanisms.
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Muscle energy technique for chronic obstructive pulmonary disease: A feasibility study
Danielle A. Baxter, Meaghan E. Coyle, Catherine J Hill, Christopher Worsnop, Johannah L. Shergis
Journal of Integrative Medicine    2023, 21 (3): 245-253.   DOI: 10.1016/j.joim.2023.03.006
Accepted: 28 October 2022
Online available: 14 April 2023

Abstract83)   HTML    PDF      

Objective

This study aimed to investigate the feasibility of implementing a manual therapy technique (muscle energy technique, MET) protocol in a hospital pulmonary rehabilitation (PR) program for patients with moderate to severe chronic obstructive pulmonary disease (COPD).

Methods

Participants aged 40 years and over, with moderate to severe COPD, were recruited into this 12-week study. The primary outcome measures were feasibility (acceptability of the intervention and attendance/adherence to the trial) and safety (adverse events, AEs). All participants received the MET and PR therapies. Participants and assessors were unblinded. Semi-standardized MET was delivered on 6 occasions (a maximum of once per week) at the hospital directly before a PR session. Participants undertook PR sessions as per the hospital program at a frequency of two days per week for 8 weeks. Participants were contacted 4 weeks after their final MET treatment via a telephone call to assess acceptability of the intervention.

Results

Thirty-three participants were enrolled, with a median age of 74 years (range 45–89 years). The median number of MET sessions that participants attended was 5 (range 0–6) out of a possible 6 sessions (83% attendance). At follow-up, participants overwhelmingly enjoyed the MET treatment with some subjectively reporting improved breathing. There were no major AEs related to the intervention, with the majority of AEs classified as expected events related to COPD exacerbations.

Conclusion

It is feasible to implement a manual therapy protocol using MET as an adjunct to PR in a hospital setting. Recruitment rates were satisfactory and there were no AEs related to the MET component of the intervention.

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A review of patent literature on the regulation of glucose metabolism by six phytocompounds in the management of diabetes mellitus and its complications
Anusree DasNandy, Rajashri Virge, Harsha V. Hegde, Debprasad Chattopadhyay
Journal of Integrative Medicine    2023, 21 (3): 226-235.   DOI: 10.1016/j.joim.2023.02.003
Accepted: 28 September 2022
Online available: 28 February 2023

Abstract73)   HTML    PDF      
Diabetes mellitus is a chronic disease, typified by hyperglycemia resulting from failures in complex multifactorial metabolic functions, that requires life-long medication. Prolonged uncontrolled hyperglycemia leads to micro- and macro-vascular complications. Although antidiabetic drugs are prescribed as the first-line treatment, many of them lose efficacy over time or have severe side effects. There is a lack of in-depth study on the patents filed concerning the use of natural compounds to manage diabetes. Thus, this patent analysis provides a comprehensive report on the antidiabetic therapeutic activity of 6 phytocompounds when taken alone or in combinations. Four patent databases were searched, and 17,649 patents filed between 2001 and 2021 were retrieved. Of these, 139 patents for antidiabetic therapeutic aids that included berberine, curcumin, gingerol, gymnemic acid, gymnemagenin and mangiferin were analyzed. The results showed that these compounds alone or in combinations, targeting acetyl-coenzyme A carboxylase 2, serine/threonine protein kinase, α-amylase, α-glucosidase, lipooxygenase, phosphorylase, peroxisome proliferator-activated receptor-γ (PPARγ), protein tyrosine phosphatase 1B, PPARγ co-activator-1α, phosphoinositide 3-kinase and protein phosphatase 1 regulatory subunit 3C, could regulate glucose metabolism which are validated by pharmacological rationale. Synergism, or combination therapy, including different phytocompounds and plant extracts, has been studied extensively and found effective, whereas the efficacy of commercial drugs in combination with phytocompounds has not been studied in detail. Curcumin, gymnemic acid and mangiferin were found to be effective against diabetes-related complications.
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Effects of bioactive compounds from Pleurotus mushrooms on COVID-19 risk factors associated with the cardiovascular system
Eduardo Echer dos Reis, Paulo Cavalheiro Schenkel, Marli Camassola
Journal of Integrative Medicine    2022, 20 (5): 385-395.   DOI: 10.1016/j.joim.2022.07.002
Accepted: 14 December 2021
Online available: 30 August 2022

Abstract102)   HTML    PDF      
Mushrooms are a group of fungi with great diversity and ultra-accelerated metabolism. As a consequence, mushrooms have developed a protective mechanism consisting of high concentrations of antioxidants such as selenium, polyphenols, β-glucans, ergothioneine, various vitamins and other bioactive metabolites. The mushrooms of the Pleurotus genus have generated scientific interest due to their therapeutic properties, especially related to risk factors connected to the severity of coronavirus disease 2019 (COVID-19). In this report, we highlight the therapeutic properties of Pleurotus mushrooms that may be associated with a reduction in the severity of COVID-19: antihypertensive, antihyperlipidemic, antiatherogenic, anticholesterolemic, antioxidant, anti-inflammatory and antihyperglycemic properties. These properties may interact significantly with risk factors for COVID-19 severity, and the therapeutic potential of these mushrooms for the treatment or prevention of this disease is evident. Besides this, studies show that regular consumption of Pleurotus species mushrooms or components isolated from their tissues is beneficial for immune health. Pleurotus species mushrooms may have a role in the prevention or treatment of infectious diseases either as food supplements or as sources for pharmacological agents.
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Progress in the design and quality control of placeboes for clinical trials of traditional Chinese medicine 
Ning Guo, Fei Wu, Mei Wu, Yuan Wang, Qing Lang, Xiao Lin, Yi Feng
Journal of Integrative Medicine    2022, 20 (3): 204-212.   DOI: 10.1016/j.joim.2022.02.005
Online available: 09 March 2022

Abstract135)   HTML    PDF      
In recent years, new preparations of traditional Chinese medicines (TCMs) have been developed, increasing the need for their clinical trials. Using placeboes rather than control drugs is increasingly popular in clinical trials of TCMs, as the therapeutic effects of the tested TCMs can be more properly judged. The basic attributes of TCM placeboes include similarity, safety, applicability and controllability. In particular, it is necessary to have similarities in appearance, color, smell and taste between the tested TCMs and placeboes. This is quite difficult for some TCMs due to their distinctive smell and taste. On the other hand, according to the TCM theory on homology of medicine and food, many foods also have certain bioactivities, potentially further complicating the selection of materials for TCM placeboes. In this review, firstly, studies on the special smell and taste of TCMs were introduced. Then, the preparation quality evaluation processes for TCM placeboes were summarized and discussed, based on the relevant literature published in recent years and the research results from our own lab. This review will facilitate the further research and development of TCM placeboes.
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Combining electroacupuncture and transcranial direct current stimulation as an adjuvant therapy enhances spontaneous conversation and naming in subacute vascular aphasia: A retrospective analysis
Samwel Sylvester Msigwa, Yan Li, Xiang-lin Cheng, Fen Cao
Journal of Integrative Medicine    2022, 20 (3): 244-251.   DOI: 10.1016/j.joim.2022.03.002
Accepted: 21 January 2022
Online available: 12 March 2022

Abstract133)   HTML    PDF      
Objective
Emerging evidence shows the effectiveness of speech and language therapy (SLT); however, precise therapeutic parameters remain unclear. Evidence for the use of adjunctive transcranial direct current stimulation (tDCS) to treat post-stroke aphasia (PSA) is promising; however, the utility of combining tDCS and electroacupuncture (EA) has not yet been analyzed. This study assessed the therapeutic consequences of EA and tDCS coupled with SLT in subacute PSA patients who were also undergoing hyperbaric oxygen therapy (HBOT).

Methods
A retrospective analysis was conducted on subacute (<?6 months) PSA patients who were divided into three groups: patients who received EA plus tDCS (acupuncture group), patients who underwent tDCS (tDCS group), and patients who experienced conventional therapy (HBOT + SLT). All subjects underwent 21 days of treatment and also received conventional treatment. The aphasia battery of Chinese (ABC) was used to score pre- and post-intervention status.

Results
The analysis comprised 238 patients. Cerebral infarction was the most frequent stroke type (137 [57.6%]), while motor (66 [27.7%]) and global aphasia (60 [25.2%]) were the most common types of aphasia. After 21 days of intervention, the ABC scores of all patients were improved. The acupuncture group had the highest ABC scores, but only repetition, naming, and spontaneous speech were statistically improved (P < 0.01). Post-hoc tests revealed significant improvement in word retrieval in the acupuncture and tDCS groups (P < 0.01, P = 0.037), while the acupuncture group had additional significant improvement in spontaneous conversation (P < 0.01).

Conclusion
Combining acupuncture and tDCS as an adjuvant therapy for subacute PSA led to significant spontaneous speech and word retrieval improvements. Future prospective, multi-ethnic, multi-center trials are warranted.
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Peperomia pellucida (L.) Kunth and eye diseases: A review on phytochemistry, pharmacology and toxicology
Keat Lam Ho, Phaik Har Yong, Chee Woon Wang, Umah Rani Kuppusamy, Chek Tung Ngo, Festo Massawe, Zhi Xiang Ng
Journal of Integrative Medicine    2022, 20 (4): 292-304.   DOI: 10.1016/j.joim.2022.02.002
Online available: 21 February 2022

Abstract166)   HTML    PDF      
Peperomia pellucida (L.) Kunth is a medicinal plant used to manage inflammatory illnesses such as conjunctivitis, and gastrointestinal and respiratory tract disorders in tropical and subtropical regions. However, little is known about its pharmacological mechanism of action against eye diseases. This review aims to critically discuss the phytochemistry, pharmacology and toxicology of P. pellucida as well as its roles in the treatment of cataract, glaucoma and diabetic retinopathy. Recent developments in the uses of P. pellucida for healthcare and nutraceutical products by the pharmaceutical industry are also covered in this review. For this review, a literature search was performed with PubMed, ScienceDirect, SciFinder Scholar and Scopus databases, using relevant keywords. Among the various phytochemicals identified from P. pellucida, β-caryophyllene, carotol, dillapiole, ellagic acid, pellucidin A, phytol and vitexin exhibit strong pharmacological activities within the mitogen-activated protein kinase and nuclear factor-κB signalling pathways in inflammatory eye diseases. The antihypertensive, anti-inflammatory, antioxidant, antihyperglycemic and anti-angiogenic activities displayed by P. pellucida extracts in many in vitroin vivo and clinical studies suggest its potential role in the management of inflammatory eye diseases. P. pellucida extract was non-toxic against normal cell lines but displayed mild toxicity in animal models. The growing public interest in P. pellucida has inspired the nutraceutical and pharmaceutical industries to process the plant into health products. Although the potential pharmacological mechanisms against eye diseases have been summarized, further studies of the interactions among constituent phytochemicals from P. pellucida within various signalling pathways shall support the use of the plant as an alternative therapeutic source.
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Aconitum heterophyllum Wall. ex Royle: A critically endangered medicinal herb with rich potential for use in medicine
Tareq A. Wani, Zahoor A. Kaloo, Nisar A. Dangroo
Journal of Integrative Medicine    2022, 20 (2): 104-113.   DOI: 10.1016/j.joim.2021.12.004
Online available: 28 December 2021

Abstract203)   HTML    PDF      
Aconitum heterophyllum (Patrees) is a critically endangered medicinal herb of the northwestern Himalayas and has enormous pharmacological potential. It is the only nonpoisonous member of the genus Aconitum, and has been used as a medicinal herb since ancient times. A. heterophyllum is an important ingredient in many traditional systems of medicine. Mostly, it is harvested for its roots, and its medicinal properties are due to the presence of diverse bioactive secondary metabolites, commonly known as aconites. Our understanding of the pharmacological properties of this intriguing genus is continuously growing due to its broad chemical diversity. The therapeutic uses identified by traditional medicinal practice are receiving extensive study. Multiple in vitro experimental investigations of A. heterophyllum have reported the analgesic, anti-inflammatory, antiarrhythmic, antiparasitic and anticancer properties, as well as its effects on the central nervous system. In this review, we highlight the classification, distribution, commerce, traditional uses, phytochemistry, pharmacology and conservation measures relevant to this species. Additionally, this review includes the biosynthetic pathways of A. heterophyllum’s key constituents, which could be targeted to enhance the expression levels of desired metabolites via genetic interventions. Studying the genomics, transcriptomics, proteomics and metabolomic aspects of this species would be helpful in developing highly designed genotypes and chemotypes of this species to be used in commercial production.
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Stress reduction via neuro-emotional technique to achieve the simultaneous resolution of chronic low back pain with multiple inflammatory and biobehavioural indicators: A randomized, double-blinded, placebo-controlled trial
Peter Bablis, Henry Pollard, Anthony L. Rosner
Journal of Integrative Medicine    2022, 20 (2): 135-144.   DOI: 10.1016/j.joim.2021.12.001
Online available: 28 December 2021

Abstract159)   HTML    PDF      

Background

Beginning with the concepts of stress developed by Selye, an approach to stress and pain management, known as neuro-emotional technique (NET), has been developed. It is a treatment approach based on the principle that the stressor effects of dormant and/or current unresolved issues or trauma are what determine one’s bodily responses. These responses are relatively personalized to the conditioned, experiential and emotional reality of the individual.

Objective

To determine the effect of NET on patients with chronic low back pain (CLBP) over time. 

Design, setting, participants, and interventions

In a randomized, double-blinded, placebo-controlled study conducted in a single clinic, NET or control treatments were given twice weekly for 4 weeks in a population of 112 patients. 

Main outcome measures

Outcome measures, including Oswestry Disability Index, Quadruple Visual Analogue Scale, the psychoneuroimmunology markers of blood serum levels of C-reactive protein, tumour necrosis factor-α, interleukin-1 (IL-1), IL-6, and IL-10, and 10 dimensions of the Short Form Health Survey scale, were assessed at baseline and at 1, 3 and 6 months following the intervention period.

Results

Compared to placebo, NET produced clinical and statistical significance (P < 0.001) via declines of virtually all physiological, pain and disability markers, accompanied by gains in quality-of-life indicators at 0 (baseline), 1, 3 and 6 months. Reductions of the percentages of patients whose 5 biomarkers lay outside the normative range were achieved at 1, 3 and 6 months by NET but not control interventions. 

Conclusion

A randomized, controlled trial of CLBP patients indicated that 8 NET interventions, compared to placebo, produced clinically and statistically significant reductions in pain, disability and inflammatory biomarkers, and improvements in quality-of-life measures.

Trial Registration

The trial was registered with the Australian and New Zealand Clinical Trials Registry (No. ACTRN12608000002381).

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Antiplatelet and myocardial protective effect of shexiang tongxin dropping pill in patients undergoing percutaneous coronary intervention: A randomized controlled trial
Yan-jun Lin, Kun-li Jiao, Bo Liu, Lu Fang, Shu Meng
Journal of Integrative Medicine    2022, 20 (2): 126-134.   DOI: 10.1016/j.joim.2022.01.001
Accepted: 17 December 2021
Online available: 04 January 2022

Abstract168)   HTML    PDF      
Background
High on-clopidogrel platelet reactivity could be partially explained by loss-of-function alleles of CYP2C19, the enzyme that converts clopidogrel into its active form. Shexiang Tongxin Dropping Pill (STDP) is a traditional Chinese medicine to treat angina pectoris. STDP has been shown to improve blood flow in patients with slow coronary flow and attenuate atherosclerosis in apolipoprotein E-deficient mice. However, whether STDP can affect platelet function remains unknown.

Objective
The purpose of this study is to examine the potential effects of STDP on platelet function in patients undergoing percutaneous coronary intervention (PCI) for unstable angina. The interaction between the effects of STDP with polymorphisms of CYP2C19 was also investigated.

Design, participants and intervention
This was a single-center, randomized controlled trial in patients undergoing elective PCI for unstable angina. Eligible subjects were randomized to receive STDP (210 mg per day) plus dual antiplatelet therapy (DAPT) with clopidogrel and aspirin or DAPT alone.

Main outcome measures
The primary outcome was platelet function, reflected by adenosine diphosphate (ADP)-induced platelet aggregation and platelet microparticles (PMPs). The secondary outcomes were major adverse cardiovascular events (MACEs) including recurrent ischemia or myocardial infarction, repeat PCI and cardiac death; blood biomarkers for myocardial injury including creatine kinase-MB isoenzyme (CK-MB) and high-sensitive troponin I (hsTnI); and biomarkers for inflammation including intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and galectin-3.

Results
A total of 118 subjects (mean age: [66.8 ± 8.9] years; male: 59.8%) were included into analysis: 58 in the control group and 60 in the STDP group. CYP2C19 genotype distribution was comparable between the 2 groups. In comparison to the control group, the STDP group had significantly lower CK-MB (P < 0.05) but similar hsTnI (P > 0.05) at 24 h after PCI, lower ICAM-1, VCAM-1, MCP-1 and galectin-3 at 3 months (all P < 0.05) but not at 7 days after PCI (P > 0.05). At 3 months, the STDP group had lower PMP number ([42.9 ± 37.3] vs. [67.8 ± 53.1] counts/μL in the control group, P = 0.05). Subgroup analysis showed that STDP increased percentage inhibition of ADP-induced platelet aggregation only in slow metabolizers (66.0% ± 20.8% in STDP group vs. 36.0% ± 28.1% in the control group, P < 0.05), but not in intermediate or fast metabolizers. The rate of MACEs during the 3-month follow-up did not differ between the two groups.

Conclusion
STDP produced antiplatelet, anti-inflammatory and cardioprotective effects. Subgroup analysis indicated that STDP inhibited residual platelet reactivity in slow metabolizers only.
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Antiglycation and antioxidant activities of the crude extract and saponin fraction of Tribulus terrestris before and after microcapsules release
Célia Cristina Malaguti Figueiredo, Amanda da Costa Gomes, Filipe Oliveira Granero, João Luiz Bronzel Junior, Luciana Pereira Silva, Valdecir Farias Ximenes, Regildo Márcio Gonçalves da Silva
Journal of Integrative Medicine    2022, 20 (2): 153-162.   DOI: 10.1016/j.joim.2021.12.003
Online available: 28 December 2021

Abstract181)   HTML    PDF      

Objective

The present study investigated antiglycation and antioxidant activities of crude dry extract and saponin fraction of Tribulus terrestris. It also developed a method of microencapsulation and evaluated antiglycation and antioxidant activities of crude dry extract and saponin fraction before and after microcapsules release. 

Methods

Antiglycation activity was determined by relative electrophoretic mobility (REM), free amino groups and inhibition of advanced glycation end-product (AGE) formation. Antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric ion reducing antioxidant power (FRAP), nitric oxide (NO) and thiobarbituric acid reactive species (TBARS) tests. Microcapsules were prepared using maltodextrin as wall material and freeze-drying as encapsulation technique. Morphological characterization of microcapsules was evaluated by scanning electron microscopy, and encapsulation efficiency and microcapsules release were determined by total saponins released. Antiglycation and antioxidant assays were performed using crude dry extract and saponin fraction of T. terrestris before and after release.

Results

Saponin fraction showed an increase of 32.8% total saponins. High-performance liquid chromatography-mass spectrometry analysis showed the presence of saponins in the obtained fraction. Antiglycation evaluation by REM demonstrated that samples before and after release present antiglycation activity similar to bovine serum albumin treated with aminoguanidine. Additionally, samples inhibited AGEs formation, highlighting treatment with saponins fraction after release (89.89%). Antioxidant tests demonstrated antioxidant activity of the samples. Crude dry extract before encapsulation presented the highest activities in DPPH (92.00%) and TBARS (32.49%) assays. Saponins fraction before encapsulation in FRAP test (499 μmol Trolox equivalent per gram of dry sample) and NO test (15.13 μmol nitrite formed per gram of extract) presented the highest activities. 

Conclusion

This study presented antiglycation activity of crude dry extract and saponins fraction of T. terrestris, besides it demonstrated promising antioxidant properties. It also showed that the encapsulation method was efficient and maintained biological activity of bioactive compounds after microcapsules release. These results provide information for further studies on antidiabetic and antiaging potential, and data for new herbal medicine and food supplement formulations containing microcapsules with crude extract and/or saponins fraction of T. terrestris.

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Why the “sugars” in traditional Unani formulations are a pivotal component: A viewpoint perspective
Mohammad Fazil, Sadia Nikhat
Journal of Integrative Medicine    2022, 20 (2): 91-95.   DOI: 10.1016/j.joim.2022.01.002
Online available: 18 January 2022

Abstract186)   HTML    PDF      
Traditional medicine systems around the globe, like Unani, Ayurveda and traditional Chinese medicine, include a number of sugar-based formulations, which contain a large amount of saccharide-containing sweetener, such as honey, sucrose or jaggery. With pervasive lifestyle disorders throughout the world, there have been discussions to consider alternative sweetening agents. Here, from the perspective of Unani medicine, we discuss how the saccharide-based sweeteners may be an essential component of these traditional preparations, like electuaries, which may be deprived of their bioactivities without these saccharides. With contemporary researches, it is known that apart from their own therapeutic effects, saccharides also form deep eutectic solvents which help in enhancing the bioactivity of other ingredients present in crude drugs. In addition, they provide energy for fermentation which is essential for biotransformation of compounds. Interestingly, the sugars also increase the shelf-life of these compound drugs and act as natural preservatives. On the basis of this review, we strongly believe that saccharide-based sweeteners are an essential component of traditional medicines and not merely an excipient.

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To “tell or not to tell”—Exploring disclosure about medicine use by people living with sleep disorders
Vibha Malhotra, Joanna Harnett, Erica McIntyre, Amie Steel, Keith Wong, Bandana Saini
Journal of Integrative Medicine    2022, 20 (4): 338-347.   DOI: 10.1016/j.joim.2022.03.004
Online available: 12 April 2022

Abstract97)   HTML    PDF      
Objective: To explore the difference in rates and reasons for disclosure of either conventional or complementary medicine (CM) to healthcare practitioners between people living with sleep disorders (SDs) and those without SDs.
Methods: A cross-sectional survey (N = 2019 adults) that measured sociodemographic characteristics, health status, health service utilisation, health literacy and health communication (medicine disclosure) of a representative sample of Australians was conducted. Data from participants reporting an SD (n = 265) were compared to those not reporting an SD to assess measures of health communication and disclosure about medicine use.
Results: Overall, rates of medicine disclosure to both conventional and CM practitioners were high, in respondents with (70%) and without an SD (57%). Those reporting an SD had higher expectations of their conventional health practitioner’s knowledge of CM, associated clinical decision-making skills, and approval of CM use, and held a higher degree of concern about drug interactions (P < 0.05). The main reasons cited for disclosing CM use to conventional health practitioners and conventional medicine use to CM practitioners were “I want them to fully understand my health status” and “I was concerned about drug interactions with the CMs used.”
Conclusion: The high rate of medicine use disclosure by people with SDs is driven by an intention to inform their healthcare practitioner about their health status and concerns about potential medicine interactions. Therefore, research about the expectations that people with an SD have of their conventional healthcare practitioners’ knowledge of CM and CM-drug interactions requires further examination. Likewise, further examination of CM practitioner’s conventional medicine knowledge is encouraged.
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Moxibustion regulates T-regulatory/T-helper 17 cell balance by modulating the microRNA-221/suppressor of cytokine signaling 3 axis in a mouse model of rheumatoid arthritis
Chuang Zhao, Xiao-yan Li, Zun-yuan Li, Miao Li, Zhi-dan Liu
Journal of Integrative Medicine    2022, 20 (5): 453-462.   DOI: 10.1016/j.joim.2022.06.002
Online available: 15 June 2022

Abstract98)   HTML    PDF      

Objective

Rheumatoid arthritis (RA) progression is associated with the balance of T-regulatory (Treg) and T-helper 17 (Th17) cells, while the role of microRNAs (miRs) in regulating Treg/Th17 cell balance has not been clarified. This study aimed to assess whether moxibustion could regulate Treg/Th17 cell balance by modulating the miR-221/suppressor of cytokine signaling 3 (SOCS3) axis in the RA mouse model.

Methods

A mouse model of collagen-induced arthritis (CIA) was established in male DBA/1J mice. Twenty-two days after CIA induction, the mice received daily treatment with moxibustion for 12 times. Pathological scores were assessed according to the levels of synovial hyperplasia. The expression levels of cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-17 and IL-10 were analyzed in serum by enzyme-linked immunosorbent assay. The cluster of differentiation 4 (CD4+) splenocytes was analyzed by fluorescence-activated cell sorting. The expression levels of RA-related miRs and target genes were subsequently detected, and the target of miR-221 was confirmed by the dual-luciferase reporter assay.

Results

It was revealed that moxibustion treatment decreased the pathological scores and downregulated the expression levels of IL-1β, IL-6, TNF-α, IFN-γ and IL-17, while upregulated the expression level of IL-10. The Treg/Th17 cell balance was regulated by moxibustion treatment. The expression level of miR-221 was suppressed by moxibustion treatment. Furthermore, SOCS3 was found as the direct target of miR-221, which mediated the function of moxibustion by regulating the Treg/Th17 cell balance.

Conclusion

Moxibustion therapy regulated the Treg/Th17 cell balance by modulating the miR-221/SOCS3 axis in the RA mouse model.

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Apoptotic and autophagic death union by Thuja occidentalis homeopathic drug in cervical cancer cells with thujone as the bioactive principle
Asmita Pal, Sucharita Das, Soumalee Basu, Rita Kundu
Journal of Integrative Medicine    2022, 20 (5): 463-472.   DOI: 10.1016/j.joim.2022.06.004
Online available: 17 June 2022

Abstract152)   HTML    PDF      

Objective

‘Multi-targeting’ drugs can prove fruitful to combat drug-resistance of multifactorial disease—cervical cancer. This study envisioned to reveal if Thuja homeopathic mother tincture (MT) and its bioactive component could combat human papillomavirus (HPV)-16-infected SiHa cervical cancer cells since it is globally acclaimed for HPV-mediated warts.

Methods

Thuja MT was studied for its antiproliferative and antimigratory properties in SiHa cells followed by microscopic determination of reactive oxygen species (ROS) generation by 2’,7’-dichlorodihydrofluorescein diacetate (DCFDA) staining and loss in mitochondrial membrane potential (MMP) by rhodamine (Rh) 123 staining. Apoptosis and autophagy inductions were studied by acridine orange (AO) ethidium bromide (EB) staining and immunoblot analyses of marker proteins. The bioactive component of Thuja MT detected by gas chromatography-mass spectrometry was studied for antiproliferative and antimigratory properties along with in silico prediction of its cellular targets by molecular docking and oral drug forming competency.

Results 

Thuja MT showed significant antiproliferative and antimigratory potential in SiHa cells at a 50% inhibitory concentration (IC50) dosage of 17.3 μL/mL. An increase in DCFDA fluorescence and loss in Rh123 fluorescence prove that Thuja MT acted through the burst of ROS and loss in MMP respectively. AO/EB-stained cells under the microscope and immunoblot analyses supported Thuja-induced cellular demise via dual pathways—apoptosis and autophagy. Immunoblots showed cleavage of caspase-3 and poly adenosine diphosphate-ribose polymerase-1 (PARP-1) along with upregulation of Beclin-1, microtubule-associated protein 1 light chain 3B (LC3B)-II, and p62 proteins. Hence, the apoptotic cascade followed a caspase-3-dependent pathway supported by PARP-1 cleavage, while autophagic death was Beclin-1-dependent and mediated by accumulation of LC3BII and p62 proteins. Thujone, detected as the bioactive principle of Thuja MT showed greater anti-proliferative and anti-migratory potential at an IC50 77 μg/mL along with excellent oral drug competency with the ability for gastrointestinal absorption and blood-brain-barrier permeation with nil toxicity. Molecular docking depicted thujone with the strongest affinity for mammalian target of rapamycin, phosphoinositide 3-kinase, and protein kinase B followed by B-cell lymphoma 2, murine double minute 2 and adenosine monophosphate-activated protein kinase, which might act as upstream triggers of apoptotic-autophagic crosstalk. 

Conclusion

Robust ‘multi-targeting’ anticancer potential of Thuja drug and thujone for HPV-infected cervical cancer ascertain its therapeutic efficacy for HPV infections. 


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Efficacy of acupuncture on cardiovascular complications in patients with diabetes mellitus in Korea: A nationwide retrospective cohort
Hyejin Jung, Tiana Won, Ga-Yeon Kim, Jowon Jang, Sujung Yeo, Sabina Lim
Journal of Integrative Medicine    2023, 21 (2): 176-183.   DOI: 10.1016/j.joim.2023.01.007
Accepted: 18 October 2022
Online available: 02 February 2023

Abstract71)   HTML    PDF      
Objective
The main aim of this study is to investigate whether acupuncture could be an effective complementary treatment for reducing the risk of macrovascular complications in diabetic patients currently taking antidiabetic medications using a nationwide population-based database.

Methods
We conducted a retrospective cohort study to assess the efficacy of acupuncture on cardiovascular complications in diabetic patients using data from patients between 40 and 79 years of age, newly diagnosed with diabetes between 2003 and 2006, found in the National Health Insurance Service-National Sample Cohort (NHIS-NSC) in Korea. From the data, we identified 21,232 diabetic patients who were taking antidiabetic medication between 2003 and 2006. The selected patients were divided into two groups—those who received acupuncture at least three times and those who received no acupuncture (non-acupuncture) in the year following their diagnosis of diabetes. After 1:1 propensity score matching (PSM), each group had 3350 patients, and the observation ceased at the occurrence of a major adverse cardiovascular event (MACE), which was defined as either myocardial infarction, stroke, or death due to cardiovascular cause.

Results
After PSM, the acupuncture group had a lower incidence of MACE (hazard ratio [HR]: 0.87; 95% confidence interval [CI]: 0.81–0.94; P = 0.0003) and all-cause mortality (HR: 0.77; 95% CI: 0.70–0.84; P < 0.0001) than the non-acupuncture group; the HRs for stroke-related mortality (HR: 0.75; 95% CI: 0.56–1.00; P = 0.0485), ischemic heart disease mortality (HR: 0.53; 95% CI: 0.34–0.84; P = 0.006) and circulatory system disease mortality (HR: 0.67; 95% CI: 0.55–0.82; P < 0.0001) were lower in the acupuncture group than in the non-acupuncture group in the secondary analysis.

Conclusion
Our results indicate that diabetic patients receiving acupuncture treatment might have a lower risk of MACE, all-cause mortality and cardiovascular mortality. This population-based retrospective study suggests beneficial effects of acupuncture in preventing macrovascular complications associated with diabetes. These findings call for further prospective cohort or experimental studies on acupuncture treatment for cardiovascular complications of diabetes.
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Momordica charantia fruit extract with antioxidant capacity improves the expression of tyrosine-phosphorylated proteins in epididymal fluid of chronic stress rats
Supatcharee Arun, Therachon Kamollerd, Nareelak Tangsrisakda, Sudtida Bunsueb, Arada Chaiyamoon, Alexander Tsang-Hsien Wu, Sitthichai Iamsaard
Journal of Integrative Medicine    2022, 20 (6): 534-542.   DOI: 10.1016/j.joim.2022.09.002
Accepted: 06 February 2022
Online available: 22 November 2022

Abstract81)   HTML    PDF      
Objective: Although the protective effects of Momordica charantia L. (MC) extract on chemical-induced testicular damage have been studied, the preventive effects of MC extract on functional proteins in the epididymis under chronic stress have never been reported. This study investigated the protective effects of MC fruit extract on protein secretion, especially tyrosine-phosphorylated proteins, in the epididymis of rats exposed to chronic unpredictable stress (CUS).
Methods: Total phenolic compounds (TPC), total flavonoid compounds (TFC) and antioxidant capacities of MC extract were measured. Adult male rats were divided into 4 groups: control group, CUS group, and 2 groups of CUS that received different doses of MC extract (40 or 80 mg/kg). In treated groups, rats were given MC daily, followed by induction of CUS (1 stressor was randomly applied from a battery of 9 potential stressors) for 60 consecutive days. Plasma corticosterone and testosterone levels were analyzed after the end of experiment. Expressions of heat-shock protein 70 (HSP-70) and tyrosine-phosphorylated proteins present in the fluid of the head and tail of the epididymis were quantified using Western blot.
Results: MC extract contained TPC of (19.005 ± 0.270) mg gallic acid equivalents and TFC of (0.306 ± 0.012) mg catechin equivalents per gram, and had 2,2-diphenyl-1-picrylhydrazyl antioxidant capacity of (4.985 ± 0.086) mg trolox equivalents per gram, radical half-maximal inhibitory concentration of (2.011 ± 0.008) mg/mL and ferric reducing antioxidant power of (23.697 ± 0.819) μmol Fe(II) per gram. Testosterone level in the epididymis was significantly increased, while the corticosterone level was significantly improved in groups treated with MC extract, compared to the CUS animals. Particularly, an 80 mg/kg dose of MC extract prevented the impairments of HSP-70 and tyrosine-phosphorylated protein expressions in the luminal fluid of the epididymis of CUS rats.
Conclusion: MC fruit extract had antioxidant activities and improved the functional proteins secreted from the head and tail of the epididymis. It is possible to develop the MC fruit extract as a male fertility supplement for enhancing functional sperm maturation in stressed men.
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Lipidomic investigation of the protective effects of Polygonum perfoliatum against chemical liver injury in mice
Lei Peng, Hua-guo Chen, Xin Zhou
Journal of Integrative Medicine    2023, 21 (3): 289-301.   DOI: 10.1016/j.joim.2023.03.002
Accepted: 07 November 2022
Online available: 09 March 2023

Abstract70)   HTML    PDF      
Objective: Recent investigations have demonstrated that Polygonum perfoliatum L. can protect against chemical liver injury, but the mechanism behind its efficacy is still unclear. Therefore, we studied the pharmacological mechanism at work in P. perfoliatum protection against chemical liver injury.
Methods: To evaluate the activity of P. perfoliatum against chemical liver injury, levels of alanine transaminase, lactic dehydrogenase, aspartate transaminase, superoxide dismutase, glutathione peroxidase and malondialdehyde were measured, alongside histological assessments of the liver, heart and kidney tissue. A nontargeted lipidomics strategy based on ultra-performance liquid chromatography quadrupole-orbitrap high-resolution mass spectrometry method was used to obtain the lipid profiles of mice with chemical liver injury and following treatment with P. perfoliatum; these profiles were used to understand the possible mechanisms behind P. perfoliatum’s protective activity.
Results: Lipidomic studies indicated that P. perfoliatum protected against chemical liver injury, and the results were consistent between histological and physiological analyses. By comparing the profiles of liver lipids in model and control mice, we found that the levels of 89 lipids were significantly changed. In animals receiving P. perfoliatum treatment, the levels of 8 lipids were significantly improved, relative to the model animals. The results showed that P. perfoliatum extract could effectively reverse the chemical liver injury and significantly improve the abnormal liver lipid metabolism of mice with chemical liver injury, especially glycerophospholipid metabolism.
Conclusion: Regulation of enzyme activity related to the glycerophospholipid metabolism pathway may be involved in the mechanism of P. perfoliatum’s protection against liver injury.
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Huangqi Decoction, a compound Chinese herbal medicine, inhibits the proliferation and activation of hepatic stellate cells by regulating the long noncoding RNA-C18orf26-1/microRNA-663a/transforming growth factor-β axis
Ben-sheng Dong, Fu-qun Liu, Wen-na Yang, Xiao-dong Li, Miao-juan Shi, Mao-rong Li, Xiu-li Yan, Hui Zhang
Journal of Integrative Medicine    2023, 21 (1): 47-61.   DOI: 10.1016/j.joim.2022.11.002
Accepted: 31 October 2022
Online available: 23 January 2023

Abstract97)   HTML    PDF      

Objective

Huangqi Decoction (HQD), a classical traditional Chinese medicine formula, has been used as a valid treatment for alleviating liver fibrosis; however, the underlying molecular mechanism is still unknown. Although our previous studies showed that microRNA-663a (miR-663a) suppresses the proliferation and activation of hepatic stellate cells (HSCs) and the transforming growth factor-β/small mothers against decapentaplegic (TGF-β/Smad) pathway, whether long noncoding RNAs (lncRNAs) are involved in HSC activation via the miR-663a/TGF-β/Smad signaling pathway has not yet reported. The present study aimed to investigate the roles of lncRNA lnc-C18orf26-1 in the activation of HSCs and the mechanism by which HQD inhibits hepatic fibrosis.

Methods

The expression levels of lnc-C18orf26-1, miR-663a and related genes were measured by quantitative reverse transcription-polymerase chain reaction. HSCs were transfected with the miR-663a mimic or inhibitor and lnc-C18orf26-1 small interfering RNAs. The water-soluble tetrazolium salt-1 assay was used to assess the proliferation rate of HSCs. Changes in lncRNA expression were evaluated in miR-663a-overexpressing HSCs by using microarray to identify miR-663a-regulated lncRNAs. RNA hybrid was used to predict the potential miR-663a binding sites on lncRNAs. Luciferase reporter assays further confirmed the interaction between miR-663a and the lncRNA. The expression levels of collagen α-2(I) chain (COL1A2), α-smooth muscle actin (α-SMA) and TGF-β/Smad signaling pathway-related proteins were determined using Western blotting.

Results

Lnc-C18orf26-1 was upregulated in TGF-β1-activated HSCs and competitively bound to miR-663a. Knockdown of lnc-C18orf26-1 inhibited HSC proliferation and activation, downregulated TGF-β1-stimulated α-SMA and COL1A2 expression, and inhibited the TGF-β1/Smad signaling pathway. HQD suppressed the proliferation and activation of HSCs. HQD increased miR-663a expression and decreased lnc-C18orf26-1 expression in HSCs. Further studies showed that HQD inhibited the expression of COL1A2, α-SMA, TGF-β1, TGF-β type I receptor (TGF-βRI) and phosphorylated Smad2 (p-Smad2) in HSCs, and these effects were reversed by miR-663a inhibitor treatment.

Conclusion

Our study identified lnc-C18orf26-1 and miR-663a as promising therapeutic targets for hepatic fibrosis. HQD inhibits HSC proliferation and activation at least partially by regulating the lnc-C18orf26-1/miR-663a/TGF-β1/TGF-βRI/p-Smad2 axis.

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Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity
Yan-qiong Zhang, Chun-xia Shi, Dan-mei Zhang, Lu-yi Zhang, Lu-wen Wang, Zuo-jiong Gong
Journal of Integrative Medicine    2023, 21 (5): 464-473.   DOI: 10.1016/j.joim.2023.08.002
Accepted: 01 June 2023
Online available: 21 August 2023

Abstract92)      PDF      

Objective

Acute liver failure (ALF) is characterized by severe liver dysfunction, rapid progression and high mortality and is difficult to treat. Studies have found that sulforaphane (SFN), a nuclear factor E2-related factor 2 (NRF2) agonist, has anti-inflammatory, antioxidant and anticancer effects, and has certain protective effects on neurodegenerative diseases, cancer and liver fibrosis. This paper aimed to explore the protective effect of SFN in ALF and it possible mechanisms of action.

Methods

Lipopolysaccharide and D-galactosamine were used to induce liver injury in vitro and in vivo. NRF2 agonist SFN and histone deacetylase 6 (HDAC6) inhibitor ACY1215 were used to observe the protective effect and possible mechanisms of SFN in ALF, respectively. Cell viability, lactate dehydrogenase (LDH), Fe2+, glutathione (GSH) and malondialdehyde (MDA) were detected. The expression of HDAC6, NRF2, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4) and solute carrier family 7 member 11 (SLC7A11) were detected by Western blotting and immunofluorescence.

Results

Our results show that NRF2 was activated by SFN. LDH, Fe2+, MDA and ACSL4 were downregulated, while GSH, GPX4 and SLC7A11 were upregulated by SFN in vitro and in vivo, indicating the inhibitory effect of SFN on ferroptosis. Additionally, HDAC6 expression was decreased in the SFN group, indicating that SFN could downregulate the expression of HDAC6 in ALF. After using the HDAC6 inhibitor, ACY1215, SFN further reduced HDAC6 expression and inhibited ferroptosis, indicating that SFN may inhibit ferroptosis by regulating HDAC6 activity.

Conclusion

SFN has a protective effect on ALF, and the mechanism may include reduction of ferroptosis through the regulation of HDAC6.


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Integrated therapeutic plasma exchange and traditional Chinese medicine treatment in a patient with severe COVID-19: A case report
Chia-Wei Lin, Wei-Chen Hsu, Chien-Lu Lu, Su-Hsing Cheng, Cheng-Pin Chen, Yu-Chang Hou
Journal of Integrative Medicine    2022, 20 (6): 575-580.   DOI: 10.1016/j.joim.2022.09.001
Accepted: 06 February 2022
Online available: 22 November 2022

Abstract96)   HTML    PDF      
This report presents the case of a 59-year-old man with severe COVID-19 that gradually progressed to cytokine release syndrome and then acute respiratory distress syndrome; he was successfully treated via integration of therapeutic plasma exchange and traditional Chinese medicine. The patient initially presented with a sore throat, severe muscle aches, productive cough and fever. On the worsening of symptoms, remdesivir was administered. However, as the symptoms continued to worsen and a cytokine release syndrome was suspected, oxygen was provided through a high-flow nasal cannula (50 L/min) and therapeutic plasma exchange was performed to prevent worsening of the acute respiratory distress syndrome. On the same day, a course of traditional Chinese medicine was introduced in consultation with the infectious house staff. The patient’s symptoms gradually improved; the levels of C-reactive protein and D-dimers reduced, and the patient was weaned to a simple oxygen mask and eventually to room air. This is the first reported case of the integration of these treatments. Together, they prevented the patient from requiring intubation, played a role in cytokine management, and also improved the clinical symptoms, including productive purulent sputum, cough, frequent stool passage and intermittent fever, with no adverse effects. As a result, the patient was discharged within two weeks of the integration of these treatments. Therefore, the integration of therapeutic plasma exchange and traditional Chinese medicine is an effective therapy for patients with severe COVID-19.
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Endocannabinoids are potential inhibitors of glioblastoma multiforme proliferation
Ashraf Duzan, Desiree Reinken, Timothy L. McGomery, Nicholas M. Ferencz, Jacob M. Plummer, Mufeed M. Basti
Journal of Integrative Medicine    2023, 21 (2): 120-129.   DOI: 10.1016/j.joim.2023.01.005
Accepted: 14 September 2022
Online available: 02 February 2023

Abstract54)   HTML    PDF      
Globally, it is evident that glioblastoma multiforme (GBM) is an aggressive malignant cancer with a high mortality rate and no effective treatment options. Glioblastoma is classified as the stage-four progression of a glioma tumor, and its diagnosis results in a shortened life expectancy. Treatment options for GBM include chemotherapy, immunotherapy, surgical intervention, and conventional pharmacotherapy; however, at best, they extend the patient’s life by a maximum of 5 years. GBMs are considered incurable due to their high recurrence rate, despite various aggressive therapeutic approaches which can have many serious adverse effects. Ceramides, classified as endocannabinoids, offer a promising novel therapeutic approach for GBM. Endocannabinoids may enhance the apoptosis of GBM cells but have no effect on normal healthy neural cells. Cannabinoids promote atypical protein kinase C, deactivate fatty acid amide hydrolase enzymes, and activate transient receptor potential vanilloid 1 (TRPV1) and TRPV2 to induce pro-apoptotic signaling pathways without increasing endogenous cannabinoids. In previous in vivo studies, endocannabinoids, chemically classified as amide formations of oleic and palmitic acids, have been shown to increase the pro-apoptotic activity of human cancer cells and inhibit cell migration and angiogenesis. This review focuses on the biological synthesis and pharmacology of endogenous cannabinoids for the enhancement of cancer cell apoptosis, which have potential as a novel therapy for GBM.
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Understanding health literacy from a traditional Chinese medicine perspective
Zhiyi Qian, Grace Y. Wang, Marcus Henning, Yan Chen
Journal of Integrative Medicine    2023, 21 (3): 215-220.   DOI: 10.1016/j.joim.2023.03.001
Accepted: 19 January 2023
Online available: 04 March 2023

Abstract84)   HTML    PDF      
Health literacy is critical to improving individual and public health. However, indigenous perceptions of health are largely absent from Western-derived measurements, contributing to disparities in health outcomes between indigenous and non-indigenous populations. China is the country with the world’s largest population and only officially introduced the term “health literacy” in 2008. Current measures of health literacy in China are primarily based on Western-derived constructs, which have been shown to have poor comparability to the unique dual medical system in China. Given its significant importance to health management globally, understanding health perceptions from a traditional Chinese medicine perspective is essential. This review explores the concept and core elements of indigenous health literacy, evaluates the existing definitions and measurement tools as applied to the concept, and proposes a new model of traditional Chinese medicine health literacy.
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ISSN 2095-4964
CN 31-2083/R

Editors-in-Chief:
Changquan Ling, Shanghai, China
Lixing Lao, Virginia, USA
Frequency: 6 issues per year
Publisher: Science Press, China

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