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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

Abstract125)      PDF(pc) (1367KB)(120)    PDF(mobile) (1367KB)(12)   
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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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

Abstract254)   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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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

Abstract154)   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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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

Abstract107)   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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Melittin analog p5RHH enhances recombinant adeno-associated virus transduction efficiency
Jing-shun Meng, Yun He, Heng-bin Yang, Li-ping Zhou, Si-yuan Wang, Xi-lin Feng, Omar Yahya Al-shargi, Xiao-min Yu, Li-qing Zhu, Chang-quan Ling
Journal of Integrative Medicine    2024, 22 (1): 72-82.   DOI: 10.1016/j.joim.2023.10.030
Accepted: 22 May 2023
Online available: 12 November 2023

Abstract206)   HTML    PDF      

Objective

Melittin and its derivatives have been characterized to establish effective gene delivery systems. Their capability of facilitating endosomal release enhances the nanoparticles-based gene delivery. Nevertheless, little investigation has been conducted to explore its potential application in the context of viral vectors.

Methods

Various melittin-derived peptides were inserted into the loop VIII of the capsid proteins of recombinant adeno-associated virus vectors. These vectors carrying either gfp or fluc genes were subjected to qPCR assays and transduction assays of HEK293T cells to investigate the efficiency of vector production and gene delivery. In addition, the ability of a specific p5RHH-rAAV vector to deliver genes was examined through in vitro transduction of different cultured cells and in vivo tail vein administration to C57BL/6 mice. Finally, the intricate details of the vector-mediated transduction mechanisms were revealed by specific pharmacological inhibitors of every stage of the rAAV2 intracellular life cycle.

Results

A total of 76 melittin-related peptides were compiled from existing literature. Among them, cMA2, Melt13, p5RHH and aAR3 were found to significantly enhance the gene delivery efficiency of rAAV2 vectors. The p5RHH-rAAV2 vectors efficiently transduced not only rAAV-potent cell lines but also cell lines previously considered resistant to rAAV. Mechanistically, bafilomycin A1, a vacuolar endosome acidification inhibitor, completely inhibited the transgene expression mediated by the p5RHH-rAAV2 vectors. Most importantly, p5RHH-rAAV8 vectors also demonstrated increased hepatic transduction in vivo in C57BL/6 mice.

Conclusion

The incorporation of melittin analogues into the rAAV capsids results in a significant improvement in rAAV-mediated transgene expression. While further modifications remain an area of interest, our studies have substantially broadened the pharmacological prospects of melittin in the context of viral vector-mediated gene delivery.

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Abstracts for SAR/RCMI PolyU International Research Conference
Journal of Integrative Medicine    2024, 22 (3): 303-378.   DOI: 10.1016/S2095-4964(24)00328-5
Online available: 20 May 2024

Abstract41)      PDF(pc) (1776KB)(16)      
May 23–25, 2024, the Hong Kong Polytechnic University, Hong Kong, China
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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

Abstract137)   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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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

Abstract145)   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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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

Abstract74)   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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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

Abstract216)   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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Xiaoyao San, a Chinese herbal formula, ameliorates depression-like behavior in mice through the AdipoR1/AMPK/ACC pathway in hypothalamus
Kai-rui Tang, Xiao-wei Mo, Xing-yi Zhou, Yue-yue Chen, Dong-dong Liu, Liang-liang He, Qing-yu Ma, Xiao-juan Li, Jia-xu Chen
Journal of Integrative Medicine    2022, 20 (5): 442-452.   DOI: 10.1016/j.joim.2022.07.003
Abstract140)   HTML    PDF      

Objective

Depression and metabolic disorders have overlapping psychosocial and pathophysiological causes. Current research is focused on the possible role of adiponectin in regulating common biological mechanisms. Xiaoyao San (XYS), a classic Chinese medicine compound, has been widely used in the treatment of depression and can alleviate metabolic disorders such as lipid or glucose metabolism disorders. However, the ability of XYS to ameliorate depression-like behavior as well as metabolic dysfunction in mice and the underlying mechanisms are unclear.

Methods

An in vivo animal model of depression was established by chronic social defeat stress (CSDS). XYS and fluoxetine were administered by gavage to the drug intervention group. Depression-like behaviors were analyzed by the social interaction test, open field test, forced swim test, and elevated plus maze test. Glucose levels were measured using the oral glucose tolerance test. The involvement of certain molecules was validated by immunofluorescence, histopathology, and Western blotting. In vitro, hypothalamic primary neurons were exposed to high glucose to induce neuronal damage, and the neuroprotective effect of XYS was evaluated by cell counting kit-8 assay. Immunofluorescence and Western blotting were used to evaluate the influences of XYS on adiponectin receptor 1 (AdipoR1), adenosine 5’-monophosphate-activated protein kinase (AMPK), acetyl-coenzyme A carboxylase (ACC) and other related proteins.

Results

XYS ameliorated CSDS-induced depression-like behaviors and glucose tolerance impairment in mice and increased the level of serum adiponectin. XYS also restored Nissl bodies in hypothalamic neurons in mice that exhibited depression-like behaviors and decreased the degree of neuronal morphological damage. In vivo and in vitro studies indicated that XYS increased the expression of AdipoR1 in hypothalamic neurons.

Conclusion

Adiponectin may be a key regulator linking depression and metabolic disorders;  regulation of the hypothalamic AdipoR1/AMPK/ACC pathway plays an important role in treatment of depression by XYS.

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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

Abstract162)   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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Clinical practice guideline for acupuncture and moxibustion: Female urinary incontinence
Chao Yang, Shan-ze Wang, Sheng Chen, Shuo Du, Guan-qun Wang, Wei Guo, Xiao-long Xie, Bi-hui Peng, Shi-hao Du, Ji-ping Zhao
Journal of Integrative Medicine    2024, 22 (3): 258-269.   DOI: 10.1016/j.joim.2024.03.011
Accepted: 07 March 2024
Online available: 07 March 2024

Abstract155)   HTML    PDF      
Urinary incontinence (UI) is a common problem worldwide. It has a major impact on the physical and social activities and interpersonal relationships. UI is common in women, but is under-reported and under-treated. It affects the quality of life in female patients severely and is known as a “nonlethally social cancer.” Acupuncture and moxibustion has been proposed as a potentially effective intervention for female UI. Hence, for the benefit of acupuncture practitioners around the world, the World Federation of Acupuncture-moxibustion Societies have initiated a project to develop the clinical practice guideline (CPG) for the use of acupuncture and moxibustion to treat female UI. The CPG was developed according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology, referring to the principles of the World Health Organization Handbook for Guideline Development. During the development of the CPGs, the guideline development group (GDG) played an important role. The clinical questions, recommendations and therapeutic protocols were all formulated by GDG using the modified Delphi method. The CPGs contain ten recommendations about the use of acupuncture and moxibustion interventions for ten clinical questions, which include nine conditional recommendations for the intervention, one conditional recommendations for either the intervention or the comparison. The CPG also provide one conventional filiform needle therapy protocol, two deep puncturing stimulation on lumbosacral acupoints therapy protocols, and four moxibustion therapy protocols, based on the protocols presented in RCTs reviews by the GDG.
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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
Abstract118)   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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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

Abstract190)   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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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

Abstract94)   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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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

Abstract108)   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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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

Abstract262)   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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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

Abstract190)   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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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

Abstract186)   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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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

Abstract111)   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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Clinical practice guideline for acupuncture and moxibustion: Allergic rhinitis
Shi-hao Du, Sheng Chen, Shan-ze Wang, Guan-qun Wang, Shuo Du, Wei Guo, Xiao-long Xie, Bi-hui Peng, Chao Yang, Ji-ping Zhao
Journal of Integrative Medicine    2024, 22 (3): 245-257.   DOI: 10.1016/j.joim.2024.03.009
Accepted: 25 December 2023
Online available: 01 March 2024

Abstract100)   HTML    PDF      
Acupuncture is one of the most effective complementary therapies for allergic rhinitis (AR) and has been recommended by several clinical practice guidelines (CPGs) for AR. However, these CPGs mentioned acupuncture without making recommendations for clinical implementation and therapeutic protocols, therefore limiting the applicability of acupuncture therapies for AR. Hence, for the benefit of acupuncture practitioners around the world, the World Federation of Acupuncture-moxibustion Societies have initiated a project to develop the CPGs for the use of acupuncture and moxibustion to treat AR. The CPGs were developed according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology, referring to the principles of the World Health Organization Handbook for Guideline Development. During the development of the CPGs, the guideline development group (GDG) played an important role. The clinical questions, recommendations and therapeutic protocols were all formulated by the GDG using the modified Delphi method. The CPGs contain recommendations for 15 clinical questions about the use of acupuncture and moxibustion interventions. These include one strong recommendation for the intervention based on high-quality evidence, three conditional recommendations for either the intervention or standard care, and 11 conditional recommendations for the intervention based on very low quality of evidence. The CPGs also provide one filiform needle acupuncture protocol and five moxibustion protocols extracted based on the protocols presented in randomized clinical trials (RCTs) reviewed by the GDG.

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Blinding assessment in clinical trials of traditional Chinese medicine: Exploratory principles and protocol
Xiao-cong Wang, Xiao-yu Liu, Kang-le Shi, Qing-gang Meng, Yue-fan Yu, Shi-yao Wang, Juan Wang, Chang Qu, Cong Lei, Xin-ping Yu
Journal of Integrative Medicine    2023, 21 (6): 528-536.   DOI: 10.1016/j.joim.2023.10.003
Accepted: 11 September 2023
Online available: 29 October 2023

Abstract111)   HTML    PDF      
As one of the key components of clinical trials, blinding, if successfully implemented, can help to mitigate the risks of implementation bias and measurement bias, consequently improving the validity and reliability of the trial results. However, successful blinding in clinical trials of traditional Chinese medicine (TCM) is hard to achieve, and the evaluation of blinding success through blinding assessment lacks established guidelines. Taking into account the challenges associated with blinding in the TCM field, here we present a framework for assessing blinding. Further, this study proposes a blinding assessment protocol for TCM clinical trials, building upon the framework and the existing methods. An assessment report checklist and an approach for evaluating the assessment results are presented based on the proposed protocol. It is anticipated that these improvements to blinding assessment will generate greater awareness among researchers, facilitate the standardization of blinding, and augment the blinding effectiveness. The use of this blinding assessment may further advance the quality and precision of TCM clinical trials and improve the accuracy of the trial results. The blinding assessment protocol will undergo continued optimization and refinement, drawing upon expert consensus and experience derived from clinical trials.
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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

Abstract129)   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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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

Abstract123)   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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The use of melittin to enhance transgene expression mediated by recombinant adeno-associated virus serotype 2 vectors both in vitro and in vivo
Yi-lin Xie, Ji-yao Wang, Yun He, Xiao-min Yu, Qing-yun Zheng, Chen Ling, Xi-lin Feng, Li-qing Zhu
Journal of Integrative Medicine    2023, 21 (1): 106-116.   DOI: 10.1016/j.joim.2022.10.003
Accepted: 26 June 2022
Online available: 14 October 2022

Abstract151)   HTML    PDF      
Objective: Melittin, a cell-penetrating peptide, improves the efficiency of many non-viral gene delivery vectors, yet its application in viral vectors has not been well studied. The non-pathogenic recombinant adeno-associated virus (rAAV) vector is an ideal in vivo gene delivery vector. However, its full potential will only be achieved after improvement of its transduction efficiency. To improve the transduction efficiency of rAAV2 vectors, we attempted to develop a melittin-based rAAV2 vector delivery strategy.
Methods: The melittin peptide was inserted into the rAAV2 capsid either in the loop VIII of all viral proteins (VPs) or at the N terminus of VP2. Various rAAV2-gfp or -fluc vectors were subjected to quantitative real-time polymerase chain reaction and Western blot assays to determine their titers and integrity of capsid proteins, respectively. Alternatively, the vectors based on wild-type capsid were pre-incubated with melittin, followed by transduction of cultured cells or tail vein administration of the mixture to C57BL/6 and BALB/c nude mice. In vivo bioluminescence imaging was performed to evaluate the transgene expression.
Results: rAAV2 vectors with melittin peptide inserted in the loop VIII of VPs had low transduction efficiency, probably due to dramatically reduced ability to bind to the target cells. Fusing the melittin peptide at the N-terminus of VP2 produced vectors without the VP2 subunit. Interestingly, among the commonly used rAAV vectors, pre-incubation of rAAV2 and rAAV6 vectors with melittin significantly enhanced their transduction efficiency in HEK293 and Huh7 cells in vitro. Melittin also had the ability to increase the rAAV2-mediated transgene expression in mouse liver in vivo. Mechanistically, melittin did not change the vector-receptor interaction. Moreover, cell counting kit-8 assays of cultured cells and serum transaminase levels indicated melittin had little cytotoxicity.
Conclusion: Pre-incubation with melittin, but not insertion of melittin into the rAAV2 capsid, significantly enhanced rAAV2-mediated transgene expression. Although further in vivo evaluations are required, this research not only expands the pharmacological potential of melittin, but also provides a new strategy to improve gene therapy mediated by rAAV vectors.
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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

Abstract126)   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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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

Abstract122)   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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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

Abstract101)   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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Efficacy and safety of acupuncture for polycystic ovary syndrome: An overview of systematic reviews
Han Yang, Zhi-yong Xiao, Zi-han Yin, Zheng Yu, Jia-jia Liu, Yan-qun Xiao, Yao Zhou, Juan Li, Jie Yang, Fan-rong Liang
Journal of Integrative Medicine    2023, 21 (2): 136-148.   DOI: 10.1016/j.joim.2022.12.002
Accepted: 10 November 2022
Online available: 28 December 2022

Abstract106)   HTML    PDF      
Background:
Polycystic ovary syndrome (PCOS) is the primary cause of anovulatory infertility, bringing serious harm to women's physical and mental health. Acupuncture may be an effective treatment for PCOS. However, systematic reviews (SRs) on the efficacy and safety of acupuncture for PCOS have reported inconsistent results, and the quality of these studies has not been adequately assessed.

Objective:
To summarize and evaluate the current evidence on the efficacy and safety of acupuncture for PCOS, as well as to assess the quality and risks of bias of the available SRs.

Search strategy:
Nine electronic databases (Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, Chinese National Knowledge Infrastructure, Wanfang Data, Chongqing VIP Chinese Science and Technology Periodical Database, and China Biology Medicine disc) were searched from their establishment to July 27, 2022. Based on the principle of combining subject words with text words, the search strategy was constructed around search terms for “acupuncture,” “polycystic ovary syndrome,” and “systematic review.”

Inclusion criteria:
SRs of randomized controlled trials that explored the efficacy and (or) safety of acupuncture for treating patients with PCOS were included.

Data extraction and analysis:
Two authors independently extracted study data according to a predesigned form. Tools for evaluating the methodological quality, risk of bias, reporting quality, and confidence in study outcomes, including A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2), Risk of Bias in Systematic Reviews (ROBIS), Preferred Reporting Items for Systematic Reviews and Meta-analyses for Acupuncture (PRISMA-A), and the Grading of Recommendations Assessment, Development and Evaluation (GRADE), were used to score the included SRs.

Results:
A total of 885 studies were retrieved, and 11 eligible SRs were finally included in this review. The methodological quality of 2 SRs (18.18%) was low, while the other 9 SRs (81.82%) were scored as extremely low. Four SRs (36.36%) were considered to be of low risk of bias. As for reporting quality, the reporting completeness of 9 SRs (81.82%) was more than 70%. Concerning the confidence in study results, 2 study results were considered to have a high quality of evidence (3.13%), 14 (21.88%) a “moderate” quality, 28 (43.75%) a “low” quality, and 20 (31.24%) considered a “very low” quality. Descriptive analyses suggested that combining acupuncture with other medicines can effectively improve the clinical pregnancy rate (CPR) and ovulation rate, and reduce luteinizing hormone/follicle-stimulating hormone ratio, homeostasis model assessment of insulin resistance, and body mass index (BMI). When compared with medicine alone, acupuncture alone also can improve CPR. Further, when compared with no intervention, acupuncture had a better effect in promoting the recovery of menstrual cycle and reducing BMI. Acupuncture was reported to cause no adverse events or some adverse events without serious harm.

Conclusion:
The efficacy and safety of acupuncture for PCOS remains uncertain due to the limitations and inconsistencies of current evidence. More high-quality studies are needed to support the use of acupuncture in PCOS.
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Electro-acupuncture promotes gut motility and alleviates functional constipation by regulating gut microbiota and increasing butyric acid generation in mice
Ming-min Xu, Yu Guo, Ying Chen, Wei Zhang, Lu Wang, Ying Li
Journal of Integrative Medicine    2023, 21 (4): 397-406.   DOI: 10.1016/j.joim.2023.05.003
Accepted: 17 March 2023
Online available: 01 June 2023

Abstract153)   HTML    PDF      

Objective

Abnormalities in the gut microbiota and intestinal short-chain fatty acid (SCFA) levels are implicated in the pathogenesis of functional constipation (FC). Electro-acupuncture (EA) has been shown to improve constipation-related symptoms and rebalance the gut microbiota. However, it is currently unknown whether the gut microbiota is a key mechanistic target for EA or how EA promotes gut motility by regulating the gut microbiota and SCFAs. Therefore, we assessed the effects of EA in FC mice and pseudo-germfree (PGF) mice to address these questions.

Methods

Forty female Kunming mice were randomly separated into a normal control group (n = 8), an FC group (n = 8), an FC + EA group (n = 8), a PGF group (n = 8) and a PGF + EA group (n = 8). The FC group and FC + EA group were treated with diphenoxylate to establish the FC model; the PGF group and PGF + EA group were given an antibiotic cocktail to initiate the PGF model. After maintaining the model for 14 d, mice in the FC + EA and PGF + EA groups received EA stimulation at the ST25 and ST37 acupoints, once a day, 5 times per week, for 2 weeks. Fecal parameters and intestinal transit rate were calculated to assess the efficacy of EA on constipation and gastrointestinal motility. Colonic contents were used to quantify gut microbial diversity using 16S rRNA sequencing, and measure SCFA concentrations using gas chromatography-mass spectrometry.

Results

EA significantly shortened the first black stool defecation time (P < 0.05) and increased the intestinal transit rate (P < 0.01), and fecal pellet number (P < 0.05), wet weight (P < 0.05) and water content (P < 0.01) over 8 h, compared with the FC group, showing that EA promoted gut motility and alleviated constipation. However, EA treatment did not reverse slow-transit colonic motility in PGF mice (P > 0.05), demonstrating that the gut microbiota may play a mechanistic role in the EA treatment of constipation. In addition, EA treatment restored the Firmicutes to Bacteroidetes ratio and significantly increased butyric acid generation in FC mice (P < 0.05), most likely due to the upregulation of Staphylococcaceae microorganisms (P < 0.01).

Conclusion

EA-mediated resolution of constipation occurs through rebalancing the gut microbiota and promoting butyric acid generation.

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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

Abstract92)   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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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

Abstract126)      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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Efficacy and safety of Huzhang Granule, a compound Chinse herbal medicine, for acute gouty arthritis: A double-blind, randomized controlled trial
Hao Wang, Si-ting Chen, Xiao-jie Ding, Le Kuai, Liang Hua, Xin Li, Yi-fei Wang, Ming Zhang, Bin Li, Rui-ping Wang, Mi Zhou
Journal of Integrative Medicine    2024, 22 (3): 270-278.   DOI: 10.1016/j.joim.2024.03.008
Accepted: 22 February 2024
Online available: 26 March 2024

Abstract58)   HTML    PDF      

Background

Acute gouty arthritis (AGA) is an inflammatory joint disease with a high prevalence. Typical medical interventions, including nonsteroidal anti-inflammatory drugs, colchicine and glucocorticoids, can have serious adverse reactions. Huzhang Granule (HZG), a compound Chinse herbal medicine, has been used to treat AGA for more than 30 years with satisfactory effects and no significant adverse reactions. However, the efficacy and safety of HZG in AGA patients remains unknown.

Objective

The present investigation was designed to examine the efficacy and safety profile of HZG in managing AGA patients.

Design, setting, participants and interventions

The current study was conducted as a noninferiority, randomized controlled clinical trial on 180 eligible enrolled participants. Participants were randomly assigned into the HZG and etoricoxib groups. Treatments were administered for 5 d, during which the HZG group received HZG and placebo etoricoxib, while the etoricoxib group received etoricoxib and placebo HZG in the same ratio (1:1).

Main outcome measures

The primary outcome was pain experienced by the patient in the gout-afflicted joint from days 2 to 5 of the treatment window. The pain level was measured via a visual analogue scale, ranging from 0 mm to 100 mm. The secondary outcomes comprised joint tenderness and swelling, reduction of inflammatory biomarkers, and the patient’s and investigator’s global evaluations of therapeutic response.

Results

The mean reduction in pain was –51.22 mm (95% confidence interval [CI], [–53.42, –49.03] mm) for the HZG and –52.00 mm (95% CI, [–54.06, –49.94] mm) for the etoricoxib groups. The mean difference between the two groups was 0.78 mm (95% CI, [–2.25, 3.81] mm). All additional efficacy endpoints, covering decreased inflammation and pain relief, yielded compelling proof of noninferiority. Patients in the HZG group exhibited a comparatively lower rate of adverse events compared to those in the etoricoxib group (4.44% vs 13.33%; P ≤ 0.05).

Conclusion

HZG and etoricoxib groups demonstrated similar levels of analgesic effectiveness. The safety and efficacy of HZG indicates that it can be used as a potential therapeutic option for treating AGA.

Trial registration

Chinese Clinical Trial Registry (ChiCTR2000036970).


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Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway
Yuan-yuan Ding, Feng Xu, Ya-feng Wang, Lin-lin Han, Shi-qian Huang, Shuai Zhao, Lu-lin Ma, Tian-hao Zhang, Wen-jing Zhao, Xiang-dong Chen
Journal of Integrative Medicine    2023, 21 (5): 496-508.   DOI: 10.1016/j.joim.2023.07.001
Accepted: 28 June 2023
Online available: 05 July 2023

Abstract90)   HTML    PDF      
Objective
This work explores the impact of electroacupuncture (EA) on acute postoperative pain (APP) and the role of stimulator of interferon genes/type-1 interferon (STING/IFN-1) signaling pathway modulation in the analgesic effect of EA in APP rats.

Methods
The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36 (Zusanli) and SP6 (Sanyinjiao) acupoints. Mechanical, thermal and cold sensitivity tests were performed to measure the pain threshold, and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP. Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation. A STING inhibitor (C-176) was administered intrathecally to verify its role in EA.

Results
APP rats displayed mechanical and thermal hypersensitivities compared to the control group (P < 0.05). APP significantly reduced the amplitude of θ, α and γ oscillations compared to their baseline values (P < 0.05). Interestingly, expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP (P < 0.05). Further, APP increased pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α and inducible nitric oxide synthase, and downregulated anti-inflammatory factors, including interleukin-10 and arginase-1 (P < 0.05). EA effectively attenuated APP-induced painful hypersensitivities (P < 0.05) and restored the θ, α and γ power in APP rats (P < 0.05). Meanwhile, EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response (P < 0.05). Furthermore, STING/IFN-1 was predominantly expressed in isolectin-B4- or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn. Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP (P < 0.05).

Conclusion
EA can generate robust analgesic and anti-inflammatory effects on APP, and these effects may be linked to activating the STING/IFN-1 pathway, suggesting that STING/IFN-1 may be a target for relieving APP.
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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

Abstract102)   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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Traditional Chinese medicine treatment for COVID-19: An overview of systematic reviews and meta-analyses
Han-ting Wu, Cong-hua Ji, Rong-chen Dai, Pei-jie Hei, Juan Liang, Xia-qiu Wu, Qiu-shuang Li, Jun-chao Yang, Wei Maob, Qing Guo
Journal of Integrative Medicine    2022, 20 (5): 416-426.   DOI: 10.1016/j.joim.2022.06.006
Accepted: 06 May 2022
Online available: 05 August 2022

Abstract143)   HTML    PDF      
Background: Coronavirus disease 2019 (COVID-19) is a rapidly spreading disease that has caused an extensive burden to the world. Consequently, a large number of clinical trials have examined the efficacy of traditional Chinese medicine (TCM) for treating and preventing COVID-19, with coinciding proliferation of reviews summarizing these studies.
Objective: This study aimed to evaluate the methodological quality and evidence quality of systematic reviews and meta-analyses on the efficacy of TCM.
Search strategy: Seven electronic databases, including PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chongqing VIP, Wanfang Data and SinoMed, were searched for systematic reviews and meta-analyses in October 2021. Search terms such as “Chinese medicine,” “Lianhua Qingwen” and “COVID-19” were used.
Inclusion criteria: Systematic reviews and meta-analyses of randomized controlled trials that evaluated the efficacy of TCM treatment of COVID-19 were included.
Data extraction and analysis: A Measurement Tool to Assess Systematic Reviews Version 2.0 (AMSTAR 2) was used to evaluate the methodological quality. The quality of evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Data extraction and analysis were performed by two reviewers independently.
Results: There were 17 meta-analyses included in our overview. The intervention group was defined as TCM combined with Western medicine, while the control group was Western medicine alone. The methodological quality of all the included studies was moderate to poor. A total of 89 outcome indicators were evaluated, of which, 8 were rated as moderate quality, 39 as low quality, and 41 as very low quality. Only one outcome measure was graded as being of high quality. The moderate quality of evidence indicated that, for the treatment of COVID-19, the clinical efficacy of TCM in combination with Western medicine was better, in terms of lung recovery, rate of conversion to severe/critical cases, symptom scores, duration of symptoms, mortality, and length of hospital stay.
Conclusion: Evidence from the included studies shows that, compared with conventional Western medical therapy alone, the addition of TCM to COVID-19 treatment may improve clinical outcomes. Overall, the quality of evidence of TCM for COVID-19 was moderate to poor. Meta-analyses of the use of TCM in the treatment of COVID-19 can be used for clinical decision making by accounting for the experiences of clinical experts, medical policies, and other factors.
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Liver injury and dietary supplements: Does hydroxycitric acid trigger hepatotoxicity?
AndreaZovi, Roberto Langella, Andrea Nisic, Antonio Vitiello, Umberto M. Musazzi
Journal of Integrative Medicine    2022, 20 (5): 473-475.   DOI: 10.1016/j.joim.2022.05.003
Accepted: 11 May 2022
Online available: 30 May 2022

Abstract141)   HTML    PDF      
Rising rates of obesity has increased the global use of herbal supplements intended to control weight. However, taking these preparations without appropriate medical supervision could increase the risk of manifestation of side effects, especially at the hepatic level. In literature, different cases of acute liver injury consequent to the use of food supplements containing Garcinia cambogia and hydroxycitric acid are reported. This letter aims to review the most recent literature that analysed the herb-induced liver disease due to the use of hydroxycitric acid, from the first alert coming from the European Food and Drug Administration in 2009, to the last recent European food alerts from 2020 to 2021. It is noteworthy that in some cases it demonstrated the relationship between hydroxycitric acid and hepatotoxicity. Therefore, there is a need to draw more attention to the relationship between a safe use and a more awareness in the intake of these supplements, to preserve the safety of the consumers who increasingly purchase food supplements, products that have only nutritive properties and are never curative.
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Fructus Zanthoxyli extract improves glycolipid metabolism disorder of type 2 diabetes mellitus via activation of AMPK/PI3K/Akt pathway: Network pharmacology and experimental validation
Ting Zhang, Qing Zhang, Wei Zheng, Ting Tao, Ruo-lan Li, Li-yu Wang, Wei Peng, Chun-jie Wu
Journal of Integrative Medicine    2022, 20 (6): 543-560.   DOI: 10.1016/j.joim.2022.07.004
Accepted: 13 May 2022
Online available: 05 August 2022

Abstract162)   HTML    PDF      
Objective: This study investigated the potential mechanisms behind the beneficial effects of Fructus Zanthoxyli (FZ) against type 2 diabetes mellitus (T2DM) based on network pharmacology and experimental validation.
Methods: Ultra-high-performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry, and gas chromatography-mass spectrometry were used to identify the constituents of FZ. Next, the differentially expressed genes linked to the treatment of diabetes with FZ were screened using online databases (including Gene Expression Omnibus database and Swiss Target Prediction online database), and the overlapping genes and their enrichment were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, the pathway was verified by in vitro experiments, and cell staining with oil red and Nile red showed that the extract of FZ had a therapeutic effect on T2DM.
Results: A total of 43 components were identified from FZ, and 39 differentially expressed overlapping genes were screened as the possible targets of FZ in T2DM. The dug component-target network indicated that PPARA, PPARG, PIK3R3, JAK2 and GPR88 might be the core genes targeted by FZ in the treatment of T2DM. Interestingly, the enrichment analysis of KEGG showed that effects of FZ against T2DM were closely correlated with the adenosine monophosphate-activated protein kinase (AMPK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathways. In vitro experiments further confirmed that FZ significantly inhibited palmitic acid-induced lipid formation in HepG2 cells. Moreover, FZ treatment was able to promote the AMPK and PI3K/Akt expressions in HepG2 cells.
Conclusion: Network pharmacology combined with experimental validation revealed that FZ extract can improve the glycolipid metabolism disorder of T2DM via activation of the AMPK/PI3K/Akt pathway.
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Potential medicinal plants involved in inhibiting 3CLpro activity: A practical alternate approach to combating COVID-19
Fan Yang, Xiao-lan Jiang, Akash Tariq, Sehrish Sadia, Zeeshan Ahmed, Jordi Sardans, Muhammad Aleem, Riaz Ullah, Rainer W. Bussmann
Journal of Integrative Medicine    2022, 20 (6): 488-496.   DOI: 10.1016/j.joim.2022.08.001
Accepted: 29 June 2022
Online available: 09 August 2022

Abstract101)   HTML    PDF      
At present, a variety of vaccines have been approved, and existing antiviral drugs are being tested to find an effective treatment for coronavirus disease 2019 (COVID-19). However, no standardized treatment has yet been approved by the World Health Organization. The virally encoded chymotrypsin-like protease (3CLpro) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which facilitates the replication of SARS-CoV in the host cells, is one potential pharmacological target for the development of anti-SARS drugs. Online search engines, such as Web of Science, Google Scholar, Scopus and PubMed, were used to retrieve data on the traditional uses of medicinal plants and their inhibitory effects against the SARS-CoV 3CLpro. Various pure compounds, including polyphenols, terpenoids, chalcones, alkaloids, biflavonoids, flavanones, anthraquinones and glycosides, have shown potent inhibition of SARS-CoV-2 3CLpro activity with 50% inhibitory concentration (IC50) values ranging from 2–44 μg/mL. Interestingly, most of these active compounds, including xanthoangelol E (isolated from Angelica keiskei), dieckol 1 (isolated from Ecklonia cava), amentoflavone (isolated from Torreya nucifera), celastrol, pristimerin, tingenone and iguesterin (isolated from Tripterygium regelii), tannic acid (isolated from Camellia sinensis), and theaflavin-3,3'-digallate, 3-isotheaflavin-3 gallate and dihydrotanshinone I (isolated from Salvia miltiorrhiza), had IC50 values of less than 15 μg/mL. Kinetic mechanistic studies of several active compounds revealed that their mode of inhibition was dose-dependent and competitive, with Ki values ranging from 2.4–43.8 μmol/L. Given the significance of plant-based compounds and the many promising results obtained, there is still need to explore the phytochemical and mechanistic potentials of plants and their products. These medicinal plants could serve as an effective inexpensive nutraceutical for the general public to help manage COVID-19.
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Pharmacological action of quercetin against testicular dysfunction: A mini review
Damilare E. Rotimi, Tomilola D. Olaolu, Oluyomi S. Adeyemi
Journal of Integrative Medicine    2022, 20 (5): 396-401.   DOI: 10.1016/j.joim.2022.07.001
Accepted: 10 May 2022
Online available: 05 August 2022

Abstract104)   HTML    PDF      
The testis is an immune-privileged organ susceptible to oxidative stress and inflammation, two major factors implicated in male infertility. A reduction in the concentration and activities of testicular function biomarkers has been shown to correlate with impaired hypothalamic-pituitary-testicular axis and oxidative stress. However, the use of natural products to ameliorate these oxidative stress-induced changes may be essential to improving male reproductive function. Quercetin possesses several pharmacological activities that may help to combat cellular reproduction-related assaults, such as altered sperm function and reproductive hormone dysfunction, and dysregulated testicular apoptosis, oxidative stress, and inflammation. Studies have shown that quercetin ameliorates testicular toxicity, largely by inhibiting the generation of reactive oxygen species, with the aid of the two antioxidant pharmacophores present in its ring structure. The radical-scavenging property of quercetin may alter signal transduction of oxidative stress-induced apoptosis, prevent inflammation, and increase sperm quality in relation to the hormonal concentration. In this review, the therapeutic potential of quercetin in mediating male reproductive health is discussed.
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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

Abstract108)   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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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

Abstract76)   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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Laser acupuncture combined with auricular acupressure improves low-back pain and quality of life in nurses: A randomized controlled trial
Hsueh-Hua Yang, Yu-Chu Chung, Pai-Pei Szeto, Mei-Ling Yeh, Jaung-Geng Lin
Journal of Integrative Medicine    2023, 21 (1): 26-33.   DOI: 10.1016/j.joim.2022.10.004
Accepted: 01 July 2022
Online available: 01 March 2023

Abstract117)   HTML    PDF      

Background

Low-back pain (LBP) in nurses is a major health concern that affects their quality of life and ability to work, with consequences for their economic status.

Objective

This study evaluates the effect of low-level laser acupuncture combined with auricular acupressure (LAA) on pain intensity, pain interference and quality of life in nurses with LBP.

Design, setting, participants and interventions

This randomized controlled trial recruited a convenience sample of hospital-based nurses from one teaching hospital in Taiwan, China. Participants were randomly assigned to the LAA group (n = 38) receiving low-level laser acupuncture and auricular acupressure for 4 weeks, and the control group (n = 38) receiving only sham laser acupuncture treatment without laser energy output.

Main outcome measures

Data were collected for the primary pain outcome using the Short Form of the Brief Pain Inventory, while the secondary outcome, quality of life, was evaluated using the Roland-Morris Disability Questionnaire. Both primary and secondary outcomes were scored before the intervention, and after 2-week and 4-week intervention. The rate of LBP recurrence was evaluated at the 4th week and 8th week after the end of intervention.

Results

After controlling for prior pain, the result of linear mixed model analysis showed trends in significant between-group differences in the level of current pain occurring in week 4 (P < 0.001), worst pain in week 2 (P < 0.001) and week 4 (P < 0.001), least pain in week 2 (P = 0.032) and week 4 (P < 0.001), pain interference in week 2 (P = 0.009) and week 4 (P < 0.001), and in the life dysfunction in week 2 (P < 0.001) and week 4 (P < 0.001). Recurrence rates of LBP at the 4th and 8th weeks after the end of intervention were 0% and 36.89% in the LAA group, and 69.44% and 36.11% in the control group.

Conclusion

This study shows that 4-week LAA intervention reduced pain intensity and pain interference, and improved quality of life for hospital-based nurses with LBP. These effects were maintained continuously for at least 4 weeks after the intervention. The nonpharmacological intervention, LAA, may be another efficacious, feasible, noninvasive, analgesic intervention for LBP.

Trial registration

This study is registered at Clinicaltrials.gov (registration number NCT04423445).

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COVID-19: Reducing the risk via diet and lifestyle
Jessica L. Campbell
Journal of Integrative Medicine    2023, 21 (1): 1-16.   DOI: 10.1016/j.joim.2022.10.001
Accepted: 08 March 2022
Online available: 15 July 2022

Abstract82)   HTML    PDF      
This review shows that relatively simple changes to diet and lifestyle can significantly, and rapidly, reduce the risks associated with coronavirus disease 2019 (COVID-19) in terms of infection risk, severity of disease, and even disease-related mortality. A wide range of interventions including regular exercise, adequate sleep, plant-based diets, maintenance of healthy weight, dietary supplementation, and time in nature have each been shown to have beneficial effects for supporting more positive health outcomes with COVID-19, in addition to promoting better overall health. This paper brings together literature from these areas and presents the argument that non-pharmaceutical approaches should not be overlooked in our response to COVID-19. It is noted that, in several cases, interventions discussed result in risk reductions equivalent to, or even greater than, those associated with currently available vaccines. Where the balance of evidence suggests benefits, and the risk is minimal to none, it is suggested that communicating the power of individual actions to the public becomes morally imperative. Further, many lives could be saved, and many harms from the vaccine mandates avoided, if we were willing to embrace this lifestyle-centred approach in our efforts to deal with COVID-19.
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Physical exercise suppresses hepatocellular carcinoma progression by alleviating hypoxia and attenuating cancer stemness through the Akt/GSK-3β/β-catenin pathway
Chu-lan Xiao, Zhi-peng Zhong, Can Lü, Bing-jie Guo, Jiao-jiao Chen, Tong Zhao, Zi-fei Yin, Bai Li
Journal of Integrative Medicine    2023, 21 (2): 184-193.   DOI: 10.1016/j.joim.2023.01.002
Accepted: 27 October 2022
Online available: 20 January 2023

Abstract129)   HTML    PDF      
Objective:
Physical exercise, a common non-drug intervention, is an important strategy in cancer treatment, including hepatocellular carcinoma (HCC). However, the mechanism remains largely unknown. Due to the importance of hypoxia and cancer stemness in the development of HCC, the present study investigated whether the anti-HCC effect of physical exercise is related to its suppression on hypoxia and cancer stemness.

Methods:
A physical exercise intervention of swimming (30 min/d, 5 d/week, for 4 weeks) was administered to BALB/c nude mice bearing subcutaneous human HCC tumor. The anti-HCC effect of swimming was assessed in vivo by tumor weight monitoring, hematoxylin and eosin (HE) staining, and immunohistochemistry (IHC) detection of proliferating cell nuclear antigen (PCNA) and Ki67. The expression of stemness transcription factors, including Nanog homeobox (NANOG), octamer-binding transcription factor 4 (OCT-4), v-Myc avian myelocytomatosis viral oncogene homolog (C-MYC) and hypoxia-inducible factor-1α (HIF-1α), was detected using real-time reverse transcription polymerase chain reaction. A hypoxia probe was used to explore the intratumoral hypoxia status. Western blot was used to detect the expression of HIF-1α and proteins related to protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling pathway. The IHC analysis of platelet endothelial cell adhesion molecule-1 (CD31), and the immunofluorescence co-location of CD31 and desmin were used to analyze tumor blood perfusion. SMMC-7721 cells were treated with nude mice serum. The inhibition effect on cancer stemness in vitro was detected using suspension sphere experiments and the expression of stemness transcription factors. The hypoxia status was inferred by measuring the protein and mRNA levels of HIF-1α. Further, the expression of proteins related to Akt/GSK-3β/β-catenin signaling pathway was detected.

Results:
Swimming significantly reduced the body weight and tumor weight in nude mice bearing HCC tumor. HE staining and IHC results showed a lower necrotic area ratio as well as fewer PCNA or Ki67 positive cells in mice receiving the swimming intervention. Swimming potently alleviated the intratumoral hypoxia, attenuated the cancer stemness, and inhibited the Akt/GSK-3β/β-catenin signaling pathway. Additionally, the desmin+/CD31+ ratio, rather than the number of CD31+ vessels, was significantly increased in swimming-treated mice. In vitro experiments showed that treating cells with the serum from the swimming intervention mice significantly reduced the formation of SMMC-7721 cell suspension sphere, as well as the mRNA expression level of stemness transcription factors. Consistent with the in vivo results, HIF-1α and Akt/GSK-3β/β-catenin signaling pathway were also inhibited in cells treated with serum from swimming group.

Conclusion:
Swimming alleviated hypoxia and attenuated cancer stemness in HCC, through suppression of the Akt/GSK-3β/β-catenin signaling pathway. The alleviation of intratumoral hypoxia was related to the increase in blood perfusion in the tumor.
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Ethanol extract of Herpetospermum caudigerum Wall ameliorates psoriasis-like skin inflammation and promotes degradation of keratinocyte-derived ICAM-1 and CXCL9
Ya Zhong, Bo-wen Zhang, Jin-tao Li, Xin Zeng, Jun-xia Pei, Ya-mei Zhang, Yi-xi Yang, Fu-lun Li, Yu Deng, Qi Zhao
Journal of Integrative Medicine    2023, 21 (6): 584-592.   DOI: 10.1016/j.joim.2023.11.004
Accepted: 25 October 2023
Online available: 11 November 2023

Abstract50)   HTML    PDF      
Objective
To explore whether the ethanol extract of Herpetospermum caudigerum Wall (EHC), a Xizang medicinal plant traditionally used for treating liver diseases, can improve imiquimod-induced psoriasis-like skin inflammation.

Methods
Immunohistochemistry and immunofluorescence staining were used to determine the effects of topical EHC use in vivo on the skin pathology of imiquimod-induced psoriasis in mice. The protein levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-17A (IL-17A) in mouse skin samples were examined using immunohistochemical staining. In vitro, IFN-γ-induced HaCaT cells with or without EHC treatment were used to evaluate the expression of keratinocyte-derived intercellular cell adhesion molecule-1 (ICAM-1) and chemokine CXC ligand 9 (CXCL9) using Western blotting and reverse transcription-quantitative polymerase chain reaction. The protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132 were utilized to validate the EHC-mediated mechanism underlying degradation of ICAM-1 and CXCL9.

Results
EHC improved inflammation in the imiquimod-induced psoriasis mouse model and reduced the levels of IFN-γ, TNF-α, and IL-17A in psoriatic lesions. Treatment with EHC also suppressed ICAM-1 and CXCL9 in epidermal keratinocytes. Further mechanistic studies revealed that EHC suppressed keratinocyte-derived ICAM-1 and CXCL9 by promoting ubiquitin–proteasome-mediated protein degradation rather than transcriptional repression. Seven primary compounds including ehletianol C, dehydrodiconiferyl alcohol, herpetrione, herpetin, herpetotriol, herpetetrone and herpetetrol were identified from the EHC using ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry.

Conclusion
Topical application of EHC ameliorates psoriasis-like skin symptoms and improves the inflammation at the lesion sites.
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Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells
Jia-jia Liu, Xue Zhang, Bang-lan Cai, Man-man Qi, Yong-bin Chi, Bin Peng, Deng-hai Zhang
Journal of Integrative Medicine    2024, 22 (3): 286-294.   DOI: 10.1016/j.joim.2024.03.007
Accepted: 27 November 2023
Online available: 16 March 2024

Abstract45)   HTML    PDF      
Objective
Research has shown that celastrol can effectively treat a variety of diseases, yet when passing a certain dosage threshold, celastrol becomes toxic, causing complications such as liver and kidney damage and erythrocytopenia, among others. With this dichotomy in mind, it is extremely important to find ways to preserve celastrol’s efficacy while reducing or preventing its toxicity.

Methods
In this study, insulin-resistant HepG2 (IR-HepG2) cells were prepared using palmitic acid and used for in vitro experiments. IR-HepG2 cells were treated with celastrol alone or in combination with N-acetylcysteine (NAC) or ferrostatin-1 (Fer-1) for 12, 24 or 48 h, at a range of doses. Cell counting kit-8 assay, Western blotting, quantitative reverse transcription-polymerase chain reaction, glucose consumption assessment, and flow cytometry were performed to measure celastrol’s cytotoxicity and whether the cell death was linked to ferroptosis.

Results
Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-HepG2 cells. Celastrol downregulated glutathione peroxidase 4 (GPX4) mRNA. Molecular docking models predicted that solute carrier family 7 member 11 (SLC7A11) and GPX4 were covalently bound by celastrol. Importantly, we found for the first time that the application of ferroptosis inhibitors (especially NAC) was able to reduce celastrol’s toxicity while preserving its ability to improve insulin sensitivity in IR-HepG2 cells.

Conclusion
One potential mechanism of celastrol’s cytotoxicity is the induction of ferroptosis, which can be alleviated by treatment with ferroptosis inhibitors. These findings provide a new strategy to block celastrol’s toxicity while preserving its therapeutic effects.
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Similarities and differences between kaiy in Persian medicine and moxibustion in Chinese medicine
Amir Mohammad Jaladat, Mahdi Alizadeh Vaghasloo, Fatemeh Atarzadeh, Mohammad Hossein Ayati, Amir Human Kazemi, Emine Akin, Mohammad Hashem Hashempur
Journal of Integrative Medicine    2023, 21 (4): 354-360.   DOI: 10.1016/j.joim.2023.05.002
Accepted: 26 December 2022
Online available: 10 May 2023

Abstract101)   HTML    PDF      
Kaiy (medieval cautery) is an ancient method of heat therapy in traditional Persian medicine (TPM). Some of its important applications have been neglected during the medical revolution. Meanwhile, different treatment modalities that incorporate heat, including moxibustion, have progressed in traditional Chinese medicine. In this study, we reviewed the main TPM textbooks that were written specifically in the field of kaiy. We consider the traditional teachings in the context of contemporary information gathered from the scientific literature about moxibustion and modern cauterization. Some surgical therapeutic indications of kaiy (e.g., debridement and coagulative procedures) have been advanced by the innovation of electro-cauterization, but those therapeutic applications that were based on the TPM humoral theory for relieving body coldness or myofascial pains—which are similar to moxibustion usages—have not received the same attention. Apart from the broad similarities of kaiy and moxibustion as thermal therapies with similar indications, there is a striking correspondence between kaiy point mapping and acupoints. Therefore, further research on different kaiy aspects is recommended.

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Chrononutrition in traditional European medicine—ideal meal timing for cardiometabolic health promotion
Nora Selena Eberli, Ludivine Colas, Anne Gimalac
Journal of Integrative Medicine    2024, 22 (2): 115-125.   DOI: 10.1016/j.joim.2024.02.002
Accepted: 01 February 2024
Online available: 01 March 2024

Abstract33)           
Meal timing plays a crucial role for cardiometabolic health, given the circadian regulation of cardiometabolic function. However, to the best of our knowledge, no concept of meal timing exists in traditional European medicine (TEM). Therefore, in this narrative review, we aim to define the optimal time slot for energy intake and optimal energy distribution throughout the day in a context of TEM and explore further implications. By reviewing literature published between 2002 and 2022, we found that optimal timing for energy intake may be between 06:00 and 09:00, 12:00 and 14:00, and between 15:00 and 18:00, with high energy breakfast, medium energy lunch and low energy dinner and possibly further adjustments according to one’s chronotype and genetics. Also, timing and distribution of energy intake may serve as a novel therapeutic strategy to optimize coction, a concept describing digestion and metabolism in TEM.
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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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