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Analgesic and anti-inflammatory properties of hydroalcoholic extracts of Malva sylvestris, Carum carvi or Medicago sativa, and their combination in a rat model
Masoud Seddighfar, Sayid Mahdi Mirghazanfari, Masoumeh Dadpay
Journal of Integrative Medicine    2020, 18 (2): 181-188.   DOI: 10.1016/j.joim.2020.02.003
Online available: 07 February 2020

Abstract222)   HTML    PDF      
Objective
The aim of this study was to evaluate the analgesic and anti-inflammatory effects of the hydroalcoholic extracts of Malva sylvestris flowers or Carum carvi and Medicago sativa seeds, alone and in combination, which have been used in traditional Iranian medicine.

Methods
Male Wistar rats were divided into 6 treatment groups: distilled water, sodium salicylate (SS), M. sylvestris extract (600 mg/kg), C. carvi extract (600 mg/kg), M. sativa extract (300 mg/kg) and combined extract (including 300 mg/kg M. sylvestris and C. carvi extracts, and 150 mg/kg M. sativa extract). The formalin pain model was used to evaluate the antinociceptive effects of the treatments. For anti-inflammatory effect, acute (one hour after injection) and chronic (during a week after injection) paw inflammation was measured after subcutaneous injection of 2.5% formalin in the hindpaw. Finally, tissue samples from all groups were prepared for histopathological studies.

Results
The combined extract significantly inhibited the nociception in the acute phase of the formalin test (P < 0.001). In the chronic phase, all the extracts and SS had significant analgesic effect (P < 0.001). Analgesic activity of the combined extract was significantly stronger than SS (P < 0.01). In the acute inflammation model, M. sylvestris, C. carvi and the combined drug had significant inhibitory effects against paw edema (P < 0.05). All extracts, individually and in combination, significantly alleviated chronic paw inflammation (P < 0.01). The combined extract had much more anti-inflammatory activity than SS (P < 0.05). Histopathological results indicated improvement and reduction of inflammatory factors in the treatment groups.

Conclusion
M. sylvestris, C. carvi and M. sativa have analgesic and anti-inflammatory properties. Potentially, each of these extracts or a mixture of them might be a valuable alternative drug to control pain and inflammation.
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Traditional Chinese medicine is a resource for drug discovery against 2019 novel coronavirus (SARS-CoV-2)
Chang-quan Ling
Journal of Integrative Medicine    2020, 18 (2): 87-88.   DOI: 10.1016/j.joim.2020.02.004
Accepted: 13 February 2020
Online available: 14 February 2020

Abstract1417)   HTML    PDF      
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In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus
Deng-hai Zhang, Kun-lun Wu, Xue Zhang, Sheng-qiong Deng, Bin Peng
Journal of Integrative Medicine    2020, 18 (2): 152-158.   DOI: 10.1016/j.joim.2020.02.005
Accepted: 13 February 2020
Online available: 14 February 2020

Abstract850)   HTML    PDF      

Objective:

In this study we execute a rational screen to identify Chinese medical herbs that are commonly used in treating viral respiratory infections and also contain compounds that might directly inhibit 2019 novel coronavirus (2019-nCoV), an ongoing novel coronavirus that causes pneumonia.

Methods

There were two main steps in the screening process. In the first step we conducted a literature search for natural compounds that had been biologically confirmed as against sever acute respiratory syndrome coronavirus or Middle East respiratory syndrome coronavirus. Resulting compounds were cross-checked for listing in the Traditional Chinese Medicine Systems Pharmacology Database. Compounds meeting both requirements were subjected to absorption, distribution, metabolism and excretion (ADME) evaluation to verify that oral administration would be effective. Next, a docking analysis was used to test whether the compound had the potential for direct 2019-nCoV interaction. In the second step we searched Chinese herbal databases to identify treatments containing the selected compounds. Plants containing 2 or more of the compounds identified in our screen were then checked against the catalogue for classic herbal usage. Finally, network pharmacology analysis was used to predict the general in vivo effects of each selected herb.

Results

Of the natural compounds screened, 13 that exist in traditional Chinese medicines were also found to have potential anti-2019-nCoV activity. Further, 125 Chinese herbs were found to contain 2 or more of these 13 compounds. Of these 125 herbs, 26 are classically catalogued as treating viral respiratory infections. Network pharmacology analysis predicted that the general in vivo roles of these 26 treatments were related to regulating viral infection, immune/inflammation reactions and hypoxia response.

Conclusion

Chinese herbal treatments classically used for treating viral respiratory infection might contain direct anti-2019-nCoV compounds.

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Active constituents and mechanisms of Respiratory Detox Shot, a traditional Chinese medicine prescription, for COVID-19 control and prevention: network-molecular docking-LC-MSE analysis
Zi-jia Zhang, Wen-yong Wu, Jin-jun Hou, Lin-lin Zhang, Fei-fei Li, Lei Gao, Xing-dong Wu, Jing-ying Shi, Rong Zhang, Hua-li Long, Min Lei, Wan-ying Wu, De-an Guo, Kai-xian Chen, Lewis A. Hofmann, Zhonghua Ci
Journal of Integrative Medicine    2020, 18 (3): 229-241.   DOI: 10.1016/j.joim.2020.03.004
Accepted: 17 March 2020
Online available: 20 March 2020

Abstract836)   HTML    PDF      

Objective 

The Lung-toxin Dispelling Formula No.1 (referred to as Respiratory Detox Shot, RDS) was established based on the theory of traditional Chinese medicine (TCM) medicinal properties and the classical prescription of TCM. It has demonstrated therapeutic benefits in both disease control and prevention in the effort to contain corona virus disease 2019 (COVID-19). However, the material basis and action mechanism of RDS are still unclear. The goal of the study is to clarify the material foundation and action mechanism of RDS.

Methods 

To achieve in-depth analyses of RDS from a holistic perspective, an integrative analytical platform was constructed, including target prediction, protein-protein interaction (PPI) network, cluster analysis, and the hub genes involved in the disease pathways were identified, and their corresponding compounds were further applied to molecular docking for in vitro biological validation. The presence of the validated compounds was also measured to demonstrate the material basis of RDS. In our network pharmacology study, a total of 26 bioinformatic software and databases were accessed, and 6 networks covering the entire Zang-fu viscera were constructed to achieve comprehensive analysis and visualization of the intricate connections among the compounds-targets-disease pathway-meridians of RDS.

Results 

For all 1071 compounds of 9 ingredients of RDS from established TCM databases, 157 compounds passed drug-likeness screening and led to 339 predicted targets in the compound-target network. 42 hub genes with core regulatory effects were extracted from the PPI network, and 134 compounds and 29 crucial disease pathways were implicated in the target-compound-disease network. Twelve disease pathways attributed to Lung-Large intestine meridian, with 6 and 5 to Kidney-Urinary bladder and Stomach-Spleen meridians, respectively. 118 candidate compounds showed a high binding affinity with SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) by molecular docking using computational pattern recognition. The in vitro activity of 22 compounds was validated by the 3CLpro inhibition assay. Finally, using the technique of liquid chromatography mass spectrometry in data-independent analysis mode, 7 out of 22 compounds were confirmed and validated in RDS aqueous decoction with reference standards in both non-targeted and targeted approaches.

Conclusion 

Our results unveiled that RDS acts primarily in the Lung-Large intestine, Kidney-Urinary bladder, and Stomach-Spleen meridians, with other Zang-fu viscera strategically covered by all 9 ingredients. Integrated with the context of TCM meridian theory, multiple components and targets of RDS demonstrate the action dual effects of health-strengthening and pathogen-eliminating in one prescription to achieve systemic therapeutic effects for early COVID-19 control and prevention.

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Traditional chinese medicine targeting cancer stem cells as an alternative treatment for hepatocellular carcinoma
Kai-yue Tang, Shi-lin Du, Qian-lei Wang, Yi-fan Zhang, Hai-yan Song
Journal of Integrative Medicine    2020, 18 (3): 196-202.   DOI: 10.1016/j.joim.2020.02.002
Online available: 11 February 2020

Abstract280)   HTML    PDF      
Hepatocellular carcinoma (HCC) is a prevalent and highly malignant cancer throughout the world. Effective treatment of this disease is impeded by the high rate of metastasis, recurrence, and chemoresistance. Recent studies have revealed the close relationship between the malignant phenotype of HCC and cancer stem cells (CSCs). Therefore, CSC-targeted therapy is considered a promising strategy to eradicate HCC. Traditional Chinese medicine (TCM) can be effective in preventing recurrence and metastasis of some advanced HCC. A growing amount of literature has discovered that extracts or compounds derived from TCM exert an anti-CSC effect. This review introduces some formulas and chemical compounds derived from TCMs that have been reported to inhibit CSCs of HCC; these TCM-related drugs may help to provide an alternative approach to help manage cancers, especially for HCC which has a great potential of metastasis, recurrence, and chemoresistance.
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Evaluation of antioxidant capacity and reproductive toxicity of aqueous extract of Thai Mucuna pruriens seeds
Sitthichai Iamsaard, Supatcharee Arun, Jaturon Burawat, Supataechasit Yannasithinon, Saranya Tongpan, Sudtida Bunsueb, Natthapol Lapyuneyong, Pannawat Choowong-in, Nareelak Tangsrisakda, Chadaporn Chaimontri, Wannisa Sukhorum
Journal of Integrative Medicine    2020, 18 (3): 265-273.   DOI: 10.1016/j.joim.2020.03.003
Accepted: 04 February 2020
Online available: 23 March 2020

Abstract162)   HTML    PDF      
Objective
In traditional medicine, the seeds of Thai Mucuna pruriens (T-MP) are used to treat male dysuria and are believed to enhance fertility. However, information pertaining to the toxicity of T-MP and its interaction with other properties is limited. This study was thus conducted to evaluate the antioxidant capacity and subacute toxicity of T-MP in the reproductive system.

Methods
Total phenolic content and antioxidant capacity of T-MP seed extract were determined using total phenolic content, 2,2-diphenyl-1-picrylhydrazyl and ferric reducing antioxidant power assays. Male and female adult rats were treated orally with T-MP at a dosage of 150 or 300 mg/kg body weight for 14 consecutive days. Sex hormones and functional parameters in the liver and kidney were evaluated. Histopathology of all tissue was conducted using Masson’s trichrome staining. Sperm parameters, including concentration, morphology, acrosome reaction status and DNA damage, were also examined. Expression of tyrosine phosphorylated protein (TyrPho), androgen receptor and A-kinase-anchoring protein 4 (AKAP4) were investigated using the Western blot technique.

Results
T-MP seed extract contained phenolic compounds and exhibited high antioxidant capacity with no toxicity at the tested doses. It did not affect liver or kidney function parameters in the male rats, but increased estradiol, aspartate aminotransferase and alanine aminotransferase levels in the females. Additionally, it decreased serum progesterone and alkaline phosphatase levels in female rats. Serum and intratesticular testosterone levels were significantly lower in male rats that received a high dosage of T-MP. Histopathological changes were not observed in any tissue treated with T-MP. T-MP also significantly increased sperm concentration (but did not affect sperm parameters), and enhanced testicular TyrPho protein and androgen receptor and expression of AKAP4 in sperms.

Conclusion
T-MP seed extract exhibited antioxidant capacity and was not harmful to reproductive tissues. It also had a phytoestrogenic effect on females and increased the expression of testicular and sperm markers of male fertility.
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Diagnosis and treatment of novel coronavirus infectious pneumonia based on the theory of traditional Chinese medicine
Shi-xin Wang, Yan Wang, Yu-bao Lu, Jie-yun Li, Yu-jun Song, Munkhtuya Nyamgerelt, Xue-xi Wang
Journal of Integrative Medicine    2020, 18 (4): 275-283.   DOI: 10.1016/j.joim.2020.04.001
Accepted: 20 March 2020
Online available: 20 March 2020

Abstract641)   HTML    PDF      
Since the outbreak of coronavirus disease-19 (COVID-19) in Wuhan in December 2019, it has rapidly spread to the whole country and the world, causing serious harm to the health of people and a huge social burden. However, currently, there are no clinically available drugs, except for vaccines against COVID-19 that are being evaluated. Traditional Chinese medicine (TCM) is capable of performing syndrome differentiation and treatment according to the clinical manifestations of patients, and has a better ability of epidemic prevention and control. Therefore, we comprehensively analyzed the etiology and pathogenesis of COVID-19 based on the theory of TCM, and discussed its syndrome differentiation, treatment, and prevention measures to provide strategies and reference for the prevention and treatment of COVID-19 with TCM.
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Women's preconception health patterns in traditional Chinese medicine as a predictor of fertility outcomes
Xia-qiu Wu, Wendy Satmary, Jin Peng, Ka-kit Hui
Journal of Integrative Medicine    2020, 18 (3): 222-228.   DOI: 10.1016/j.joim.2020.01.006
Online available: 26 January 2020

Abstract130)   HTML    PDF      
Objective
To examine the association between traditional Chinese medicine (TCM), preconception health patterns and fertility outcomes.

Methods
A community-based prospective cohort study was conducted in China. A total of 3012 newly married women who were willing to conceive within 2 years were enrolled in the study and took National Free Prepregnancy Checkups (NFPC). A reliably structured self-rating scale was used to measure the TCM preconception health patterns of the enrolled women. A 3-year follow-up was conducted to obtain the fertility outcomes, including pregnancy rate, time to pregnancy, spontaneous miscarriage and newborn status. Statistical analyses were conducted using Chi-square or Fisher’s exact tests, logistic regression models, general linear models and the Cox proportional hazard model.

Results
The fertility outcomes showed no statistic correlations to the terms of NFPC in this population. Approximately a half of the women (46.66%) had unhealthy patterns. Women with qi & blood-deficiency (odds ratio [OR] = 35.19, 95% confidence interval [CI] = 1.55–801.15) or qi-stagnation (OR = 4.55, 95% CI = 0.90–23.06) pattern took a longer time to get pregnant, and those with qi-stagnation (OR = 2.05, 95% CI = 1.1–3.82) or yang-deficiency (OR = 1.91, 95% CI = 1.12–3.25) pattern had a higher risk of spontaneous miscarriage.

Conclusion
Three unhealthy TCM patterns during the preconception period might be risk factors for low fecundity or poor pregnancy outcomes. The TCM preconception pattern identification may provide a convenient and effective way to screen for potential pregnancy risks beyond the NFPC. Further, appropriate interventions based on the TCM preconception health patterns are needed to improve quality in women’s fecundability and birth outcomes.

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Letter to the editor regarding "Galen's place in Avicenna's The Canon of Medicine: Respect, confirmation and criticism"
Mostafa Araj-Khodaei, Javad Ghazi Sha'rbaf, Somaiyeh Taheri-Targhi, Reza Mohammadinasab
Journal of Integrative Medicine    2020, 18 (3): 274-274.   DOI: 10.1016/j.joim.2020.03.002
Accepted: 18 March 2020
Online available: 19 March 2020

Abstract145)   HTML    PDF      
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Modified Zhibai Dihuang pill, a traditional Chinese medicine formula, on steroid withdrawal in systemic lupus erythematosus: A systematic review and meta-analysis
Liang Dai, Ka Kei Chan, Jian-chun Mao, Yu Tian, Jun-hua Gu, Jun Zhou, Linda L.D. Zhong
Journal of Integrative Medicine    2020, 18 (6): 478-491.   DOI: 10.1016/j.joim.2020.08.007
Accepted: 04 August 2020
Online available: 26 August 2020

Abstract189)   HTML    PDF      
Background
Zhibai Dihuang pill (ZBDH), a Chinese herbal formula, has been widely used as an adjunctive therapy to help reduce a patient's steroid dose while maintaining low disease activity in systemic lupus erythematosus (SLE).

Objective
This systematic review evaluates the therapeutic effect of modified ZBDH in reducing steroid use in patients with SLE.

Search strategy
A systematic literature search was carried out using seven databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, Chinese VIP Information and Wanfang Database, from their inception to June 1st, 2019. The search terms included “systemic lupus erythematosus,” “Chinese medicine” and “clinical trial,” and their synonyms. Subject headings matching the above terms were also used.

Inclusion criteria
This meta-analysis included randomized controlled trials that evaluated the reduction of steroid dose in patients with SLE. Traditional Chinese medicine (TCM) formulas in experimental group should be prescribed based on ZBDH and used as adjunctive therapy and the comparator should contain steroids.

Data extraction and analysis
Two authors independently conducted database searches, study selection, data extraction and quality assessment. The extracted information contained study design, sample size, recruitment mode, diagnostic criteria, inclusion and exclusion criteria, participant characteristics, TCM patterns, TCM formulas and treatment outcomes. The primary outcome was the change of steroid dose. Secondary outcomes included SLE Disease Activity Index (SLEDAI), biomarkers of disease activity and clinical response rate. STATA 15.0 was used to analyze the pooled effects reported as weighted mean difference (WMD) or odds ratio, with a 95% confidence interval (CI).

Results
In total, 20 trials involving 1470 SLE patients were included. The pooled result showed that modified ZBDH taken in combination with standard care led to a larger reduction in steroid dose, compared to standard care alone (WMD: 3.79; 95% CI: 2.58–5.01; P < 0.001). Favorable outcomes were also seen in secondary outcome criteria, such as SLEDAI and complement 3. The modified ZBDH treatments were well tolerated without increasing adverse effects.

Conclusion
The systematic review provided preliminary evidence supporting the use of ZBDH as a co-therapy to aid steroid dose reduction in patients with SLE. However, more rigorous studies should be conducted to validate these findings, and explore the mechanisms of ZBDH’s relevant bioactive constituents.
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Extract of Naotaifang, a compound Chinese herbal medicine, protects neuron ferroptosis induced by acute cerebral ischemia in rats
Bin Lan, Jin-wen Ge, Shao-wu Cheng, Xi-long Zheng, Jun Liao, Chao He, Zheng-qing Rao, Guo-zuo Wang
Journal of Integrative Medicine    2020, 18 (4): 344-350.   DOI: 10.1016/j.joim.2020.01.008
Online available: 04 February 2020

Abstract218)   HTML    PDF      
Objective
Our previous research showed that Naotaifang (a compound traditional Chinese herbal medicine) extract (NTE) has clinically beneficial effects on neurological improvement of patients with acute cerebral ischemia. In this study, we investigated whether NTE protected acute brain injury in rats and whether its effects on ferroptosis could be linked to the dysfunction of glutathione peroxidase 4 (GPX4) and iron metabolism.

Methods
We established an acute brain injury model of middle cerebral artery occlusion (MCAO) in rats, in which we could observe the accumulation of iron in neurons, as detected by Perl’s staining. Using assay kits, we measured expression levels of ferroptosis biomarkers, such as iron, glutathione (GSH), reactive oxygen species (ROS) and malonaldehyde (MDA); further the expression levels of transferrin receptor 1 (TFR1), divalent metal transporter 1 (DMT1), solute carrier family 7 member 11 (SLC7A11) and GPX4 were determined using immunohistochemical analysis, real-time quantitative polymerase chain reaction and Western blot assays.

Results
We found that treatment with NTE reduced the expression levels of TFR1 and DMT1, reduced ROS, MDA and iron accumulation and reduced neurobehavioral scores, relative to untreated MCAO rats. Treatment with NTE increased the expression levels of SLC7A11, GPX4 and GSH, and the number of Nissl bodies in the MCAO rats.

Conclusion
Taken together, our data suggest that acute cerebral ischemia induces neuronal ferroptosis and the effects of treating MCAO rats with NTE involved inhibition of ferroptosis through the TFR1/DMT1 and SCL7A11/GPX4 pathways.
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Aamar-e-Advia (shelf-lives) of drugs in Unani system of medicine: A conceptual review
Ameena Yasmeen, Ghulamuddin Sofi, Kaleemullah Khan
Journal of Integrative Medicine    2020, 18 (2): 114-124.   DOI: 10.1016/j.joim.2020.01.003
Online available: 16 January 2020

Abstract152)   HTML    PDF      
In an era of globalization and increased global demand for herbal medicines, it is essential to ensure the quality and consistency of drugs. Changes in the quality of an herbal product over time should be detectable. The assessments of chemical quality and therapeutic efficacy of herbal drugs are necessary to establish their shelf-lives. Thus, stability testing is needed to establish standards for herbal products. Unani medicine has its own conceptual framework for studying health and disease. The mode of treatment includes Ilaj bit Tadbeer (regimental therapy), Ilaj bil Ghiza (dietotherapy), Ilaj bil Dawa (pharmacotherapy) and Ilaj bil Yad/Jarahat (surgery) as a final option. Ilaj bil Dawa is the most used mode of treatment. The drugs include either crude drugs prepared from plant, animal and mineral sources, called Mufrad(single) drugs or various formulations prepared from these crude drugs, called Murakkab (compound) drugs. To date, stability studies have been carried out on compound drugs, whereas only a few single drugs had had their stability tested. These studies are needed to understand how the quality of an herbal drug varies over the time when it is prepared and consumed. This may also help to standardize procedures for manufacturing compound formulations ab initio. The present study reviews the concept of Aamar-e-Advia (shelf-lives) described in the literature of the Unani system of medicine. Further, various factors that are considered important to assess the shelf-life of Unani drugs are discussed in the context of contemporary protocols for shelf-life assessment.
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A case-based approach to integrative medicine for cardiovascular disease prevention
Brody Slostad, Tejinder Khalsa, Kathleen Young, Hildalicia Guerra, Anjali Bhagra
Journal of Integrative Medicine    2020, 18 (2): 159-162.   DOI: 10.1016/j.joim.2019.12.001
Online available: 30 December 2019

Abstract76)   HTML    PDF      
Cardiovascular disease is commonly encountered in the adult population and has large impacts on morbidity and mortality. The ever-expanding evidence base for the use of integrative medicine in cardiology necessitates providers caring for patients with cardiovascular disease to be familiar with these therapies. However, providers may find it difficult to adequately discuss these therapies in an average office visit. Through a case-based, question-and-answer approach, the authors review some clinically relevant and helpful research that addresses the incorporation of integrative medicine in cardiovascular disease prevention.
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Phenolic constituents and anticancer properties of Morus alba (white mulberry) leaves
Eric Wei Chiang Chan, Siu Kuin Wong, Joseph Tangah, Tomomi Inoue, Hung Tuck Chan
Journal of Integrative Medicine    2020, 18 (3): 189-195.   DOI: 10.1016/j.joim.2020.02.006
Accepted: 14 January 2020
Online available: 20 February 2020

Abstract194)   HTML    PDF      
Flavonoids are by far the most dominant class of phenolic compounds isolated from Morus alba leaves (MAL). Other classes of compounds are benzofurans, phenolic acids, alkaloids, coumarins, chalcones and stilbenes. Major flavonoids are kuwanons, moracinflavans, moragrols and morkotins. Other major compounds include moracins (benzofurans), caffeoylquinic acids (phenolic acids) and morachalcones (chalcones). Research on the anticancer properties of MAL entailed in vitro and in vivo cytotoxicity of extracts or isolated compounds. Flavonoids, benzofurans, chalcones and alkaloids are classes of compounds from MAL that have been found to be cytotoxic towards human cancer cell lines. Further studies on the phytochemistry and anticancer of MAL are suggested. Sources of information were PubMed, PubMed Central, ScienceDirect, Google, Google Scholar, J-Stage, PubChem and China National Knowledge Infrastructure.
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Traditional Chinese medicine in the treatment of idiopathic pulmonary fibrosis based on syndrome differentiation: Study protocol of exploratory trial
Xue-qing Yu, Shu-guang Yang, Yang Xie, Jian-sheng Li
Journal of Integrative Medicine    2020, 18 (2): 163-168.   DOI: 10.1016/j.joim.2019.12.005
Online available: 27 December 2019

Abstract170)   HTML    PDF      

Background

Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and is often a kind of heavy financial burden to patients. Currently, few treatments are available for IPF. Clinical practice of traditional Chinese medicine (TCM), using a syndrome differentiation approach, offers some treatment success in IPF. However, there is insufficient evidence-based study of the role of TCM in IPF management to make strong conclusions. This study evaluates the efficacy and safety of TCM, using a syndrome differentiation approach, in the treatment of IPF. 


Methods and design

A multicenter, exploratory, randomized, double-blind and placebo-controlled trial is planned. A total of 80 patients will be enrolled in the study, which will include 26 weeks of treatment. Participants will be randomly assigned into TCM group or control group in a 1:1 ratio. The TCM group are designed to be given TCM granules based on syndrome differentiation. Formulae include Bu-Fei Yi-Qi granule for lung qi deficiency, Bu-Fei Yi-Shen granule for lung-kidney qi deficiency and Yang-Yin Qing-Re granule for yin deficiency and inter heat. The control group will be given a corresponding TCM granule placebo. The efficacy and safety of interventions will be evaluated by the outcome variables, including frequencies of acute exacerbations, pulmonary function, clinical symptoms, dyspnea, health-related quality of life (HRQoL), 6-minute walk distance and safety indicators. 


Discussion

It is hypothesized that TCM will decrease the frequency of adverse events, improve pulmonary function and HRQoL, based on our clinical experience. This trial is the first study of TCM treatment in IPF that is based on syndrome differentiation and will evaluate efficacy and safety of TCM in IPF. 


Trial registration

This study was registered on www.Chictr.org.cn: ChiCTR-IIR-17013532. Register date: November 24, 2017.

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Effects of a Plantago ovata-based herbal compound in prevention and treatment of oral mucositis in patients with breast cancer receiving chemotherapy: A double-blind, randomized, controlled crossover trial
Fatemeh Sadat Hasheminas, Seyed Mehdi Hashemi, Azizallah Dehghan, Fariba Sharififar, Mohammad Setayesh, Pegah Sasanpour, Mojtaba Tasbandi, Mahboobeh Raeiszadeh
Journal of Integrative Medicine    2020, 18 (3): 214-221.   DOI: 10.1016/j.joim.2020.02.008
Accepted: 18 January 2020
Online available: 05 March 2020

Abstract196)   HTML    PDF      
Background
Oral mucositis (OM) is one of the most common complications of mucotoxic cancer therapy. Mucositis induces clinically significant pain, increases the risk of infections and affects the patients’ quality of life.

Objective
This study investigated the effects of an herbal preparation from Plantago ovata hydrocolloid in the prevention and treatment of OM, in breast cancer patients undergoing chemotherapy with a regimen including adriamycin.

Design, setting, participants, and interventions
This research was a double-blind, randomized, controlled crossover trial. The herbal compound consisted of a mixture of 500 mg of P. ovate husk in 30 mL water plus three drops of vinegar per dose, which was used as a mouthwash. Phytochemical and physicochemical tests of the compound were also performed. Twenty-eight patients who developed mucositis during the chemotherapy screening cycle were randomized to the herbal compound (n = 14) and placebo (n = 14) groups. They received herbal compound or placebo three times per day during their next chemotherapy cycle (cycle 1 of treatment). Patients were crossed over during cycle 2 of treatment and received the alternative therapy. An oral care protocol was prescribed to all patients in cycles 1 and 2 of the treatment.

Main outcome measures
The patients were visited at baseline, the end of the first and second weeks of the screening cycle, and the end of the first and second weeks of each of two treatment cycles. The degree of mucositis was used as the main treatment outcome. Other indexes, such as the severity of pain, xerostomia grade and the quality of life were also measured.

Results
Compared with the placebo, the herbal compound significantly reduced the degree of mucositis, the severity of pain and the xerostomia grade; it also improved the patients’ quality of life (P < 0.05). Comparison between the screening cycle and placebo treatment group showed that the oral care protocol had a significant effect in the reduction of OM (P < 0.05).

Conclusion
The oral care protocol and the herbal compound based on P. ovata are effective ways for preventing and treating OM in patients undergoing mucotoxic cancer therapy.

Trial registration: Iranian registry of clinical trials IRCT20180923041093N1.
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Caulerpa okamurae extract attenuates inflammatory interaction, regulates glucose metabolism and increases insulin sensitivity in 3T3-L1 adipocytes and RAW 264.7 macrophages
Bikash Manandhar, Hyun Jung Kim, Dong Young Rhyu
Journal of Integrative Medicine    2020, 18 (3): 253-264.   DOI: 10.1016/j.joim.2020.02.001
Accepted: 23 December 2019
Online available: 26 February 2020

Abstract240)   HTML    PDF      

Objective

To examine whether Caulerpa okamurae ethanolic extract (COE) could inhibit obesity-mediated inflammation, improve glucose metabolism and increases insulin sensitivity, using in vitro cell models of RAW 264.7 macrophages and 3T3-L1 adipocytes. 


Methods

We cocultured 3T3-L1 adipocytes in direct contact with lipopolysaccharide-stimulated RAW 264.7 macrophages and induced insulin resistance in 3T3-L1 adipocytes with tumor necrosis factor-α (TNF-α) in the presence or absence of 250 μg/mL of COE. We investigated various markers of inflammation, glucose regulation and insulin sensitivity in these models using Griess reagent to measure nitric oxide (NO) production, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose to measure glucose uptake, Western blot analysis to quantify protein expression and reverse transcriptase-polymerase chain reaction to evaluate mRNA expression.


Results

We found that COE (250 μg/mL) significantly inhibited the lipopolysaccharide-induced inflammatory response in RAW 264.7 macrophages by downregulating NO production, nitric oxide synthase 2 expression and nuclear translocation of nuclear factor-κB. COE also showed similar anti-inflammatory activity in coculture, along with decreased TNF-α, interleukin-6 and monocyte chemoattractant protein mRNA expression. In addition, COE also improved glucose uptake in coculture by upregulating glucose transporter-4 (GLUT-4) and adiponectin and reducing serine phosphorylation of insulin receptor substrate-1 (IRS1). In the TNF-α-induced insulin resistance model of 3T3-L1 adipocytes, COE significantly improved both basal and insulin-stimulated glucose uptake, accompanied by phosphorylation of IRS1 at tyrosine 632, phospho-5' adenosine monophosphate-activated protein kinase α and glycogen synthase kinase-3β (Ser9) as well as upregulation of GLUT-4.


Conclusion

Together, these findings suggest that COE has potential to treat or prevent obesity-induced metabolic disorders.

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Berberine for prevention of dementia associated with diabetes and its comorbidities: A systematic review
Noriko Shinjyo, James Parkinson, Jimmy Bell, Tatsuro Katsuno, Annie Bligh
Journal of Integrative Medicine    2020, 18 (2): 125-151.   DOI: 10.1016/j.joim.2020.01.004
Online available: 17 January 2020

Abstract106)   HTML    PDF      
Background

A growing number of epidemiological studies indicate that metabolic syndrome (MetS) and its associated features play a key role in the development of certain degenerative brain disorders, including Alzheimer’s disease and vascular dementia. Produced by several different medicinal plants, berberine is a bioactive alkaloid with a wide range of pharmacological effects, including antidiabetic effects. However, it is not clear whether berberine could prevent the development of dementia in association with diabetes.


Objective

To give an overview of the therapeutic potential of berberine as a treatment for dementia associated with diabetes.


Search strategy

Database searches A and B were conducted using PubMed and ScienceDirect. In search A, studies on berberine’s antidementia activities were identified using “berberine” and “dementia” as search terms. In search B, recent studies on berberine’s effects on diabetes were surveyed using “berberine” and “diabetes” as search terms.


Inclusion criteria

Clinical and preclinical studies that investigated berberine’s effects associated with MetS and cognitive dysfunction were included.


Data extraction and analysis

Data from studies were extracted by one author, and checked by a second; quality assessments were performed independently by two authors.


Results

In search A, 61 articles were identified, and 22 original research articles were selected. In search B, 458 articles were identified, of which 101 were deemed relevant and selected. Three duplicates were removed, and a total of 120 articles were reviewed for this study. The results demonstrate that berberine exerts beneficial effects directly in the brain: enhancing cholinergic neurotransmission, improving cerebral blood flow, protecting neurons from inflammation, limiting hyperphosphorylation of tau and facilitating β-amyloid peptide clearance. In addition, evidence is growing that berberine is effective against diabetes and associated disorders, such as atherosclerosis, cardiomyopathy, hypertension, hepatic steatosis, diabetic nephropathy, gut dysbiosis, retinopathy and neuropathy, suggesting indirect benefits for the prevention of dementia.


Conclusion
Berberine could impede the development of dementia via multiple mechanisms: preventing brain damages and enhancing cognition directly in the brain, and indirectly through alleviating risk factors such as metabolic dysfunction, and cardiovascular, kidney and liver diseases. This study provided evidence to support the value of berberine in the prevention of dementia associated with MetS.
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Nigerian antimalarial plants and their anticancer potential: A review
Kayode Ezekiel Adewole
Journal of Integrative Medicine    2020, 18 (2): 92-113.   DOI: 10.1016/j.joim.2020.01.001
Online available: 12 January 2020

Abstract114)   HTML    PDF      
Cancer is a leading cause of death globally, while malaria is the leading cause of death from parasitic diseases in Nigeria. Historically, plant remedies have been used to manage both cancer and malaria. Interestingly, the possibility of treating cancer with antimalarial remedies has long been reported, even though the two diseases appear to have little in common. However, a body of research has indicated the potential anticancer activity of both synthetic and nature-derived antimalarials. In Nigeria, over 100 plants are used for the management of malaria, but little is known for their potential role in combatting cancer. Therefore, this review is to highlight the documented anticancer activities of plants used to treat malaria in Nigeria, with the goal of supporting anticancer drug discovery. Scientific databases were used to research antimalarial plants through keyword searches. Of over 100 plants used to treat malaria in Nigeria, 56 have documented anticancer properties, containing alkaloids, flavonoids, tannins, terpenes, terpenoids, quinones, anthraquinones, saponins, steroids, sterols, organo-sulfur compounds and other polyphenols as the major bioactive components. The major mechanisms of anticancer activity include induction of apoptosis and autophagy, arrest of cell growth, generation of reactive oxygen species and inhibition of angiogenesis. However, mechanistic and clinical investigations of the anticancer properties of most of the plants are still lacking. Notwithstanding the huge anticancer potential uncovered by the in vitro or in vivo studies and a few clinical studies, Nigerian antimalarial plants may provide a valuable resource, ready to be harnessed for anticancer drug development.
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Acceptability of an adjunct equine-assisted activities and therapies program for veterans with posttraumatic stress disorder and/or traumatic brain injury
Louisa Sylvia, Emerson West, Allyson M. Blackburn, Carina Gupta, Eric Bui, Tara Mahoney, Geraldine Duncan, Edward C. Wright, Simon Lejeune, Thomas J. Spencer
Journal of Integrative Medicine    2020, 18 (2): 169-173.   DOI: 10.1016/j.joim.2020.01.005
Accepted: 29 August 2019
Online available: 23 January 2020

Abstract75)   HTML    PDF      
Objective
Equine-assisted activities and therapies (EAATs) have been a growing adjunctive integrative health modality, as they allow participants to practice mindfulness, emotional regulation, and self-mastery or self-esteem building skills. Preliminary evidence suggests that these programs may be helpful in reducing posttraumatic stress disorder (PTSD), anxiety, and depressive symptoms. The current study examines the acceptability of integrating an EAAT program as part of a two-week, intensive clinical program for veterans with PTSD and/or traumatic brain injury (TBI).

Methods
A family member or support person could accompany veterans and participate in the program. One hundred and six participants (veteran n = 62, family n = 44) left the urban environment in an intensive outpatient program (IOP) to attend a two-day, weekend EAAT in rural New Hampshire. Satisfaction surveys were conducted on the last day of the program and examined using thematic analysis.

Results
The following themes were reported in the surveys: ability of horses to catalyze emotional rehabilitation, effectiveness of immersion in equine-assisted activities, program’s ability to foster interpersonal relationships and necessity of education about PTSD for staff. Participants also reported enjoying the program as highlighted by qualitative feedback, a mean score of 9.76 (standard deviation [SD] = 0.61) as reported by veterans and a mean score of 9.91 (SD = 0.29) as reported by family members on a 10-point visual analog scale with higher scores indicating a greater overall experience.

Conclusion
These data offer preliminary evidence that an adjunct EAAT program is acceptable for veterans with PTSD and/or TBI participating in an IOP.
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Effects of traditional Chinese exercises on blood glucose and hemoglobin A1c levels in patients with prediabetes: A systematic review and meta-analysis
Dong-dong Yu, Liang-zhen You, Wan-qiu Huang, Hui Cao, Fan-jing Wang, Xiu-qin Tang, Zhao-hui Fang, Guo-ming Shen, Yu-xiang Guan
Journal of Integrative Medicine    2020, 18 (4): 292-302.   DOI: 10.1016/j.joim.2020.04.003
Accepted: 06 January 2020
Online available: 08 June 2020

Abstract88)   HTML    PDF      
Objective
The objective of this study was to systematically investigate the effects of TCEs on blood glucose control in patients with prediabetes.

Search strategy:
Comprehensive retrieval of randomized controlled trials (RCTs) was carried out using PubMed, Cochrane Library, EMbase, China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals, Wanfang Data Knowledge Service Platform, China Biology Medicine disc, Google Scholar and Baidu academic databases. The retrieval window ranged from the establishment of the database to December 2018, and references related to the included trials were searched without language restrictions.

Inclusion criteria:
The study included RCTs with a clinical diagnosis of prediabetes that was also treated with TCEs.

Data extraction and analysis:
Literature screening, data extraction and literature quality assessment were performed independently by two researchers. In the case of disagreement, a third party was invited to negotiate and make a decision. Standardized mean difference (SMD) was used to estimate the therapeutic effect. Meta-analysis was performed using Review Manager 5.3.5 and Stata 15.0. Heterogeneity was assessed using Q test and I2, and the source of heterogeneity was determined using Galbraith diagram and sensitivity analysis. A Q test resulting in P < 0.1 and I2 > 50% indicated significant difference and random effect model analysis was performed. Otherwise, a fixed effect model was applied. Begg’s and Egger’s tests were used to assess publication bias.

Results
Nine RCTs involving 485 participants were included in this study. The results showed that TCEs could reduce fasting blood glucose (FBG), 2 h blood glucose (2hPBG) and HbA1c in patients with prediabetes. The treatment subgroup showed that an intervention of 6 months had better results, while the Gongfa subgroup showed that the TCE Baduanjin yielded better results. (1) FBG: SMD = –0.73, 95% confidence interval (CI) [–0.97, –0.50], < 0.00001; Baduanjin: SMD = –0.83, 95% CI [–1.13, –0.53], < 0.00001; 6 months treatment: SMD = –0.73, 95% CI [–1.20, –0.26], P = 0.002. (2) 2hPBG: SMD = –0.75, 95% CI [–0.94, –0.57], P < 0.00001; Baduanjin: SMD = –0.62, 95% CI [–0.91, –0.32], < 0.00001; 6 months treatment: SMD = –0.91, 95% CI [–1.39, –0.44], P = 0.0002. (3) HbA1c: SMD = –0.56, 95% CI [–0.89, –0.23], P = 0.00008; Baduanjin: SMD = –0.46, 95% CI [–0.83, –0.08], = 0.02; 6 months treatment: SMD = –0.77, 95% CI [–1.24, –0.29], P = 0.002.

Conclusion
TCEs had positive effects in improving blood glucose levels in patients with prediabetes. Hence, TCEs may be of potential therapeutic value for patients with prediabetes, as an adjuvant therapy along with other treatments. Although the evidence suggests that the intervention is effective for 6 months, the mechanism of TCEs on glycemic control, the minimum exercise dose and their safety remain to be further studied.
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Controversial conclusions from two randomized controlled trials for acupuncture's effects on polycystic ovary syndrome or in vitro fertilization support
Sherman Gu, Arthur Yin Fan
Journal of Integrative Medicine    2020, 18 (2): 89-91.   DOI: 10.1016/j.joim.2020.01.007
Online available: 04 February 2020

Abstract150)   HTML    PDF      
Two reports of trials investigating the potential effect of acupuncture in increasing live birth rate (LBR) in women with polycystic ovary syndrome (PCOS) or those undergoing in vitro fertilization (IVF) were published by Journal of American Medical Association in 2017 and 2018 respectively. The trial investigators did not recommend acupuncture for the women with PCOS or IVF based on their findings. This paper raises the concern that the findings that acupuncture did not increase LBR for women with PCOS or undergoing IVF may be the result of methodological flaws in the studies and unintended bias such as use of an invalid control intervention and underestimation of the true acupuncture effect. Therefore, their findings may not be a valid reflection of acupuncture’s effect in improving LBR in women with these clinical conditions.
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Evaluation of anticancer effects of a pharmaceutically viable extract of a traditional polyherbal mixture against non-small-cell lung cancer cells
Varuni Colamba Pathiranage, Ira Thabrew, Sameera R. Samarakoon, Kamani H. Tennekoon, Umapriyatharshini Rajagopalan, Meran K. Ediriweera
Journal of Integrative Medicine    2020, 18 (3): 242-252.  
Accepted: 20 August 2019
Online available: 26 February 2020

Abstract183)   HTML    PDF      
Objective:
The present work tested organic solvents to prepare an extract with anticancer properties from a polyherbal mixture containing Nigella sativa (seeds), Hemidesmus indicus (roots) and Smilax glabra (rhizomes). We evaluate anticancer effects in non-small-cell lung cancer cells (NCI-H292), and discuss optimization for pharmaceutical use in the context of efficacy, yield and toxicity.
Methods:
Using different organic solvents, six extracts were prepared from the polyherbal mixture. Based on the cytotoxic effects of these extracts on NCI-H292 cells and normal lung cells (MRC-5), as evaluated by the sulphorhodamine B assay, the total ethyl acetate (T-EA) extract was selected for further analysis. The possible anticancer mechanisms were assessed by evaluating the extract’s effects on apoptosis (through fluorescent microscopic analysis, DNA fragmentation analysis, caspase 3/7 assay and analysis of expression levels of apoptosis-related genes p53, Bax, survivin, Hsp70 and Hsp90), colony formation and antioxidant activity.
Results:
The extract had cytotoxic effects against NCI-H292 cells in a time- and dose-dependent manner. Significant antioxidant activity and inhibition of colony formation were also observed. The expression level of caspase 3/7 significantly (P ? 0.001) increased in NCI-H292 cells treated with 50 μg/mL of the extract. The same dosage led to a significant increase in expression levels of Bax and p53 (P ? 0.05 and P ? 0.01 respectively), accompanied by a significant decrease (P ? 0.0001) in survivin, Hsp 70 and Hsp 90.
Conclusion:
T-EA extract of the above polyherbal mixture has cytotoxicity against NCI-H292 cells via induction of apoptosis, antioxidant effects and inhibition of colony formation
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Effects of the plant-derived analgesic compounds sinomenine and salvinorin A in infant rats
Conrad J. Mascarenhas, Ren-yu Liu, Gordon A. Barr
Journal of Integrative Medicine    2020, 18 (2): 174-180.   DOI: 10.1016/j.joim.2020.01.002
Accepted: 03 July 2019
Online available: 05 February 2020

Abstract106)   HTML    PDF      

Objective

Premature and ill neonates undergo painful but medically necessary procedures while hospitalized. Although opiate drugs are administered as analgesics, problems associated with their side effects, tolerance, and potential dependence necessitate research into alternative pain-relieving medications. Here we test two plant-derived compounds in infant rats: sinomenine, which targets the Mas-related G-protein coupled receptor member X2 opioid receptor; and salvinorin A, which is a κ opioid receptor agonist. In adult animals both sinomenine and salvinorin A are analgesic, but neither has been tested in infants. 


Methods

We used the formalin and thermal plantar tests in rats 7- and 21-days of age (PN7; PN21) for behavioral signs of pain. In addition, brain sections were stained using Fos immunohistochemistry to examine patterns of brain activation in the midbrain periaqueductal gray and the paraventricular nucleus of the hypothalamus. 


Results

Sinomenine was analgesic in both the formalin and thermal tests on animals 21 days of age. At PN7 only the highest dose elevated response latencies in the thermal test and there were no effects of sinomenine in the formalin test. Analysis of Fos expression in the sinomenine-treated animals showed no drug effect, in contrast to the behavioral results. Salvinorin A was analgesic in the formalin test only at the highest dose at 21 days of age but not in the thermal test at either age. 


Conclusion

The increased modest effectiveness of sinomenine in older animals and the minimum salvinorin A drug effect suggest that the compounds act on sites that develop during the preweaning period (sinomenine) or after weaning (salvinorin A).

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Chinese herbal medicine for COVID-19: Current evidence with systematic review and meta-analysis
Arthur Yin Fan, Sherman Gu, Sarah Faggert Alemi, Research Group for Evidence-based Chinese Medicine
Journal of Integrative Medicine    2020, 18 (5): 385-394.   DOI: 10.1016/j.joim.2020.07.008
Accepted: 28 June 2020
Online available: 06 July 2020

Abstract664)   HTML    PDF      

Background
There is currently no drug or therapy that cures COVID-19, a highly contagious and life-threatening disease.
Objective
This systematic review and meta-analysis summarized contemporary studies that report the use of Chinese herbal medicine (CHM) to treat COVID-19.
Search strategy: Six electronic databases (PubMed/MEDLINE, Cochrane Library, ScienceDirect, Google Scholar, Wanfang Data and China National Knowledge Infrastructure) were searched from their beginning to May 15, 2020 with the following search terms: traditional Chinese medicine, Chinese medicine, Chinese herbal medicine, COVID-19, new coronavirus pneumonia, SARS-CoV-2, and randomized controlled trial.
Inclusion criteria: Randomized controlled trials (RCTs) from peer-reviewed journals and non-reviewed publications were included. Further, included RCTs had a control group that was given standard care (SC; such as conventional Western medicine treatments or routine medical care), and a treatment group that was given SC plus CHM.
Data extraction and analysis: Two evaluators screened and collected literature independently; information on participants, study design, interventions, follow-up and adverse events were extracted, and risk of bias was assessed. The primary outcomes included scores that represented changes in symptoms and signs over the course of treatment. Secondary outcomes included the level of inflammatory markers, improvement of pneumonia confirmed by computed tomography (CT), and adverse events. Dichotomous data were expressed as risk ratio or hazard ratio with 95% confidence interval (CI); where time-to-event analysis was used, outcomes were expressed as odds ratio with 95% CI. Continuous data were expressed as difference in means (MD) with 95% CI, and standardized mean difference (SMD) was used when different outcome scales were pooled.
Results
Seven original studies, comprising a total of 732 adults, were included in this meta-analysis. Compared to SC alone, CHM plus SC had a superior effect on the change of symptom and sign score (–1.30 by SMD, 95% CI [–2.43, –0.16]; 3 studies; n = 261, P = 0.03), on inflammatory marker C-reactive protein (CRP, mg/L; –11.82 by MD, 95% CI [–17.95, –5.69]; 5 studies; n = 325, P = 0.0002), on number of patients with improved lung CT scans (1.34 by risk ratio, 95% CI [1.19, 1.51]; 4 studies; n = 489, P < 0.00001). No significant adverse events were recorded in the included RCTs.


Conclusion
Current evidence shows that CHM, as an adjunct treatment with standard care, helps to improve treatment outcomes in COVID-19 cases.

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Fuzheng Huayu recipe, a traditional Chinese compound herbal medicine, attenuates renal interstitial fibrosis via targeting the miR-21/PTEN/AKT axis
Qing-lan Wang, Yan-yan Tao, Hong-dong Xie, Cheng-hai Liu, Ping Liu
Journal of Integrative Medicine    2020, 18 (6): 505-513.   DOI: 10.1016/j.joim.2020.08.006
Accepted: 01 July 2020
Online available: 28 August 2020

Abstract190)   HTML    PDF      
Objective

MicroRNAs (miRNAs) may be viable targets for treating renal interstitial fibrosis (RIF). Fuzheng Huayu recipe (FZHY), a traditional Chinese compound herbal medicine, is often used in China to treat fibrosis. This study sought to assess the mechanisms through which FZHY influences miRNAs to treat RIF.

Methods

RIF was induced in rats by mercury chloride and treated with FZHY. Hydroxyproline content, Masson’s staining and type I collagen expression were used to evaluate renal collagen deposition. Renal miRNA profiles were evaluated using a miRNA microarray. Those miRNAs that were differentially expressed following FZHY treatment were identified and subjected to bioinformatic analyses. The miR-21 target gene phosphatase and tensin homolog (PTEN) expression and AKT phosphorylation in kidney tissues were assessed via Western blotting. In addition, HK-2 human proximal tubule epithelial cells were treated using angiotensin II (Ang-II) to induce epithelial-to-mesenchymal transition (EMT), followed by FZHY exposure. miR-21 and PTEN expressions were evaluated via quantitative reverse transcription-polymerase chain reaction (qRT-PCR), while E-cadherin and α-smooth muscle actin (α-SMA) expressions were assessed by immunofluorescent staining and qRT-PCR. Western blotting was used to assess PTEN and AKT phosphorylation.

Results

FZHY significantly decreased kidney collagen deposition, hydroxyproline content and type I collagen level. The miRNA microarray identified 20 miRNAs that were differentially expressed in response to FZHY treatment. Subsequent bioinformatic analyses found that miR-21 was the key fibrosis-related miRNA regulated by FZHY. FZHY also decreased PTEN expression and AKT phosphorylation in fibrotic kidneys. Results from in vitro tests also suggested that FZHY promoted E-cadherin upregulation and inhibited α-SMA expression in Ang-II-treated HK-2 cells, effectively reversing Ang-II-mediated EMT. We also determined that FZHY reduced miR-21 expression, increased PTEN expression and decreased AKT phosphorylation in these cells.

Conclusion

miR-21 is the key fibrosis-related miRNA regulated by FZHY. The ability of FZHY to modulate miR-21/PTEN/AKT signaling may be a viable approach for treating RIF.
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Effects of co-administration of Ganoderma terpenoid extract with chloroquine on inflammatory markers and antioxidant status in Plasmodium berghei-infected mice
Olarewaju M. Oluba, Oghenerobor B. Akpor, Feyikemi D. Adebiyi, Sunday J. Josiah, Olayinka O. Alabi, Ayoola O. Shoyombo, Augustine O. Olusola
Journal of Integrative Medicine    2020, 18 (6): 522-529.   DOI: 10.1016/j.joim.2020.08.002
Accepted: 20 July 2020
Online available: 21 August 2020

Abstract172)   HTML    PDF      
Objective

To understand the protective effects of Ganoderma terpenoid extract (GTE) against Plasmodium berghei-malarial infection in mice, the present study was carried out to evaluate the effects of GTE in combination with chloroquine disulphate (CQ) on erythrocyte-selected inflammatory markers and antioxidant defense status in P. berghei-infected mice. 

Methods

P. berghei-infected mice were divided into six groups: infected control (IC) group, administered 1 mL Tween 20; GTE100 and GTE250 groups, administered 100 and 250 mg/kg GTE, respectively; GT100 + CQ and GT250 + CQ groups, co-administered 100 and 250 mg/kg GTE plus 30 mg/kg CQ, respectively; and CQ group, administered 30 mg/kg CQ. A separate group of non-infected mice were given 1 mL Tween 20, and served as a normal control group (NC). Extract and drug were dissolved in Tween 20 and administered orally once daily for 12 consecutive days. At the end of the treatment period, mice were anesthetized with chloroform and sacrificed by cervical dislocation. Plasma was prepared from blood obtained from each mouse. Parameters evaluated at the end of the treatment period include parasitemia, red blood cell count, hematocrit, malondialdehyde (MDA), glutathione (GSH), catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10). 

Results

Infected mice treated with a combination of GTE and CQ (GT100 + CQ and GT250 + CQ groups) showed significantly reduced parasitemia levels (P < 0.05) compared to those administered GTE alone as well as IC. Significant improvement in body weight (P < 0.05) was also observed in infected mice treated with a combination of GTE and CQ (GT100 + CQ and GT250 + CQ groups), compared to mice receiving GTE alone (GTE100 and GTE250 groups). Plasma MDA and TNF-α concentrations were significantly lowered, and IL-10 concentration was significantly increased in GT100 + CQ and GT250 + CQ groups, relative to the IC group (P < 0.05). GSH concentration and SOD, CAT and GPx activities were significantly higher in GT100 + CQ and GT250 + CQ groups compared to the GTE100, GTE250, IC and NC groups (P < 0.05). 

Conclusion

Data generated in this study showed that GTE enhanced the anti-plasmodial action of CQ in mice through its anti-inflammatory and antioxidant activities.

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Clinical characteristics of coronavirus disease 2019 in patients aged 80 years and older
Jian-zhong Dang, Gang-yan Zhu, Ying-jie Yang, Fang Zheng
Journal of Integrative Medicine    2020, 18 (5): 395-400.   DOI: 10.1016/j.joim.2020.07.002
Accepted: 23 June 2020
Online available: 13 July 2020

Abstract106)   HTML    PDF      

Objective

oronavirus disease 2019 (COVID-19) has raised concern around the world as an epidemic or pandemic. As data on COVID-19 has grown, it has become clear that older adults have a disproportionately high rate of death from COVID-19. This study describes the early clinical characteristics of COVID-19 in patients with more than 80 years of age.

Methods

Epidemiological, clinical, laboratory, radiological, and treatment data from 17 patients diagnosed with COVID-19 between January 20 and February 20, 2020 were collected and analyzed retrospectively. Treatment outcomes among subgroups of patients with non-severe and severe symptoms of COVID-19 were compared.

Results

Of the 17 hospitalized patients with COVID-19, the median age was 88.0 years (interquartile range, 86.6–90.0 years; range, 80.0–100.0 years) and 12 (70.6%) were men. The age distribution of patients was not significantly different between non-severe group and severe group. All patients had chronic pre-existing conditions. Hypertension and cardiovascular diseases were the most common chronic conditions in both subgroups. The most common symptoms at the onset of COVID-19 were fever (n = 13; 76.5%), fatigue (n = 11; 64.7%), and cough (n = 5; 29.4%). Lymphopenia was observed in all patients, and lymphopenia was significantly more severe in the severe group than that in non-severe group (0.4 × 109/L vs 1.2 × 109/L, P = 0.014). The level of serum creatinine was higher in the severe group than in the non-severe group (99.0 μmol/L vs 62.5 μmol/L, P = 0.038). The most common features of chest computed tomography (CT) images were nodular foci in 10 (58.8%) patients and pleural thickening in 7 (41.2%) patients. All patients received antiviral therapy, while some patients also received intravenous antibiotics therapy (76.5%), Chinese medicinal preparation therapy (Lianhuaqingwen capsule, 64.7%), corticosteroids (35.3%) or immunoglobin (29.4%). Eight patients (47.1%) were transferred to the intensive care unit because of complications. Ten patients (58.8%) received intranasal oxygen, while 3 (17.6%) received non-invasive mechanical ventilation, and 4 (23.5%) received high-?ow oxygen. As of June 20, 7 (41.2%) patients had been discharged and 10 (58.8% of this cohort, 77.8% of severe patients) had died.

Conclusion

The mortality of patients aged 80 years and older with severe COVID-19 symptoms was high. Lymphopenia was a characteristic laboratory result in these patients, and the severity of lymphopenia was indicative of the severity of COVID-19. However, the majority of patients with COVID-19 in this age cohort had atypical symptoms, and early diagnosis depends on prompt use of a viral nucleic acid test.

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Calcarea carbonica treatment rescues lipopolysaccharide-induced inflammatory response in human mononuclear cells via downregulation of inducible cyclooxygenase pathway
Swatantra Kumar, Vimal K Maurya, Debadatta Nayak, Anil Khurana, Raj K Manchanda, Srinivasulu Gadugu, Madan LB Bhatt, Shailendra K Saxena
Journal of Integrative Medicine    2020, 18 (5): 441-449.   DOI: 10.1016/j.joim.2020.06.001
Accepted: 03 June 2020
Online available: 03 June 2020

Abstract135)   HTML    PDF      

Objective

Prolonged use of nonsteroidal anti-inflammatory drugs is associated with severe side effects and toxicity. Therefore, we studied the anti-inflammatory role of Calcarea carbonica which had minimal toxicity at the low doses. 


Methods

THP-1 human mononuclear cells were treated with C. carbonica to evaluate the 50% cytotoxicity concentration (CC50) and 50% effective concentration (EC50). Cell survival was evaluated in lipopolysaccharide-stimulated C. carbonica-treated cells. Nitric oxide (NO) and tumor necrosis factor-α (TNF-α) were measured to evaluate the anti-inflammatory activity of C. carbonica. Cyclooxygenase-2 (COX-2) protein expression was determined by Western blotting analysis, and the interaction of C. carbonica with the COX-2 protein was evaluated using molecular docking simulation. 


Results

The CC50 and EC50 of C. carbonica were found to be 43.26 and 11.99 μg/mL, respectively. The cell survival assay showed a 1.192-fold (P = 0.0129), 1.443-fold (P = 0.0009) and 1.605-fold (P = 0.0004) increase in cell survival at 24, 48 and 72 h after initiating C. carbonica treatment, respectively. C. carbonica-treated cells showed a reduction in NO levels by 2.355 folds (P = 0.0001), 2.181 folds (P = 0.0001) and 2.071 folds (P = 0.0001) at 24, 48 and 72 h, respectively. The treated cells also showed a reduction in TNF-α levels by 1.395 folds (P = 0.0013), 1.541 folds (P = 0.0005) and 1.550 folds (P = 0.0005) at 24, 48 and 72 h, respectively. In addition, a 1.193-fold reduction (P = 0.0126) in COX-2 protein expression was found in C. carbonica-treated cells. The simulated molecular docking showed interaction of C. carbonica with the phenylalanine 367 residue present in COX-2’s active site. 


Conclusion

C. carbonica exhibited anti-inflammatory properties in lipopolysaccharide-stimulated cells by significantly reducing NO production and TNF-α level through downregulation of the COX-2 protein. This effect is probably mediated through interaction of C. carbonica with the phenylalanine 367 residue present in COX-2’s active site.

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Treatment of pulmonary fibrosis in one convalescent patient with corona virus disease 2019 by oral traditional Chinese medicine decoction: A case report
Na Zhi, Qian Mo, Shuo Yang, Yuan-xing Qin, Hao Chen, Zeng-guang Wu, Cai-hong Lan, Jun Zhang, Yin-long Li
Journal of Integrative Medicine    2021, 19 (2): 185-190.   DOI: 10.1016/j.joim.2020.11.005
Accepted: 30 September 2020
Online available: 18 November 2020

Abstract134)   HTML    PDF      
After one-month of oral treatment with traditional Chinese medicine decoction, without using other drugs, the lung inflammatory exudate, pulmonary fibrosis and quality of life of a 61-year-old female patient with corona virus disease 2019 (COVID-19) were significantly improved. No recurrence or deterioration of the patient’s condition was found within seven weeks of treatment and follow-up, and no adverse events occurred, indicating that oral Chinese medicine decoction was able to improve the pulmonary inflammation and fibrosis in a patient recovering from COVID-19, but further research is still needed.
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Comparable effects of Jiedu granules and sorafenib for advanced hepatocellular carcinoma: A prospective multicenter cohort study
He-tong Zhao, Yong-bin Meng, Xiao-feng Zhai, Bin-bin Cheng, Sha-sha Yu, Man Yao, Hui-xia Yin, Xu-ying Wan, Yun-ke Yang, Hui Liu, Feng Shen, Chang-quan Ling
Journal of Integrative Medicine    2020, 18 (4): 319-325.   DOI: 10.1016.j.joim.2020.05.003
Accepted: 15 April 2020
Online available: 15 May 2020

Abstract131)   HTML    PDF      

Objective

The drug sorafenib has been extensively used for the treatment of advanced hepatocellular carcinoma (HCC). Chinese herbal medicine has also been used to manage advanced HCC. The present work evaluates the effectiveness and safety of Jiedu (JD) granules, a compound of traditional Chinese herbal medicines, side-by-side with sorafenib for the treatment of advance HCC.

Methods

Patients with advanced HCC were enrolled in this study during December 2014 and March 2018. Study patients were elected to receive treatment with JD granules or sorafenib. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS) and safety. Propensity score matching (PSM) analysis was used to control for possible selection bias from the study group allocation process.

Results

Of the 325 patients included in this study, 161 received JD granules and 164 received sorafenib. No significant differences were found in OS or PFS among patients receiving JD granules compared to sorafenib (P > 0.05). Median OS of the two study groups was 6.83 months (95% confidence interval [CI]: 5.83–9.47) in the group receiving JD granules and 8 months (95% CI: 6.67–9.80) in the group receiving sorafenib, with half-, 1-, and 2- year survival rates of 53.6%, 31.2% and 13.2% vs 60.1%, 35.5% and 14.2%, respectively. Even after PSM, the median survival time did not differ between the JD granules group (9.03 months; 95% CI: 6.37–14.2) and the sorafenib group (7.93 months; 95% CI: 6.5–9.97), with comparable half-, 1- and 2-year survival rates. The most common adverse events (AEs) were diarrhea (13.7%) and fatigue (5.6%) in the JD granules group, and hand-foot skin reaction (46.3%) and diarrhea (36.6%) in the sorafenib group. The JD granules was more cost-effective than sorafenib treatment for advanced HCC.

Conclusion

Compared to sorafenib, JD granules provided a comparable treatment for HCC that was more cost-effective and caused fewer AEs for the treatment of Chinese patients with advanced HCC. 


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Suppressive effect of Aurantii Fructus Immaturus and Atractylodis Macrocephalae Rhizoma on glutamic acid-induced autophagy of interstitial cells of Cajal
Shuai Yan, Yin-zi Yue, Ming-ming Sun, Ben-sheng Wu, Xiao-peng Wang
Journal of Integrative Medicine    2020, 18 (4): 334-343.   DOI: 10.1016/j.joim.2020.04.005
Accepted: 06 April 2020
Online available: 08 June 2020

Abstract109)   HTML    PDF      
Objective
To investigate the effects of Aurantii Fructus Immaturus (Zhishi, ZS) and Atractylodis Macrocephalae Rhizoma (Baizhu, BZ)-containing serum on glutamate-induced autophagy in rat colonic interstitial cells of Cajal (ICCs) and to analyze the underlying mechanism.

Methods
Rat colonic ICCs cultured in vitro were identified by fluorescence and then stimulated with glutamic acid (5 mmol/L) for 24 h to establish a cell model of autophagy. The cells were then treated with different concentrations of ZSBZ-containing serum or rat serum. The viability of the ICCs was detected with cell counting kit-8 assays, and cell apoptosis rates were examined with flow cytometry. The ultrastructure and autophagosomes in the ICCs were observed using transmission electron microscopy. The effects of ZSBZ-containing serum on apoptosis-associated mediators were assessed by Western blotting and real-time quantitative polymerase chain reaction. In addition, microtubule-associated protein light chain 3 (LC3), p-phosphoinositide 3-kinase (p-PI3K), p-Akt and p-mammalian target of rapamycin (p-mTOR) expression was detected via Western blotting analysis.

Results
Compared to those in the model group, ICC viability and apoptosis rates were significantly increased by ZSBZ-containing serum (< 0.05). In addition, the expression levels of Beclin-1, LC3, p-PI3K, p-Akt and p-mTOR were significantly lower (< 0.05) and Bcl-2 expression was higher in the ZSBZ-containing serum treatment groups than in the model group (< 0.05).

Conclusion
Our findings demonstrated that ZSBZ protects glutamic acid-stimulated ICCs, and this beneficial effect may be mediated by a reduction in autophagy via inhibition of the PI3K/Akt/mTOR pathway.
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Chinese herbal medicines for prevention and treatment of colorectal cancer: from molecular mechanisms to potential clinical applications
Mu-yan Kong, Le-yan Li, Yan-mei Lou, Hong-yu Chi, Jin-jun Wu
Journal of Integrative Medicine    2020, 18 (5): 369-384.   DOI: 10.1016/j.joim.2020.07.005
Accepted: 29 June 2020
Online available: 30 July 2020

Abstract205)   HTML    PDF      
Worldwide, colorectal cancer (CRC) is one of the most common malignant tumors, leading to immense social and economic burdens. Currently, the main treatments for CRC include surgery, chemotherapy, radiotherapy and immunotherapy. Despite advances in the diagnosis and treatment of CRC, the prognosis for CRC patients remains poor. Furthermore, the occurrence of side effects and toxicities severely limits the clinical use of these therapies. Therefore, alternative medications with high efficacy but few side effects are needed. An increasing number of modern pharmacological studies and clinical trials have supported the effectiveness of Chinese herbal medicines (CHMs) for the prevention and treatment of CRC. CHMs may be able to effectively reduce the risk of CRC, alleviate the adverse reactions caused by chemotherapy, and prolong the survival time of patients with advanced CRC. Studies of molecular mechanisms have provided deeper insight into the roles of molecules from CHMs in treating CRC. This paper summarizes the current understanding of the use of CHMs for the prevention and treatment of CRC, the main molecular mechanisms involved in these processes, the role of CHMs in modulating chemotherapy-induced adverse reactions, and CHM’s potential role in epigenetic regulation of CRC. The current study provides beneficial information on the use of CHMs for the prevention and treatment of CRC in the clinic, and suggests novel directions for new drug discovery against CRC.
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The idealist and pragmatist view of qi in tai chi and qigong: A narrative commentary and review
George Chengxi Bao
Journal of Integrative Medicine    2020, 18 (5): 363-368.   DOI: 10.1016/j.joim.2020.06.004
Accepted: 05 June 2020
Online available: 19 June 2020

Abstract98)   HTML    PDF      
Qi, often translated as “vital energy,” is a central concept in tai chi and qigong that has puzzled physicians, scientists, and people in the West. To date, qi is not falsifiable by the scientific method and thus cannot be subject to scientific inquiry, leading many to criticize it as “pseudoscientific.” Even as medical research reveals the health benefits of tai chi and qigong, many wonder how to treat this seemingly outdated concept when promoting these meditative practices. While some tai chi and qigong practitioners insist on the existence of qi, more skeptical thinkers suggest that a scientific understanding should replace this “superstitious” idea. Integrative health professionals must be equipped to discuss this concept intelligently by considering a couple of subtle and clarifying points that often miss from discussion. First, science’s inability to verify qi’s existence does not affirm its nonexistence. In fact, under the philosophical system of idealism, qi might not be said to be less real than things that are verifiable by science. Similarly, under the instrumental and pragmatic view of science, health professionals should be cautious not to declare what is metaphysically real or unreal but instead what is useful and not useful. Second, even though qi may be pseudoscientific, it remains useful and indispensable to the correct practice of tai chi and qigong. Tai chi and qigong practitioners routinely visualize and perceive the flow of qi to guide their movements, breathing, and mental activity. As such, qi and related metaphysical concepts serve as a useful mental model during practice, and belief in them may be viewed as an “expedient means” to achieve one’s health goals.
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Effects of Zataria oxymel on obesity, insulin resistance and lipid profile: A randomized, controlled, triple-blind trial
Jafar Abolghasemi, Mohammad Ali Farboodniay Jahromi, Mohammad Hossein Sharifi, Zohreh Mazloom, Leila Hosseini, Nasrindokht Zamani, Majid Nimrouzi
Journal of Integrative Medicine    2020, 18 (5): 401-408.   DOI: 10.1016/j.joim.2020.06.003
Accepted: 27 November 2019
Online available: 15 June 2020

Abstract140)   HTML    PDF      

Background

Obesity is a major public health problem and its occurrence is markedly increasing in developed and developing countries. However, few studies have investigated the use of natural products to treat obesity. The effects of taking a combination of oxymel and Zataria multiflora Boiss. (ZM), herein referred to as Zataria oxymel (ZO), on obesity, lipid profile and insulin resistance have not yet been studied.


Objective

This study evaluates the effects of oxymel and ZO on obesity, lipid profile and insulin resistance.


Design, setting, participants and interventions
In this randomized, controlled, triple-blind trial, overweight patients were randomly divided into three groups and received doses of study compounds twice per day for twelve weeks. Group A received 0.75 g ZM in 10 mL oxymel in each treatment; group B received 1.5 g ZM in 10 mL of oxymel in each treatment and group C (control) only received 10 mL of oxymel in each treatment.

Main outcome measures
Anthropometric parameters, including body mass index (BMI), waist circumference and hip circumference, were measured at the time of registration. Blood tests were carried out at the beginning and once again at end of the study. Blood parameters included fasting blood sugar (FBS), insulin levels, serum lipid profile (total cholesterol, triglyceride, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol) and liver enzymes (aspartate transaminase and alanine transaminase). Serum creatinine was also measured at the beginning of the project and in monthly intervals for three months. The homeostasis model assessment index was calculated as fasting insulin (μIU/mL) × FBS (mg/dL)/405.

Results
The results showed that patients receiving ZO experienced significant reduction in waist circumference in groups A, B and C, respectively (P < 0.001) but no significant change in BMI. Group A also experienced reduction in hip circumference (P = 0.01). Groups B and C had reduction in the homeostatic model assessment of insulin resistance (P = 0.05 and P = 0.01, respectively), with no significant reduction in FBS. No effect on lipid profile, liver enzymes or serum creatinine was observed in the three groups.

Conclusion
In this study, treatment with ZO and oxymel reduced insulin resistance, and waist and hip circumferences in overweight patients. Nonetheless, the traditional Persian use of ZO as a beverage to improve the anthropometric indices in overweight individuals still requires further research with a larger sample size.
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In vitro cytotoxic and toxicological activities of ethanolic extract of Kaempferia galanga Linn. and its active component, ethyl-p-methoxycinnamate, against cholangiocarcinoma
Porwornwisit Tritripmongkol, Tullayakorn Plengsuriyakarn, Mayuri Tarasuk, Kesara Na-Bangchang
Journal of Integrative Medicine    2020, 18 (4): 326-333.   DOI: 10.1016/j.joim.2020.04.002
Accepted: 22 June 2020
Online available: 08 June 2020

Abstract115)   HTML    PDF      
Objective
To evaluate the cytotoxic, apoptotic, mutagenic and immunomodulatory activities of Kaempferia galanga Linn. (KG) extract and ethyl-p-methoxycinnamate (EPMC) in vitro.

Methods
The present study investigated the cytotoxic [using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide test], apoptotic (using a mitochondrial membrane potential assay), mutagenic (using a micronucleus test) and immunomodulatory (using flow cytometry) activities of the ethanolic extract of KG and its bioactive component, EPMC, against two cholangiocarcinoma (CCA) cell lines, CL-6 and HuCCT1, and one normal human cell line, OUMS-36T-1F.

Results
Both KG extract and EPMC exhibited moderate cytotoxic activity against both CCA cells. The cytotoxic activity was supported by their concentration-dependent induction of apoptosis. CL-6 was most sensitive (3–4 fold) and selective to 5-fluorouracil (5-FU), compared with KG extract and EPMC [median half inhibiting concentration (IC50) and selectivity index (SI) were 23.01 μg/mL and 17.32; 78.41 μg/mL and 4.44; 100.76 μg/mL and 2.20, respectively for 5-FU vs. KG extract vs. EPMC]. HuCCT1 was relatively more sensitive and selective to 5-FU and EPMC than KG extract [median IC50 and SI were 66.03 μg/mL and 6.04; 60.90 μg/mL and 3.65; 156.60 μg/mL and 2.23, respectively for 5-FU vs. EPMC vs. KG extract]. EPMC produced relatively potent cytotoxic activity against polymorphonuclear cells (IC50 = 92.20 μg/mL). KG extract and EPMC exhibited concentration-dependent mutagenic activity, as well as inhibition of tumor necrosis factor-α and interleukin-6.

Conclusion
Considering cytotoxic, apoptotic, immunomodulatory and mutagenic activities, further development of KG as a drug candidate is likely to focus on the oral pharmaceutical formulation of a standardized KG extract rather than isolated compounds.
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Effects of L-arginine supplementation on glycemic profile: Evidence from a systematic review and meta-analysis of clinical trials
Esmaeil Yousefi Rad, Behzad Nazarian, Somayeh Saboori, Ebrahim Falahi, Azita Hekmatdoost
Journal of Integrative Medicine    2020, 18 (4): 284-291.   DOI: 10.1016/j.joim.2020.05.001
Accepted: 20 May 2020
Online available: 08 June 2020

Abstract114)   HTML    PDF      
Objective
This meta-analysis was performed to assess the effects of L-arginine supplementation on indices of glycemic control, including fasting blood glucose (FBG), hemoglobin A1c (HbA1c), serum insulin and homeostatic model assessment of insulin resistance (HOMA-IR) levels in randomized controlled trials (RCTs).

Search strategy
This study conducted a systematic review of RCTs published in PubMed, Scopus, Web of Science, Cochrane Library and Embase, up to 5 May, 2018.

Inclusion criteria
Studies were included in this meta-analysis if they were RCTs with parallel design and reported sufficient data on participants before and after intervention, and outcomes of glycemic profile parameters in both the arginine supplementation and control groups.

Data extraction and analysis
The screening of titles and abstracts was performed independently by two reviewers. Selected articles were considered if they met the study’s inclusion criteria. The quality of included studies was assessed by using the Cochrane Collaboration modified tool. From 710 articles retrieved in the initial search, only 10 trials were suitable for pooling the effects of arginine supplementation on serum glucose, insulin, HOMA-IR and HbA1c levels, with effect sizes of nine, eight, five and five, respectively.

Conclusion
Although the results of this study confirmed that supplementation with L-arginine could have significant effects on some glycemic profile indices of participants in clinical trials, the clinical importance of this reduction may not be meaningful.

Results
Pooled random-effect analysis revealed that L-arginine supplementation could significantly decrease FBG level (weighted mean difference [WMD]: 3.35 mg/dL; 95% confidence interval [CI] = [–06.55, –00.16]; = 0.04) and serum insulin level (WMD: –2.19 μIU/mL; 95% CI = [–3.70, –0.67]; P = 0.005). However, the effects of L-arginine supplementation on HOMA-IR and HbA1c were not significant. Results of subgroup analysis showed that supplementation with L-arginine could significantly decrease serum insulin levels when the dosage of L-arginine is > 6.5 g/d (WMD: –3.49 μIU/mL; 95% CI= [–5.59, –1.38]; P = 0.001), when the duration of supplementation is ≤ 12.8 weeks (WMD: –3.76; 95% CI = [–6.50, –0.98]; P= 0.008), when the participants are not diabetic patients (WMD: –2.54 μIU/mL; 95% CI= [–4.50, –0.50]; P= 0.01) and when the baseline serum level of insulin was > 20 μIU/mL (WMD: –3.98; 95% CI = [–6.31, –1.65]; P = 0.001).
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Effects of the pestle needle therapy, a type of acupoint stimulation, on post-hemorrhoidectomy pain: A randomized controlled trial
Xian Wang, Xuan Yin, Xiu-tian Guo, Yan Wang, Wen-qi Jin, Ai-jun Mao, Lixing Lao, Zhang-jin Zhang, Jie Zhang, Shi-fen Xu
Journal of Integrative Medicine    2020, 18 (6): 492-498.   DOI: 10.1016/j.joim.2020.08.001
Accepted: 13 June 2020
Online available: 07 August 2020

Abstract128)   HTML    PDF      

Background

Hemorrhoids are one of the most common conditions that lead to surgery, and until now surgical hemorrhoidectomy has been the major effective treatment. Post-operative pain from hemorrhoidectomy has been experienced by thousands of patients and remains a major inconvenience of the operation.


Objective

This study evaluates the clinical efficacy of the pestle needle therapy, an acupoint stimulation method, for relief of post-hemorrhoidectomy pain.


Design, setting, participants and interventions

This was a single-center, patient-assessor-blinded and randomized controlled trial with 154 patients receiving Milligan hemorrhoidectomy surgery. Eligible patients were randomly assigned to either a treatment group or a control group at a ratio of 1:1. The treatment group received the pestle needle therapy, with manual stimulation at Yaoshu (DU2), Mingmen (DU4), Changqiang (DU1), Chengshan (BL57), Erbai (EX-UE2) and the perianal points (1, 3, 5, 7, 9, and 11 o’clock around the lesion); while the control group received a sham treatment with very light pressure. Three sessions of treatment were performed at 30 min, 4 h and 12 h after the surgery, and each lasted for 15 min.


Main outcome measures

The primary outcome was post-operative pain measured with the visual analogue scale (VAS) at 12 h after surgery. The secondary outcomes included the VAS scores measured at 0.5, 2, 4, 6, 8, 24 and 48 h after surgery, the analgesic dose, the time and the VAS score of the patients’ first defecation after surgery, as well as the Hamilton Rating Scale for Anxiety (HAMA) evaluated before discharge.

Results: The mean pain score of the treatment group was significantly lower than that of the control group (3.10 ± 1.27 vs 4.82 ± 1.29; P < 0.001) at 12 h after surgery. Compared with the control group, patients in the treatment group needed a smaller dose of analgesic within the first 24 hours after surgery (P = 0.002); and their HAMA scores before discharge were lower (4.07 ± 2.40 vs 5.10 ± 2.45, P = 0.009). Compared to the treatment group, patients in the control group had a greater time to the first defecation after surgery ([52.34 ± 15.72] h vs [27.08 ± 13.68] h; P < 0.001), but there was no difference in their VAS scores at the first defecation (P = 0.092).


Conclusion

The pestle needle therapy was effective for relieving pain, reducing anxiety and improving bowel function after hemorrhoidectomy, and it is worthy of clinical application.


Trial registration

Chinese Clinical Trial Registry (ChiCTR1900022329).

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Mindfulness interventions during pregnancy: A narrative review
Leandro Lucena, Cristina Frange, Ana Claudia Amorim Pinto, Monica Levy Andersen, Sergio Tufik, Helena Hachul
Journal of Integrative Medicine    2020, 18 (6): 470-477.   DOI: 10.1016/j.joim.2020.07.007
Accepted: 10 June 2020
Online available: 31 July 2020

Abstract145)   HTML    PDF      
Pregnancy is a period of major transformations in a woman’s life; increased stress, and mood and sleep disorders are frequent. This review evaluates mindfulness interventions during pregnancy and their ability to help manage stress, anxiety, depression, emotional regulation, level of mindfulness and sleep quality. A search of English language scientific literature relevant to mindfulness interventions for pregnant women was conducted using PubMed, Scopus and Web of Science, without restriction on publication date. Inclusion criteria were randomized clinical trials with pregnant women, using mindfulness as an intervention for at least three weeks, in one of our main areas of interest, and using only validated scales to measure outcomes. Two hundred and thirty studies were identified in our searches of research databases, and thirteen were included in our analysis. We found a large diversity of mindfulness programs, heterogeneity among the instruments used to evaluate outcomes, and inconsistency in the gestational periods used in the studies. Mindfulness interventions were beneficial for stress, anxiety and depression. Mindfulness was also effective when applied in pregnant women with a history of depression or experiencing depression. Considering emotional regulation and the level of mindfulness, there were signs of improvement, but more studies are needed. None of the studies evaluated sleep quality. Our review provides information about current mindfulness programs, an overview of the effects of mindfulness interventions, a description of the measurements used so far, and recommendations for developing high-quality mindfulness protocols for pregnant women.
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Effects of Tanreqing Capsule on the negative conversion time of nucleic acid in patients with COVID-19: A retrospective cohort study
Xing Zhang, YanXue, Xuan Chen, Jia-min, Wu, Zi-jian Su, Meng Sun, Lu-jiong Liu, Yi-bao Zhang, Yi-le Zhang, Gui-hua Xu, Miao-yan Shi, Xiu-ming Song, Yun-fei Lu, Xiao-rong Chen, Wei Zhang, Qi Chen
Journal of Integrative Medicine    2021, 19 (1): 36-41.   DOI: 10.1016/j.joim.2020.10.002
Accepted: 07 August 2020
Online available: 09 October 2020

Abstract379)   HTML    PDF      
Objective
Traditional Chinese medicine plays a significant role in the treatment of the pandemic of coronavirus disease 2019 (COVID-19). Tanreqing Capsule (TRQC) was used in the treatment of COVID-19 patients in the Shanghai Public Health Clinical Center. This study aimed to investigate the clinical efficacy of TRQC in the treatment of COVID-19.

Methods
A retrospective cohort study was conducted on 82 patients who had laboratory-confirmed mild and moderate COVID-19; patients were treated with TRQC in one designated hospital. The treatment and control groups consisted of 25 and 57 cases, respectively. The treatment group was given TRQC orally three times a day, three pills each time, in addition to conventional Western medicine treatments which were also administered to the control group. The clinical efficacy indicators, such as the negative conversion time of pharyngeal swab nucleic acid, the negative conversion time of fecal nucleic acid, the duration of negative conversion of pharyngeal-fecal nucleic acid, and the improvement in the level of immune indicators such as T-cell subsets (CD3, CD4 and CD45) were monitored.

Results
COVID-19 patients in the treatment group, compared to the control group, had a shorter negative conversion time of fecal nucleic acid (4 vs. 9 days, P = 0.047) and a shorter interval of negative conversion of pharyngeal-fecal nucleic acid (0 vs. 2 days, P = 0.042). The level of CD3+ T cells increased in the treatment group compared to the control group ([317.09 ± 274.39] vs. [175.02 ± 239.95] counts/μL, P = 0.030). No statistically significant differences were detected in the median improvement in levels of CD4+ T cells (173 vs. 107 counts/μL, P = 0.208) and CD45+ T cells (366 vs. 141 counts/μL, P = 0.117) between the treatment and control groups.

Conclusion
Significant reductions in the negative conversion time of fecal nucleic acid and the duration of negative conversion of pharyngeal-fecal nucleic acid were identified in the treatment group as compared to the control group, illustrating the potential therapeutic benefits of using TRQC as a complement to conventional medicine in patients with mild and moderate COVID-19. The underlying mechanism may be related to the improved levels of the immune indicator CD3+ T cells.
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Therapeutic effects of herbal formula Huangqisan on metabolic disorders via SREBF1, SCD1 and AMPK signaling pathway
Ya-lei Liu, Zhen-yu Zhou, Min Gao, Guang Ji, Cheng Huang, Sheng-jie Fan
Journal of Integrative Medicine    2021, 19 (2): 167-176.   DOI: 10.1016/j.joim.2020.11.002
Accepted: 08 May 2020
Online available: 20 November 2020

Abstract141)   HTML    PDF      
Objective
Metabolic syndrome is a complex medical condition that has become an alarming epidemic, but an effective therapy for this disease is still lacking. The use of the herbal formula Huangqisan (HQS) to treat diabetes is documented in the Chinese medical literature as early as 1117 A.D.; however, its therapeutic effects and underlying mechanisms remain elusive.

Methods
To investigate the beneficial effects of HQS on metabolic disorders, high-fat diet-induced obesity (DIO), leptin receptor dysfunction (db/db) and low-density lipoprotein receptor-knockout (LDLR-/-) mice were used. Obese mice were treated with either HQS or vehicle. Blood, liver tissue, white fat tissue and brown adipose tissue were harvested at the end of the treatment. Metabolic disease-related parameters were evaluated to test HQS’s effects against diabetes, obesity and hyperlipidemia. Aortic arches from LDLR-/- mice were analyzed to investigate the effects of HQS on atherosclerosis. RNA-sequence, quantitative real-time polymerase chain reaction and Western blot were performed to investigate the mechanisms of HQS against metabolic disorder.

Results
HQS lowered body weight, fasting blood glucose and serum lipid levels and improved glucose tolerance and insulin sensitivity in DIO mice and db/db mice (P < 0.05). HQS also blocked atherosclerotic plaque formation in LDLR-/- mice. HQS suppressed de novo lipid synthesis by reducing the expression of messenger RNA for sterol regulatory element-binding factor 1, stearyl coenzyme A desaturase 1 and fatty acid synthase, and enhancing adenosine 5'-monophosphate-activated protein kinase signaling in both in vivo and in vitro experiments, indicating potential mechanisms for HQS’s activity against diabetes.

Conclusion
HQS is effective for reversing metabolic disorder and has the potential to be used as therapy for metabolic syndrome.
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Adult-onset Still's disease successfully treated with Chinese herbal medicine: A case report with 15-month follow-up
Ming-sheng Lyu, De-ying Li, Shao-zhong Zhou, Cheng-jun Ban, Jun Yan
Journal of Integrative Medicine    2020, 18 (6): 530-534.   DOI: 10.1016/j.joim.2020.08.004
Accepted: 10 July 2020
Online available: 26 August 2020

Abstract84)   HTML    PDF      
Adult-onset Still’s disease (AOSD) is a rare but clinically well-known, polygenic, and systemic autoinflammatory disease, which is characterized by spiking fever, evanescent skin rash, arthralgia, and sore throat. The application of non-steroidal anti-inflammatory drugs and glucocorticoids, which are first-line therapies of AOSD, is limited due to their side effects such as liver injury or disorder of blood glucose. Therefore, patients who suffer from systemic diseases in China prefer to seek help from Chinese herbal medicine (CHM), which is an important part of complementary and alternative medicine. In this case, we report a 28-year-old male badminton coach presenting with a 15-day history of fever and skin rash, accompanied by sore throat, fatigue, myalgia and chills. Additionally, hepatosplenomegaly, multiple lymphadenopathies, aminotransferase abnormality, and elevated inflammatory factor levels were observed during hospitalization. Infectious diseases, solid tumors, hematological diseases, and common autoimmune diseases were excluded. Not benefitting from antibiotic therapy, the patient was finally diagnosed with AOSD, after a careful examination, then showed rapid remission after a six-week treatment with CHM granules based on Xiaochaihu Decoction and Yinqiao Powder. After stopping the treatment, there was no relapse within a 15-month follow-up period. To the best of our knowledge, this is the first well-documented case of this successful treatment. The present case report suggests that CHM is a reliable choice for complementary and alternative therapy for AOSD, but confirming the utility of CHM for AOSD requires further support from prospective studies.
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Rapid acupuncture for musculoskeletal pain in the emergency room of the Hospital Servidor Publico Estadual, Brazil: A quasi-experimental study
Luciana Aikawa, Alexandre Massao Yoshizumi, Mirian Matsura Shirassu, Marcia Kiyomi Koike
Journal of Integrative Medicine    2020, 18 (4): 313-318.   DOI: 10.1016/j.joim.2020.05.002
Accepted: 21 February 2020
Online available: 08 June 2020

Abstract77)   HTML    PDF      
Objective
To compare differences in self-reported musculoskeletal pain before and after receiving rapid acupuncture for pain at an outpatient emergency department.

Methods
Exactly 102 patients presenting to the emergency room of the Hospital Servidor Publico Estadual in Sao Paulo, Brazil, participated in this before-and-after study. All participants had musculoskeletal pain and were treated with the technique proposed by Marques Filho. This emergency acupuncture involved inserting a needle at a point defined by traditional Chinese medicine and applying intense stimulation for 10 s; no more than two points were used on any individual patient. Pain was measured using a numerical visual scale before and immediately after the procedure.

Results
Participants in this study were mostly women (78%), had a college degree (47%) and were below the age of 60 (56%). The most common region of pain was the lower back (31%), and the most common type of pain was acute and exacerbated chronic pain. The meridians most commonly involved were the eight extra meridians (40%), and the points most often used for treatment were Houxi (SI3), Shenmai (BL62) and Zulinqi (GB41). Almost all participants reported a decrease in pain intensity, independent of sex, education level, pain site and pain type (acute/chronic; P < 0.05). At the end of the session, only 4% of the participants reported a desire for allopathic medication.

Conclusion
This emergency acupuncture technique for analgesia appears to reduce musculoskeletal pain.
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Effective-constituent compatibility-based analysis of Bufei Yishen formula, a traditional herbal compound as an effective treatment for chronic obstructive pulmonary disease
Jian-sheng Li, Xue-fang Liu, Hao-ran Dong, Wan-chun Zheng, Su-xiang Feng, Yan-ge Tian, Peng Zhao, Jin-di Ma, Zhou-xin Ren, Yang Xie
Journal of Integrative Medicine    2020, 18 (4): 351-362.   DOI: 10.1016/j.joim.2020.04.004
Accepted: 07 April 2020
Online available: 08 June 2020

Abstract114)   HTML    PDF      
Objective
Critical effective constituents were identified from Bufei Yishen formula (BYF), a traditional herbal compound and combined as effective-constituent compatibility (ECC) of BYF I, which may have potential bioactive equivalence to BYF.

Methods
The active constituents of BYF were identified using four cellular models and categorised into Groups 1 (Bufeiqi), 2 (Bushen), 3 (Huatan) and 4 (Huoxue) according to Chinese medicinal theory. An orthogonal design and a combination method were used to determine the optimal ratios of effective constituents in each group and the ratios of “Groups 1 to 4” according to their pharmacological activity. We also comprehensively assessed bioactive equivalence between the BYF and the ECC of BYF I in a rat model of chronic obstructive pulmonary disease (COPD).

Results
We identified 12 active constituents in BYF. The numbers of constituents in Groups 1 to 4 were 3, 2, 5 and 2, respectively. We identified the optimal ratios of effective constituents within each group. In Group 1, total ginsenosides:Astragalus polysaccharide:astragaloside IV ratio was 9:5:2. In Group 2, icariin:schisandrin B ratio was 100:12.5. In Group 3, nobiletin:hesperidin:peimine:peiminine:kaempferol ratio was 4:30:6.25:0:0. In Group 4, paeoniflorin:paeonol ratio was 4:1. An orthogonal design was then used to establish the optimal ratios of Group 1, Group 2, Group 3 and Group 4 in ECC of BYF I. The ratio for total ginsenosides:Astragalus polysaccharide:astragaloside IV:icariin:schisandrin B:nobiletin:hesperidin:peimine:paeoniflorin:paeonol was determined to be 22.5:12.5:5:100:12.5:4:30:6.25:25:6.25. A comprehensive evaluation confirmed that ECC of BYF I presented with bioactive equivalence to the original BYF.

Conclusion
Based on the ECC of traditional Chinese medicine formula method, the effective constituents of BYF were identified and combined in a fixed ratio as ECC of BYF I that was as effective as BYF itself in treating rats with COPD.
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External application of two unrestricted herbal medicines to treat costochondritis in a young collegiate athlete: A case report
Journal of Integrative Medicine    2020, 18 (5): 450-454.   DOI: 10.1016/j.joim.2020.07.001
Online available: 10 July 2020

Abstract103)   HTML    PDF      
Costochondritis (ChC), especially chronic ChC, typically manifests as spontaneous vague pain in anterior chest area and often occurs in adolescents for unknown reasons; it has prevented many collegiate athletes from participating in physical training and competitions. A 21-year-old female collegiate taekwondo athlete suffering from chronic chest pain was sent by her coaches for diagnosis and treatment. Seated motion palpation was used to identify spontaneous and motion-involved pain areas. Palpation in the supine position was used to initially rule out breast diseases. X-ray, electrocardiogram, and cardiac Doppler ultrasound were used in conjunction with myocardial enzyme testing to rule out lung and cardiovascular diseases. The patient was treated using herbal medicines applied via an external patch. The medicine was comprised of Rhizoma Corydalis and borneol, and the treatment lasted for seven weeks. For five weeks patches were applied at a frequency of two or three times per day, followed by a two-week period of once per day. The patient reported that the pain was relieved after two weeks of external herb use, and the autonomic chest pain had resolved. Re-examination after one month showed that her upper limb range of motion was close to normal, and her psychological burden had almost disappeared. It is possible to seek more active medicinal treatment and more practical external products for young athletes who is suffering chronic ChC that affects the sport training and competitive performances.
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Alleviative effects of Cannabis flower on migraine and headache
Sarah S. Stith, Jegason P. Diviant, Franco Brockelman, Keenan Keeling, Branden Hall, Storri Lucern, Jacob M. Vigil
Journal of Integrative Medicine    2020, 18 (5): 416-424.   DOI: 10.1016/j.joim.2020.07.004
Online available: 29 July 2020

Abstract192)   HTML    PDF      
Objective: Few studies to date have measured the real-time effects of consumption of common and commercially available Cannabisproducts for the treatment of headache and migraine under naturalistic conditions. This study examines, for the first time, the effectiveness of using dried Cannabis flower, the most widely used type of Cannabis product in the United States, in actual time for treatment of headache- and migraine-related pain and the associations between different product characteristics and changes in symptom intensity following Cannabis use.
Methods: Between 06/10/2016 and 02/12/2019, 699 people used the Releaf Application to record real-time details of their Cannabisuse, including product characteristics and symptom intensity levels prior to and following self-administration; data included 1910 session-level attempts to treat headache- (1328 sessions) or migraine-related pain (582 sessions). Changes in headache- or migraine-related pain intensity were measured on a 0-10 scale prior to, and immediately, following Cannabis consumption.
Results: Ninety-four percent of users experienced symptom relief within a two-hour observation window. The average symptom intensity reduction was 3.3 points on a 0-10 scale (standard deviation = 2.28, Cohen’s d = 1.58), with males experiencing greater relief than females (P < 0.001) and a trend that younger users (< 35 years) experience greater relief than older users (P = 0.08). Mixed effects regression models showed that, among the known (i.e., labeled) product characteristics, tetrahydrocannabinol levels 10% and higher are the strongest independent predictors of symptom relief, and this effect is particularly prominent in headache rather than migraine sufferers (P < 0.05), females (P < 0.05) and younger users (P < 0.001). Females and younger users also appear to gain greater symptom relief from flower labeled as “C. indica” rather than “C. sativa” or other hybrid strains. 
Conclusion: These results suggest that whole dried Cannabis flower may be an effective medication for treatment of migraine- and headache-related pain, but the effectiveness differs according to characteristics of the Cannabis plant, the combustion methods, and the age and gender of the patient. 
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Hirudotherapy attenuates arthritic pain in patients with various chronic pain syndromes: A retrospective analysis
Johannes Loeser, Brigitte Layer, Christopher Plata, Klaus-Maria Perrar, Tim Hucho, Rebecca Kulbida
Journal of Integrative Medicine    2020, 18 (5): 425-433.   DOI: 10.1016/j.joim.2020.07.003
Accepted: 19 June 2020
Online available: 18 July 2020

Abstract46)   HTML    PDF      

Objective

Osteoarthritis is a degenerative disease that affects synovial joints. Micro-injuries of articular structures initiate inflammatory processes, leading to persistent pain. Due to various risk factors, osteoarthritis is often diagnosed in multimorbid patients. This makes pain management one of the key challenges, with a consistent need for new therapeutic strategies. Hence, complementary and integrative methods such as hirudotherapy have become increasingly important, even though their mechanisms of action are not entirely understood.

Methods

We retrospectively analyzed the longitudinal effect of a single leech application on osteoarthritic joints in a heterogenic cohort of 24 cases with various chronic pain syndromes. We assessed articular pain intensity ratings and movability of the treated joint after one-time leeching for up to 12 months. We further investigated the effect of hirudotherapy on the systemic pain status and multimodal treatment strategies of the patients.

Results

There was a significant reduction in pain intensity ratings at the joint of leech application for up to 12 months after treatment. The improvements in pain intensities were independent of the form of osteoarthritis treated. In addition, we saw a considerable enhancement in local movability of the treated joint. Hirudotherapy did not seem to influence the systemic pain status as well as the previously established individualized multimodal treatment model of the patients. 

Conclusion

Leeching as an adjuvant therapy has a great potential especially in terms of safety and long-term outcome.

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Lavender and dodder combined herbal syrup versus citalopram in major depressive disorder with anxious distress: A double-blind randomized trial
Toktam Sadat Firoozeei, Majid Barekatain, Mehrdad Karimi, Arman Zargaran, Shahin Akhondzadeh, Hossein Rezaeizadeh
Journal of Integrative Medicine    2020, 18 (5): 409-415.   DOI: 10.1016/j.joim.2020.06.002
Accepted: 15 May 2020
Online available: 15 June 2020

Abstract198)   HTML    PDF      
Background
Major depressive disorder (MDD) accompanied by anxious distress is a chronic and disabling disorder. Its conventional drug therapies often have low patient compliance due to drug-related side effects. In Persian medicine, lavender-dodder syrup is one formula often recommended for such disorders.

Objective
This study compares the effects of lavender-dodder syrup to the standard drug, citalopram, for treating MDD with anxious distress.

Design, setting, participants and intervention
This six-week, double-blind, randomized, clinical trial was carried out in a psychiatric outpatient clinic. During the six-week intervention period, patients in citalopram group received citalopram tablets 20 mg/d plus 5 mL placebo syrup every 12 h; patients in group B received placebo tablets once daily plus 5 mL of lavender-dodder herbal syrup every 12 h.

Main outcome measures
Primary outcome measures, depression and anxiety, were evaluated using the Hamilton Depression/Anxiety Rating Scales, and were scored at the beginning of the study and at weeks three and six. Secondary outcome measures including response to treatment and remission rates were also compared between the two groups.

Results
Fifty-six participants with MDD and anxious distress were randomly assigned to two groups. Mean depression scores significantly decreased in citalopram and herbal groups at weeks three and six (time effect: P < 0.001), although the observed changes were not significantly different between the groups (intervention effect: P = 0.61). Mean anxiety scores were not significantly different between the two groups at week three (P = 0.75). However, at the end of week six, the observed decrease was significantly higher in the herbal syrup group than the citalopram group (intervention effect: P = 0.007).

Conclusion
The herbal syrup is an effective and tolerable supplement for treating MDD with anxious distress.
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Removing barriers to healthcare through an intercultural healthcare system: Focus group evidence
Prince Peprah, Williams Agyemang-Duah, Abdul Wahid Arimiyaw, Anthony Kwame Morgan, Stephen Uwumbordo Nachibi
Journal of Integrative Medicine    2021, 19 (1): 29-35.   DOI: 10.1016/j.joim.2020.08.008
Accepted: 18 August 2020
Online available: 18 November 2020

Abstract226)   HTML    PDF      
Objective
Barriers to healthcare in Ghana are multifaceted. Many people, including patients and providers, face them at different levels. To address these barriers, there is a need to explore the role of an intercultural healthcare system. This paper explores and provides the first evidence on ways through which an intercultural healthcare system can reduce the sociocultural and economic barriers to healthcare in Ghana.

Methods
Focus group discussions with 35 participants comprising 17 healthcare users, 11 formal healthcare providers and 7 alternative healthcare providers were conducted to gather data. Thematic analyses were performed on the transcribed data and presented based on a posteriori inductive reduction approach.

Results
Findings reveal that an intercultural healthcare system in Ghana can help reduce barriers to healthcare, especially cultural, social and economic barriers, by fostering an enhanced relationship between culture and healthcare, promoting affordable healthcare and promoting effective communication between healthcare providers and users. Weak institutional support, lack of strong political will and commitment, lack of training to meet standards of practice, poor registration and regulatory measures, inadequate general acceptance by biomedical providers and a perceived negative perception of the intercultural healthcare policy inhibit implementation of an intercultural healthcare system in Ghana.

Conclusion
The support for intercultural healthcare system and the agreement on its perceived ability to reduce social, cultural and economic healthcare barriers for service users offer an opportunity for policy makers to demonstrate a stronger political will and improved political commitment for effective education and training, enforcement of regulatory measures, improved alternative medical literacy through the inclusion of intercultural healthcare medical school curricula across the country, and ensure increased community engagement.
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Integration of network and experimental pharmacology to decipher the antidiabetic action of Duranta repens L.
Pukar Khanal, Basanagouda M. Patil
Journal of Integrative Medicine    2021, 19 (1): 66-77.   DOI: 10.1016/j.joim.2020.10.003
Accepted: 28 August 2020
Online available: 07 October 2020

Abstract175)   HTML    PDF      
Objective
Duranta repens is reported to contain a wide array of secondary metabolites, including α-amylase and α-glucosidase inhibitors, and it has potent antioxidant activity. The present study evaluated the network pharmacology of D. repens (whole plant) with targets related to diabetes mellitus and assessed its outcome by evaluating the effects of the hydroalcoholic extract of D. repens in streptozotocin-nicotinamide-induced diabetes mellitus.

Methods
Phytoconstituents of D. repens were retrieved from an open-source database and published literature, and their targets were predicted for diabetes mellitus using BindingDB and the therapeutic target database. Protein-protein interaction was predicted using STRING, and pathways involved in diabetes mellitus were identified using the Kyoto Encyclopedia of Genes and Genomes pathway browser. Druglikeness, ADMET profile (absorption, distribution, metabolism, excretion and toxicity) and cytotoxicity of compounds modulating proteins involved in diabetes were predicted using MolSoft, admetSAR2.0 and CLC-Pred, respectively. The interaction network among phytoconstituents, proteins and pathways was constructed using Cytoscape, and the docking study was performed using autodock4.0. The hydroalcoholic extract of D. repens was evaluated using streptozotocin-nicotinamide-induced diabetes mellitus animal model for 28 d, followed by an oral glucose tolerance test. At the end of the study, biochemical parameters like glycogen content, hepatic enzymes, antioxidant biomarkers and lipid profiles were quantified. Further, the liver and pancreas were collected for a histopathology study.

Results
Thirty-six different secondary metabolites from D. repens were identified to regulate thirty-one targets involved in diabetes mellitus, in which protein-tyrosine phosphatase 1B (PTP1B) was primarily targeted. Enrichment analysis of modulated proteins identified 12 different pathways in diabetic pathogenesis in which the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway was chiefly regulated. The docking study found that durantanin I possessed the highest binding affinity (–8.9 kcal/mol) with PTP1B. Similarly, ADMET profiling showed that the majority of bioactive constituents from D. repens had higher human intestinal absorptivity and minimal cytotoxicity to normal cell lines, than tumor cell lines. Further, an in vivo animal study reflected the efficacy of the hydroalcoholic extract of D. repens to lower the elevated blood glucose level by stimulating insulin secretion, maintaining pancreatic β cell mass, regulating glycolysis/gluconeogenesis and upregulating the glucose uptake in skeletal muscles.

Conclusion
The present study reflected the probable network interaction of bioactive constituents from D. repens, their targets and modulated pathways, which identified the prime regulation of the PI3K-Akt signaling pathway and PTP1B protein. Modulation of PTP1B protein and PI3K-Akt signaling pathway could contribute to enhancing glucose uptake, insulin production and glycolysis and decreasing gluconeogenesis in diabetes, which was evaluated via the experimental study.

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ISSN 2095-4964
CN 31-2083/R

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

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