The American Journal of Chinese Medicine

The worldwide spread of the 2019 novel coronavirus has become a profound threat to human health. As the use of medication without established effectiveness may result in adverse health consequences, the development of evidence-based guidelines is of critical importance for the clinical management of coronavirus disease (COVID-19). This research presents methods used to develop rapid advice guidelines on treating COVID-19 with traditional Chinese medicine (TCM). We have followed the basic approach for developing WHO rapid guidelines, including preparing, developing, disseminating and updating each process. Compared with general guidelines, this rapid advice guideline is unique in formulating the body of evidence, as the available evidence for the treatment of COVID-19 with TCM is from either indirect or observational studies, clinical first-hand data together with expert experience in patients with COVID-19. Therefore, our search of evidence not only focuses on clinical studies of treating COVID-19 with TCM but also of similar diseases, such as pneumonia and influenza. Grading of recommendations assessment, development and evaluation (GRADE) methodology was adopted to rate the quality of evidence and distinguish the strength of recommendations. The overall certainty of the evidence is graded as either high, moderate, low or very low, and to give either “strong” or “weak” recommendations of each TCM therapy. The output of this paper will produce the guideline on TCM for COVID-19 and will also provide some ideas for evidence collection and synthesis in the future development of rapid guidelines for COVID-19 in TCM as well as other areas.

This study aimed to investigate the efficacy of Traditional Chinese Medicine (TCM) decoction with different intervention timepoints in the treatment of coronavirus disease 2019 (COVID-19) patients. We retrospectively collected the medical records and evaluated the outcomes of COVID-19 patients that received TCM decoction treatment at different timepoints. A total of 234 COVID-19 patients were included in this study. Patients who received TCM decoction therapy within 3 days or 7 days after admission could achieve shorter hospitalization days and disease periods compared to those who received TCM decoction $\ge$ 7 days after admission (all $p<0.05$). Patients who received TCM decoction therapy within 3 days had significantly fewer days to negative SARS-CoV-2 from nasopharyngeal/oral swab and days to negative SARS-CoV-2 from urine/stool/blood samples compared to those received TCM decoction $\ge 7$ days after admission (all $p<0.05$). Patients who received TCM decoction therapy on the 3rd to 7th day after admission had a faster achievement of negative SARS-CoV-2 from urine/stool/blood samples compared to those who received TCM decoction $\ge 7$ days after admission ($p<0.05$). Logistic models revealed that more days from TCM decoction to admission $\ge 7$ days might be a risk factor for long hospitalization days, disease period, and slower negative-conversion of SARS-CoV-2 (all $p<0.01$). Conclusively, our results suggest that TCM decoction therapy should be considered at the early stage of COVID-19 patients.

The SARS-CoV-2 outbreak in 2019 highlighted the fact that no specific medications providing effective treatment have been identified and approved. We explored the possibilities for COVID-19 by systematically reviewing evidence on the efficacy and safety of glycyrrhizin preparations for SARS and MERS. Electronic databases were systematically searched from inception to February 2020 for eligible studies that evaluated the efficacy and safety of glycyrrhizin preparations for SARS and MERS. A quantitative analysis or descriptive analysis was applied. Five retrospective cohort studies were included, and NOS scores ranged from 5–7 points. The clinical symptoms of dry cough, chest distress and dyspnoea improved quickly, and elevated serum levels of aminotransferase decreased after compound glycyrrhizin treatment. The SARS-CoV antibody appeared earlier in the treated group than in the control group ($-2.9\pm 2.8$d). Compared to that with conventional medications, the average period from peak to 50% improvement of lesions, in terms of X-ray manifestations, was shorter with compound glycyrrhizin treatment ($-$2.1d), and treatment reduced the dosage ($-75.7\pm 42.8$mg/d) and duration of the corticosteroids used, without other serious adverse reactions. Based on the available evidence regarding glycyrrhizin preparations for treating SARS and MERS, we infer that compound glycyrrhizin could be an optional therapeutic strategy for SARS-CoV-2 infections, especially those complicated with liver damage. Further research using well-designed randomized clinical trials (RCTs) is warranted to determine the dosage and duration of use of compound glycyrrhizin and to monitor its specific adverse effects.

The aim of this research is to evaluate the clinical evidence of an herbal medicine (HM) treatment on influenza and describe the potential benefits and adverse events by reviewing all relevant randomized controlled trials. All papers published from 2010 to 2019 in all languages in six databases were searched, including all randomized controlled trials on adults and children, testing herbal medicine for treatment of influenza, alone or in combination with conventional antiviral therapy. The main outcome parameters of interest were total effective rate, time to resolution of fever, adverse events, complications, and duration of viral shedding. 25 trials of 3044 patients were included. Herbal medicine compared to placebo significantly reduced time to fever resolution by 4.96h (mean difference, $-$4.96; 95% CI, $-$7.11 to $-$2.80; $P<0.00001$), herbal medicine compared to oseltamivir showed no significant difference (mean difference, $-$1.82; 95% CI, $-$6.08 to 2.44; $P=0.40$), and herbal medicine plus oseltamivir combined treatment significantly reduced duration of fever by 7.84h compared to a single treatment with oseltamivir (mean difference, $-$7.84; 95% CI, $-$12.51 to $-$3.17; $p=0.001$). Herbal medicine compared to placebo showed a significantly better total effective rate (risk ratio, 1.90; 95% CI, 1.18 to 3.07; $P=0.008$), herbal medicine compared to oseltamivir indicated significantly better effective rate (risk ratio, 1.15; 95% CI, 1.03 to 1.29; $P=0.01$), and combined treatment showed a significantly better total effective rate compared to a single treatment with oseltamivir (risk ratio, 1.20; 95% CI, 1.06 to 1.36; $P=0.004$). Regarding safety, no serious adverse events were reported in HM treatment. HM presented fewer adverse events compared to oseltamivir, but the difference was not significant (risk difference, $-$0.04; 95% CI, $-$0.09 to 0.00; $P=0.08$), and the combined treatment did not increase adverse events compared to oseltamivir (risk difference, $-$0.02; 95% CI, $-$0.06 to 0.02; $P=0.30$). Research findings show that herbal medicine treatments have beneficial therapeutic effects on influenza and could decrease duration of fever and improve total effective rate. In addition, herbal medicine plus oseltamivir combined therapy could increase the therapeutic effect compared to a single treatment with oseltamivir.

Complementary and alternative medicine (CAM) plays a critical role in treating cancer patients. Traditional Chinese Medicine (TCM) is the main component of CAM. TCM, especially Chinese Herbal Medicine (CHM), has been increasingly used in China, some other Asian countries and European countries. It has been proven to enhance the efficacy of chemotherapy, radiotherapy, targeted-therapy, and immunotherapy. It lessens the damage caused by these therapies. CHM functions on cancer by inhibiting tumor progression and improving an organism’s immune system. Increasing evidence has shown that many CHM exert favorable effects on the immune regulation. We will summarize the role of CHM on patient’s immune system when treating cancer patients. Our evidence reveals that single herbs, including their extracts, compound formulations, and preparations, will provide current advances on CHM study, especially from the perspective of immune regulation and novel insights for CHM application in clinic. The main herbs used to treat cancer patients are health-strengthening (Fu-Zheng) herbs and pathogen eliminating (Qu-Xie) herbs. The key mechanism is regulating the immune system of cancer patients. Firstly, health-strengthening herbs are mainly functioned as immune regulatory effectors on cancer. Secondly, some of the compound formulations mainly strengthen the health of patients by regulating the immune system of cancer patients. Lastly, some Chinese medicine preparations are widely used to treat cancer for their properties of spiriting vital energy and anti-cancer effects, mainly by improving immunity. CHM plays a positive role in regulating patients’ immune system, which helps cancer patients to fight against cancer itself and finally improves patients’ life quality.

Spinal cord injury (SCI) is a catastrophic disease associated with damaged neurological structures and has become a significant social and economic burden for the health care system and patients’ families. The use of Chinese Herbal Medicine (CHM) to treat SCI has been increasing in recent years. This meta-analysis aimed to investigate the effectiveness of CHM for patients with SCI. Therefore, we included randomized controlled trials (RCTs) of CHM for SCI in seven databases. A total of 26 studies involving 1961 participants were included in this study. No serious heterogeneity or publication bias was observed across each study. The results showed that significant improvements of the American Spinal Injury Association (ASIA)-grading improvement rate ($\mathrm{\text{RR}}=1.44$, $p<0.0001$), clinical effective rate ($\mathrm{\text{RR}}=1.28$, $p<0.00001$), ASIA motor score ($\mathrm{\text{MD}}=7.34$, $p<0.00001$), ASIA sensory score (total) ($\mathrm{\text{MD}}=9.31$, $p<0.00001$), ASIA sensory score (light touch) ($\mathrm{\text{MD}}=7.31$, $p<0.00001$), ASIA sensory score (pinprick) ($\mathrm{\text{MD}}=7.33$, $p<0.0001$), and activities of daily living (ADL) score ($\mathrm{\text{SMD}}=0.68$, $p<0.00001$) in CHM group compared with the control group. Among the CHM groups, Buyang Huanwu decoction was the most frequently prescribed herbal formula, while Astragalus membranaceus was the most commonly used single herb. In addition, there were no serious and permanent adverse effects in the two groups. The methodological quality of the most included RCTs was poor and the quality of evidence for the main outcomes was from very low to moderate according to the GRADE system. Current evidence suggests that CHM is an effective and safe treatment for SCI and could be treated as a complementary and alternative option with few side effects. However, considering the low quality, small size, and high risk of the studies identified in this meta-analysis, higher methodological quality, rigorously designed RCTs with large sample sizes are needed to confirm the results.

Fucoidan is a type of polysaccharide rich in sulfuric acid groups and is mainly found in brown algae. Due to its extensive biological activities, such as anticoagulant, antitumor, antithrombotic, antiviral, anti-oxidant and enhancing immune function, fucoidan has gradually become a research hotspot. Under the scientific guidance of modern medical theory, fucoidan and its mechanism in oxidative stress, carbohydrate and lipid metabolism, inflammatory response, tumor proliferation, and metastasis have become a new research direction and an important basis as an effective liver protection drug. In this paper, we discuss the important role of fucoidan in viral hepatitis, liver fibrosis, liver cancer, nonalcoholic fatty liver and liver injury induced by drugs and ischemia and briefly discuss its underlying mechanism. We supplement the theoretical basis for its clinical application and provide effective targets for the development of follow-up dominant drugs.

Bufalin is an anticancer drug extract from traditional Chinese medicine. Several articles about bufalin have been published. However, the literature on bufalin has not yet been systematically studied. This study aimed to identify the study status and knowledge structures of bufalin and to summarize the antitumor mechanism. Data were retrieved and downloaded from the PubMed database. The softwares of BICOMB, gCLUTO, Ucinet 6.0, and NetDraw2.084 were used to analyze these publications. The bufalin related genes were recognized and tagged by ABNER software. Then these BF-related genes were performed by Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, and protein-protein interaction (PPI) network analysis. A total of 474 papers met the search criteria from 2000 to 2019. By biclustering clustering analysis, the 50 high-frequency main MeSH terms/subheadings were classified into 5 clusters. The clusters of drug therapy and the mechanism of bufalin were hotspot topics. A total of 50 genes were identified as BF-related genes. PPI network analysis showed that inducing apoptosis was the main effect of bufalin, and apoptosis-related gene Caspase 3 was the most reported by people. Bufalin could inhibit the proliferation, invasion, and metastasis of cancer cells through multiple signaling pathways, such as PI3K/AKT, Hedgehog, MAPK/JNK, Wnt/$\beta$-catenin, TGF-$\beta$/Smad, Integrin signaling pathway, and NF-KB signaling pathway via KEGG analysis. Through the quantitative analysis of bufalin literature, we revealed the research status and hot spots in this field and provided some guidance for further research.

Autophagic defects are a hallmark of neurodegenerative disorders, such as Parkinson’s disorder (PD). Enhancing autophagy to remove impaired mitochondria and toxic protein aggregation is an essential component of PD treatment. In particular, activation of autophagy confers neuroprotection in cellular and preclinical models of neurodegenerative diseases. In this study, we investigated the therapeutic mechanisms of electroacupuncture (EA) treatment in mice with established PD and evaluated the relationship between EA, autophagy, and different neurons in the mouse brain. We report that EA improves PD motor symptoms in mice and enhances (1) autophagy initiation (increased Beclin 1), (2) autophagosome biogenesis (increased Atg5, Atg7, Atg9A, Atg12, Atg16L, Atg3, and LC3-II), (3) autophagy flux/substrate degradation (decreased p62), and (4) mitophagy (increased PINK1 and DJ-1) in neurons of the substantia nigra, striatum, hippocampus, and cortex (affected brain areas of PD, Huntington disease, and Alzheimer’s disease). EA enhances autophagy initiation, autophagosome biogenesis, mitophagy, and autophagy flux/substrate degradation in certain brain areas. Our findings are the first to show that EA regulates neuronal autophagy and suggest that this convenient, inexpensive treatment has exciting therapeutic potential in neurodegenerative disorders.

Traditional herbal formula Gushukang (GSK) was clinically applied to treat primary osteoporosis and showed osteoprotective effect in ovariectomized rodent animals and regulatory action on calcium transporters. This study aimed to determine if GSK could ameliorate aged osteoporosis by modulating serum level of calciotropic hormones and improving calcium balance. 18-month-old male mice were orally administered with either GSK (0.38g/kg body weight) or calcitriol (1$\mu$g/kg body weight) combined with high calcium diet (HCD, 1.2% Ca) for 60 days. The aged mice fed with normal calcium diet (NCD, 0.6% Ca) were a negative control. Trabecular bone and cortical bone properties as well as calcium balance were determined. Treatment with GSK significantly increased 25(OH)D and 1,25-(OH)₂D levels in serum, moreover, it markedly attenuated trabecular bone micro-architectural deteriorations and elevated trabecular bone mass as well as strengthened cortical bone mechanical properties shown by the increase in maximal bending load and elastic modulus. Calcium balance, including urinary Ca excretion, fecal Ca level and net calcium retention, was remarkably improved by GSK, which up-regulated TRPV6 expression in duodenum and TRPV5 expression in kidney and down-regulated claudin-14 expression in duodenum and kidney. Additionally, 1-OHase and 24-OHase expression was significantly decreased (vs. NCD group) and increased (vs. HCD group), respectively, in kidney of GSK- and calcitriol-treated mice. Taken together, this study demonstrated the ameliorative effects of Gushukang on aged osteoporosis by effectively stimulating vitamin D production and improving calcium balance of aged mice with high dietary calcium supplement.

Ulcerative colitis is a chronic and recurrent inflammatory bowel disease mediated by immune response. Geniposide is the main active ingredient extracted from Gardenia jasminoides, which has been suggested to exert excellent efficacy on inflammatory disease. Herein, in this study, we aimed to uncover the systematic understanding of the mechanism and effects of geniposide in ameliorating inflammatory responses in colitis. In brief, the TCMSP server and GEO DataSets were used to analyze the systematic understanding of the mechanism and effects of geniposide in ameliorating inflammatory responses in colitis. Dextran Sulfate Sodium (DSS)-induced acute colitis of mice were administered with 25–100mg/kg of geniposide for 7 days by gavage. Lipopolysaccharide (LPS)-induced Bone Marrow Derived Macrophage (BMDM) cell or RAW264.7 cell models were treated with 20, 50 and 100$\mu$M of geniposide for 4h. Myeloperoxidase (MPO) activity and Interleukin-1$\beta$ (IL-1$\beta )$ levels were measured using MPO activity kits and IL-1$\beta$ levels enzyme-linked immunosorbent assay (ELISA) kits, respectively. Additionally, Western blot was used to determine the relevant protein expression. As a result, Geniposide could ameliorate inflammatory responses and prevent colitis in DSS-induced acute colitis of mice by activating AMP-activated protein kinase (AMPK)/Transcription 1 (Sirt1) dependent signaling via the suppression of nod-like receptor protein 3 (NLRP3) inflammasome. Geniposide attenuated macrophage differentiation in DSS-induced acute colitis of mice. Geniposide suppressed NLRP3 inflammasome and induced AMPK/Sirt1 signaling in LPS-induced BMDM cell or RAW264.7 cell models. In mechanism studies, the inhibition of AMPK/Sirt1 attenuated the anti-inflammatory effects of geniposide in colitis. The activation of NLRP3 attenuated the anti-inflammatory effects of geniposide in colitis. Taken together, our results demonstrated that geniposide ameliorated inflammatory responses in colitis vai the suppression of NLRP3 inflammasome in macrophages by AMPK/Sirt1-dependent signaling.

Pterostilbene (PTB) is a derivative of resveratrol present in grapes and blueberries. PTB is structurally similar to resveratrol, possessing properties such as being analgesic, anti-aging, antidiabetic, anti-inflammatory, anti-obesity, anti-oxidation, cholesterol-reductive, and neuroprotective. However, there have not been reports on the effect of PTB on macrophage-myofibroblast transition (MMT) induced fibrosis in kidney. In this study, we investigated the antifibrotic effects of PTB on the in vivo mouse unilateral ureteral obstruction (UUO) model and in vitro MMT cells. Kidneys subjected to UUO with PTB treatment were collected for the investigation of PTB mediating MMT derived renal interstitial fibrosis. We conducted kidney RNA-seq transcriptomes and TGF-$\beta$1-induced bone marrow-derived macrophages assays to determine the mechanisms of PTB. We found that PTB treatment suppressed the interstitial fibrosis in UUO mice. PTB also attenuated the number of MMT cells in vivo and in vitro. The transcriptomic analysis showed that CXCL10 may play a central role in the process of PTB-treated renal fibrosis. The siRNA-mediated CXCL10 knockdown decreased the number of MMT cells in TGF-$\beta$1-induced bone marrow-derived macrophages. Our results suggested that PTB attenuated renal interstitial fibrosis by mediating MMT by regulating transcriptional activity of CXCL10.