The American Journal of Chinese Medicine

Menopausal syndrome (MPS) is a common gynecological disorder around the time of menopause, and hormone therapy (HT) is the first-line treatment for it. However, HT is prone to cause adverse reactions in MPS patients treated with HT. Acupuncture is a popular non-pharmaceutical therapy for MPS, but the differences in the efficacy and safety between acupuncture and HT remain unclear. The purpose of this evidence-based study is to address this issue. Five databases were searched for potentially eligible RCTs. All RCTs comparing acupuncture with HT in the treatment of MPS were included in this study. The clinical effective rate was the primary outcome. Kupperman index, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E${}_2)$, and side effects were the secondary outcomes. A total of 15 RCTs recruiting 1376 MPS patients were included. Results of meta-analysis showed that compared with HT, acupuncture significantly improved clinical effective rate (RR = 1.09, 95% CI 1.03 to 1.16, $p$ = 0.005), decreased the Kupperman index (WMD = −2.55, 95% CI = −2.93 to −2.17, $p$ < 0.00001) and the incidence of side effects (RR = 0.14, 95% CI = 0.06–0.32, $p$ < 0.00001). There were no statistically significant differences in serum FSH (WMD = −1.36, 95% CI = −3.25–0.53, $p$ = 0.16), E₂(WMD = −1.11, 95% CI = −2.59–0.37, $p$ = 0.14), or LH (WMD = −1.87, 95% CI = −4.58–0.83, $p$ = 0.17) between the acupuncture and HT groups. Based on the current evidence, manual acupuncture is safer and more effective than HT and is recommended for the treatment of MPS, but the evidence for the efficacy of other types of acupuncture is inconclusive.

The incidence of diabetes worldwide continues to rise, placing a huge economic and medical burden on human society. More than 90% of diabetic cases are type 2 diabetes (T2D). At present, the pathogenesis of T2D is not yet fully understood. Metabolomics uses high-resolution analytical techniques (typically NMR and MS) to help identify biomarkers associated with the risk of T2D and reveal potential pathogenesis. Many metabolites such as branched-chain amino acids (BCAAs), aromatic amino acids, glycine, 2-hydroxybutyric acid (2-HB), lysophosphatidylcholine (LPC) (18:2), and trehalose have proven to be biomarkers of T2D. Insulin resistance (IR) induced by BCAA in T2D mice is related to the activation of mammalian target of rapamycin (mTOR) and phosphorylation of insulin receptor substrate-1 (IRS1). Incomplete LCFA $\beta$-oxidation promote acylcarnitine byproduct accumulation and stimulates proinflammatory NF$\kappa$B-related pathways to inhibit insulin action. Traditional Chinese Medicine (TCM) presents unique advantages in the treatment of T2D. Multiple metabolites and metabolic pathways have been identified in the treatment of TCM, providing valuable biomarkers and novel targets for drug therapy and pharmacological mechanism. Therefore, this paper reviews the modern achievements of metabolomics in T2D research and the progress of TCM management in recent years, in order to provide valuable information for related research.

The role of traditional Chinese medicine (TCM) on treatment of metastatic colorectal cancer (mCRC) remains controversial, and its active components and potential targets are still unclear. This study mainly aimed to assess the efficacy and safety of TCM in mCRC treatment through meta-analysis and explore the effective components and potential targets based on the network pharmacology method. We systematically searched PubMed, EMBASE, Cochrane, CBM, WanFang, and CNKI database for randomized controlled trials (RCTs) comparing the treatment of mCRC patients with and without TCM. A meta-analysis using RevMan 5.4 was conducted. In total, 25 clinical trials were analyzed, and the result demonstrated that TCM was closely correlated with the improved OS (HR: 0.63; 95% CI: 0.52–0.76; $p$ < 0.00001) and PFS (HR: 0.73; 95% CI: 0.61–0.88; $p$ = 0.0010). Then, high-frequency Chinese herbs from the prescriptions extracted from the trails included in the OS meta-analysis were counted to construct a core-effective prescription. The TCMSP database was used to retrieve the active chemical components and predict herb targets. The Genecards, OMIM, Disgenet, DrugBank, and TTD database were searched for colorectal cancer targets. R-package was used to construct the Component-Target (C-T) network based on the intersection genes. Further, we extracted hub genes from C-T network and performed functional enrichment and pathway analysis. Finally, the C-T network showed 120 herb and disease co-target genes, and the most important top 10 active components were: Quercetin, Luteolin, Wogonin, Kaempferol, Nobiletin, Baicalein, Licochalcone A, Naringenin, Isorhamnetin, and Acacetin. The first 20 hub genes were extracted: CDKN1A, CDK1, CDK2, E2F1, CDK4, PCNA, RB1, CCNA2, MAPK3, CCND1, CCNB1, JUN, MAPK1, RELA, FOS, MAPK8, STAT3, MAPK14, NR3C1, and MYC. Thus, effective Chinese herb components may inhibit the mCRC by targeting multiple biological processes of the above hub genes.

Shikonin is one of the primary active components extracted from the dried root ofZicao (Lithospermum erythrorhizon, Onosma paniculata, or Arnebia euchroma), a traditional Chinese herbal medicine. Shikonin is known to not only exert anti-proliferative, anti-inflammatory, and anti-angiogenic activities, but also play a crucial role in triggering the production of reactive oxygen species, suppressing the release of exosomes, and inducing apoptosis. Increasing evidence suggests that shikonin has a protective effect against skin diseases, including psoriasis, melanoma, and hypertrophic scars. In order to evaluate the application potential of shikonin in the treatment of skin diseases, this review is the first of its kind to provide comprehensive and up-to-date information regarding the uses of shikonin and its derivatives on skin diseases and its underlying mechanisms. In this review, we have focused on the signaling pathways and cellular targets involved in the anti-dermatosis effects of shikonin to bridge the gaps in the literature, thereby providing scientific support for the research and development of new drugs from a traditional medicinal plant.

Ginsenosides of orally administered red ginseng (RG) extracts are metabolized and absorbed into blood. Here, we examined the pharmacokinetic profiles of ginsenosides Rd and Rg3 in mice orally gavaged with RG, then investigated the correlations between these and gut microbiota composition. RG water extract (RGw), RG ethanol extract (RGe), or fermented RGe (fRGe) was orally gavaged in mice. The plasma concentrations of the ginsenosides were determined, and the gut microbiota composition was analyzed. RGe and fRGe-treated mice showed higher plasma concentration levels of ginsenoside Rd compared with RGw-treated mice; particularly, ginsenoside Rd absorbed was substantially high in fRGe-treated mice. Oral administration of RG extracts modified the gut microbiota composition; the modified gut microbiota, such as Peptococcaceae, Rikenellaceae, and Hungateiclostridiaceae, were closely correlated with the absorption of ginsenosides, such as Rd and Rg3. These results suggest that oral administration of RG extracts can modify gut microbiome, which may consequently affect the bioavailability of RG ginsenosides.

Myocardial ischemia/reperfusion injury (MIRI) is the major cause of myocardial cell damage in acute myocardial infarction, and its treatment remains a clinical challenge. Ginsenoside Rb1 showed protective effects on the cardiovascular system; however, the underlying mechanism remains largely unclear. Effects of Ginsenoside Rb1 on rat MIRI-induced myocardial infarct size were evaluated through TTC staining. TUNEL assay and flow cytometry analysis were employed to estimate cell apoptosis. Apoptosis, autophagy and PI3K/Akt/mTOR pathway-related proteins were estimated via western blot. Expression of Beclin1 in myocardial tissues were examined by immunohistochemical analysis. Expression levels of IL-1$\beta$, TNF-$\alpha$ and IL-6 were tested by enzyme-linked immunosorbent assay (ELISA). Here, we found that Ginsenoside Rb1 treatment not only alleviated MIRI in rats but also protected H9C2 cells against hypoxia/reoxygenation induced damage. Ginsenoside Rb1 abolished the MIRI-induced activation of autophagy. Meanwhile, we found that treatment of 3-MA (autophagy inhibitor) could enhance the protective effects of Ginsenoside Rb1 on H9C2 cells during H/R. Moreover, Ginsenoside Rb1 treatment resulted in the activation of the PI3K/Akt/mTOR pathway, and treatment of LY294002 (PI3K/Akt pathway repressor) abolished the protective effects of Ginsenoside Rb1 on myocardial in vitro and in vivo. Our results suggest that Ginsenoside Rb1 functions as a protector against MIRI by repressing cardiomyocyte autophagy through the PI3K/Akt/mTOR signaling pathway.

Although gomisin A (GA) alleviates cancer and inflammation, its anti-obesity effect and the underlying mechanism have not yet been elucidated. Therefore, in this study, we aimed to elucidate the anti-obesity effects of GA by investigating the phenotypic changes involved in the browning and whitening of adipocytes. Here, obesity was induced to C57BL/6J mice using a high-fat diet (HFD). We administrated GA and checked weight changes for 12 weeks. We found that GA decreased the weight of weight gain, epididymal white adipose tissue (eWAT), and liver in the mice. In addition, the administration of GA elevated the levels of high-density lipoprotein (HDL)-cholesterol in the mice serum. Moreover, even after 12 weeks of treatment with GA, it did not cause any hepatic and renal toxicity. However, we found that GA induced the browning of eWAT and inhibited the whitening of brown adipose tissue. We further confirmed the anti-obesity mechanism of GA using 3T3-L1 cells, the human adipose mesenchymal stem cells (hAMSCs), and primary brown adipocytes (BAs) in vitroexperiments. We found that GA suppressed adipogenesis via the activation of AMP-activated protein kinase (AMPK). Furthermore, GA-induced browning by increasing the expression levels of uncoupling protein 1 (UCP1) in hAMSCs. The results of our study indicate that GA can inhibit weight gain by regulating the phenotypic changes involved in the browning and whitening of adipose tissues, which makes it a potential therapeutic agent for the treatment of obesity.

Secondary metabolic disturbances in patients with schizophrenia or bipolar disorder may be attributed to olanzapine. It is important to prevent mild metabolic disorders progressing to metabolic syndrome. This study aims to investigate the effects of berberine on intestinal flora in patients with mild metabolic disorders induced by olanzapine. A total of 132 patients with schizophrenia, bipolar disorder, or schizoaffective psychosis that had been treated with olanzapine for at least 9 months were randomly assigned ($n$ = 66 each) to receive berberine or placebo tablets for 12 weeks. Metabolic assessments and intestinal flora were quantified at baseline and after 4, 8, and 12 weeks of treatment. Incidence rates of adverse reactions were recorded. FPG, FPI, HOMA-IR, HbA1, TG, BMI, and WC were significantly lower in patients who received berberine compared to placebo after 12 weeks of treatment ($P$< 0.05). The abundance of firmicutes and coliform were significantly lower and the abundance of bacteroides significantly higher in patients who received berberine compared to placebo after 12 weeks of treatment ($P$< 0.05). In patients who received berberine, the abundance of firmicutes was significantly decreased, and the abundance of bacteroides was significantly increased, and in patients who received placebo, the abundance of firmicutes was significantly increased post-treatment, compared to baseline (both $P$< 0.05). In conclusions, berberine may regulate intestinal flora and metabolism in patients with schizophrenia or bipolar disorder and mild metabolic disturbances induced by olanzapine.

Pulmonary fibrosis (PF) is a chronic and irreversible interstitial lung disease that even threatens the lives of some patients infected with COVID-19. PF is a multicellular pathological process, including the initial injuries of epithelial cells, recruitment of inflammatory cells, epithelial-mesenchymal transition, activation and differentiation of fibroblasts, etc. TGF-$\beta$1 acts as a key effect factor that participates in these cellular processes of PF. Recently, much attention was paid to inhibiting TGF-$\beta$1 mediated cell processes in the treatment of PF with Chinese herbal medicines (CHM), an important part of traditional Chinese medicine. Here, this review first summarized the effects of TGF-$\beta$1 in different cellular processes of PF. Then, this review summarized the recent research on CHM (compounds, multi-components, single medicines and prescriptions) to directly and/or indirectly inhibit TGF-$\beta$1 signaling (TLRs, PPARs, micrRNA, etc.) in PF. Most of the research focused on CHM natural compounds, including but not limited to alkaloids, flavonoids, phenols and terpenes. After review, the research perspectives of CHM on TGF-$\beta$1 inhibition in PF were further discussed. This review hopes that revealing the inhibiting effects of CHM on TGF-$\beta$1-mediated cellular processes of PF can promote CHM to be better understood and utilized, thus transforming the therapeutic activities of CHM into practice.

Chronic pancreatitis (CP) is a multifactorial, inflammatory syndrome characterized by acinar atrophy and fibrosis. Activation of NOD-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome is a central mediator of multiple chronic inflammatory responses and chronic fibrosis including pancreatic fibrosis in CP. The Psidium guajavaleaf is widely used in traditional medicine for the treatment of chronic inflammation, but the anti-inflammatory effect of Psidium guajavaleaf on CP has not yet been revealed. In this study, we investigated whether the extract of total flavonoids from Psidium guajava leaves (TFPGL) plays a therapeutic mechanism on CP through NLRP3 inflammasome signaling pathway in a mouse CP model. The H&E and acid-Sirius red staining indicted that TFPGL attenuated the inflammatory cell infiltration and fibrosis significantly. The results of immunohistological staining, western blot and RT-qPCR showed that the expressions of NLRP3 and caspase-1 were significantly increased in the CP model group, while TFPGL significantly decreased the NLRP3 and caspase-1 expression at both the gene and protein levels. Moreover, ELISA assay was used to examine the levels of NLRP3 inflammasome target genes, such as caspase-1, IL-1$\beta$ and IL-18. We found that TFPGL treatment decreased the expression of caspase-1, IL-1$\beta$ and IL-18, which is critical for the NLRP3 inflammasome signaling pathway and inflammation response significantly. These results demonstrated that TFPGL attenuated pancreatic inflammation and fibrosis via preventing NLRP3 inflammasome activation and TFPGL can be used as a potential therapeutic agent for CP.

Osteosarcoma is the most common malignant bone-forming tumor, wherein most patients with high grade osteosarcomas are treated with chemotherapy. Despite this, survival for metastatic or relapsed osteosarcoma patients has remained at an overall 5-year survival rate of 20%. In particular, the extracts of Corylopsis coreana (Korean winter hazel), a cultivated woody plant in South Korea, have shown beneficial anti-inflammatory, anti-oxidative, anti-osteoclastic, and antihyperuricemic properties. Therefore, this study aimed to demonstrate the antitumor activities and underlying mechanism of 11-O-Galloyl bergenin (OGAL) isolated from Corylopsis coreanas leaves in human osteosarcoma cells. Herein, we found that OGAL inhibited MG63 cell proliferation and induced cellular apoptosis as evidenced by cleaved-PARP, cleaved-caspase 3, TUNEL-positive cells, and Annexin V-positive cells. Specifically, OGAL-induced apoptosis was accompanied by p53 and p21 upregulation, BAX expression, and decreased Bcl-2 and cdk2. Moreover, OGAL induced autophagy via AKT inactivation, LC3II upregulation, and MG63 cell autophagosome formation. OGAL-induced autophagy was also accompanied by increased p38 phosphorylation, whereas JNK and ERK1/2 activities were found to be unaffected upon examining the MAPK signaling pathway. Furthermore, wound healing and Boyden chamber assays showed that OGAL suppressed MG63 cell migration and invasion. Given these findings, this study provided evidence that OGAL has antitumor effects by apoptosis and autophagy enhancement through increased p53, AKT, and p38 signaling, suggesting that OGAL may be a potential therapeutic strategy for osteosarcoma treatment.

Liver cancer is a gastrointestinal malignant tumor with high lethality. The prognosis of liver cancer remains poor. Compounds derived from natural products have been confirmed to alleviate the progression of various diseases, including cancers. Additionally, 6-Shogaol has been reported to induce apoptosis in liver cancer cells. However, the mechanism by which 6-shogaol regulates apoptosis in liver cancer cells remains unclear. To investigate the function of 6-shogaol in liver cancer, RT–qPCR and western blotting were used to detect the expression of TLR4 and FOXO3a in liver cancer cells, respectively. The OD value of liver cancer cells was measured using the MTT assay. Flow cytometry was used to measure cell apoptosis. 6-Shogaol inhibited the growth of liver cancer cells. TLR4 and Wnt/$\beta$-catenin were upregulated in liver cancer cells, and FOXO3a was inactivated, but 6-Shogaol reversed the expression of TLR4, Wnt/$\beta$-catenin and FOXO3a in liver cancer cells. Additionally, TLR4 overexpression partially reversed the inhibitory effect of 6-shogaol on the progression of liver cancer cells via Wnt/$\beta$-catenin signaling. Furthermore, the 6-shogaol-induced increase in FOXO3a expression in liver cancer was notably suppressed by TLR4 or Wnt/$\beta$-catenin upregulation. Thus, 6-Shogaol suppresses the progression of liver cancer by mediating Wnt/$\beta$-catenin signaling and is a potential agent for the treatment of liver cancer.