Ginsenoside Rh4 alleviates gastrointestinal mucositis and enhances chemotherapy efficacy through modulating gut microbiota.

BACKGROUND: Gastrointestinal mucositis stands as one of the most severe side effects of irinotecan (CPT-11). however, only palliative treatment is available at present. Therefore, there is an urgent need for adjunctive medications to alleviate the side effects of CPT-11. PURPOSE: In this study, our objective was to explore whether ginsenoside Rh4 could serve as a modulator of the gut microbiota and an adjunctive agent for chemotherapy, thereby alleviating the side effects of CPT-11 and augmenting its anti-tumor efficacy. STUDY DESIGN: A CPT-11-induced gastrointestinal mucositis model was used to investigate whether ginsenoside Rh4 alleviated CPT-11-induced gastrointestinal mucositis and enhanced the anti-tumor activity of CPT-11. METHODS: In this study, we utilized CT26 cells to establish a xenograft tumor model, employing transcriptomics, genomics, and metabolomics techniques to investigate the impact of ginsenoside Rh4 on CPT-11-induced gastrointestinal mucositis and the effect on the anti-tumor activity of CPT-11. Furthermore, we explored the pivotal role of gut microbiota and their metabolites through fecal microbiota transplantation (FMT) experiments and supplementation of the key differential metabolite, hyodeoxycholic acid (HDCA). RESULTS: The results showed that ginsenoside Rh4 repaired the impairment of intestinal barrier function and restored intestinal mucosal homeostasis in a gut microbiota-dependent manner. Ginsenoside Rh4 treatment modulated gut microbiota diversity and upregulated the abundance of beneficial bacteria, especially Lactobacillus_reuteri and Akkermansia_muciniphila, which further regulated bile acid biosynthesis, significantly promoted the production of the beneficial secondary bile acid hyodeoxycholic acid (HDCA), thereby alleviating CPT-11-induced gut microbiota dysbiosis. Subsequently, ginsenoside Rh4 further alleviated gastrointestinal mucositis through the TGR5-TLR4-NF-κB signaling pathway. On the other hand, ginsenoside Rh4 combination therapy could further reduce the weight and volume of colon tumors, promote tumor cell apoptosis, and enhance the anti-tumor activity of CPT-11 by inhibiting the PI3K-Akt signaling pathway, thus exerting a synergistic anti-tumor effect. CONCLUSION: In summary, our findings confirm that ginsenoside Rh4 can alleviate CPT-11-induced gastrointestinal mucositis and enhance the anti-tumor activity of CPT-11 by modulating gut microbiota and its related metabolites. Our study validates the potential of ginsenoside Rh4 as a modulator of the gut microbiota and an adjunctive agent for chemotherapy, offering new therapeutic strategies for addressing chemotherapy side effects and improving chemotherapy efficacy.

Expression of Multicopy Tandem Recombinant Ginseng Hexapeptide in Bacillus subtilis and the Evaluation of Antiaging Activity.

Ginseng oligopeptides are naturally occurring small-molecule peptides extracted from ginseng that exhibit positive effects on health and longevity. However, the current industrial production of ginseng oligopeptides primarily relies on plant extraction and chemical synthesis. In this study, we proposed a novel genetic engineering approach to produce active ginseng peptides through multicopy tandem insertion (5 and 15 times). The recombinant ginseng peptides were successfully produced from engineered Bacillus subtilis with an increasing yield from 356.55 to 2900 mg/L as the repeats multiple. Additionally, an oxidative stress-induced aging model caused by H2O2 was established to evaluate whether the recombinant ginseng peptides, without enzymatic hydrolysis into individual peptides, also have positive effects on antiaging. The results demonstrated that all two kinds of recombinant ginseng peptides could also delay cellular aging through various mechanisms, such as inhibiting cell cycle arrest, suppressing the expression of pro-inflammatory factors, and enhancing cellular antioxidant capacity.

Ginsenoside Rg5 inhibits lipid accumulation and hepatocyte apoptosis via the Notch1 signaling pathway in NASH mice.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a prevalent chronic liver disease that lacks an FDA-approved treatment medicine. Despite the known antitumor and hypoglycemic properties of Ginsenoside Rg5, its effects and underlying mechanisms in the context of NASH remain largely unexplored. PURPOSE: This study aims to investigate the effect of Rg5 on NASH mice induced by a high-fat diet and CCl4. STUDY DESIGN: In vivo experiments, a mouse NASH model was established by a HFHC diet plus intraperitoneal injection of low-dose CCl4. In vitro experiments, a cellular steatosis model was established using free fatty acids (FFA) induced HepG2 cells. In addition, a fibrogenesis model was established using HSC-LX2 cells. METHODS: The effects of Ginsenoside Rg5 on lipid accumulation and oxidative damage were analyzed by ELISA kit, H&E staining, Oil Red O staining, flow cytometry and Western blot. The effects of Ginsenoside Rg5 on liver fibrosis were analyzed by Masson staining, Sirus Red staining, immunohistochemistry and Western blot. The effect of Ginsenoside Rg5 on Notch1 signaling pathway in liver was studied by protein Oil Red staining, protein immunoblotting and immunofluorescence. RESULTS: In terms of lipid accumulation, Rg5 has the ability to regulate key proteins related to lipogenesis, thereby inhibiting hepatic lipid accumulation and oxidative stress. Additionally, Rg5 can reduce the occurrence of hepatocyte apoptosis by regulating the p53 protein. Moreover, after Rg5 intervention, the presence of fibrotic proteins (α-SMA, Collagen 1, TGF-ß) in the liver is significantly suppressed, thus inhibiting liver fibrosis. Lastly, Rg5 leads to a decrease in the expression levels of Notch1 and its ligand Jagged-1 in the liver. CONCLUSION: In summary, the regulatory effects of Rg5 on the Notch1 signaling pathway play a crucial role in modulating hepatic lipid metabolism and preventing hepatocyte apoptosis, thereby impeding the progression of NASH. These findings highlight the potential of Rg5 as a promising natural product for interventions targeting NASH.

Ginsenoside Rh4 delays skeletal muscle aging through SIRT1 pathway.

BACKGROUND: The aging of skeletal muscle is the leading cause of physical disability in older adults, currently effective treatment methods are lacking. Ginsenoside Rh4, an active component extracted from ginseng, possesses beneficial anti-inflammatory and anti-oxidative effects. PURPOSE: The aim of this study was to elucidate the antioxidant effect of ginsenoside Rh4 on aging skeletal muscle and its molecular mechanism of anti-aging of skeletal muscle. STUDY DESIGN: In this study, we employed a D-galactose-induced model of skeletal muscle aging to investigate whether ginsenoside Rh4 can delay the process of skeletal muscle senescence. METHODS: The effects of ginsenoside Rh4 on oxidative damage and inflammation in aging skeletal muscle were analyzed using immunofluorescence, immunohistochemistry, ELISA kits, H&E staining, flow cytometry, and protein immunoblotting. The changes of ginsenoside Rh4 on mitochondrial morphology were observed by transmission electron microscopy, and ELISA kits and protein immunoblotting analyzed the effects of ginsenoside Rh4 on mitochondrial homeostasis in skeletal muscle cells. The influence of ginsenoside Rh4 on the SIRT1 signaling pathway in aging skeletal muscle were investigated by protein immunoblotting, immunofluorescence, and ß-galactosidase staining. RESULTS: Our results showed that Rh4 improved the morphology of muscle fibers and produced an anti-inflammatory response. Furthermore, in vitro experiments indicated that ginsenosides reduced the production of senescent cells, while Rh4 effectively alleviated oxidative damage in skeletal muscle and restored mitochondrial balance. Transcriptome analysis and molecular docking showed that Rh4 improved mitochondrial homeostasis and delayed skeletal muscle aging by regulating the PGC-1α-TFAM and HIF-1α-c-Myc pathways via targeting SIRT1. CONCLUSION: Ginsenoside Rh4 improves oxidative stress and inflammation in skeletal muscle by activating SIRT1, deacetylating Nrf2, regulating PGC-1α-TFAM and HIF-1α-c-Myc pathways, and enhancing mitochondrial homeostasis, thus achieving the effect of delaying skeletal muscle aging.

Mussel-inspired adhesive bilayer hydrogels for bacteria-infected wound healing via NIR-enhanced nanozyme therapy.

Preventing bacterial infection in situ and accelerating skin generation simultaneously are essentially important for wound healing. Herein, a mussel-inspired Ag nanozyme-based bilayer hydrogel is constructed to address the above concerns. The bilayer hydrogel is composed of a layer with large pores absorbing the wound exudate and allowing oxygen exchange and a layer with small pores keeping the wound moist and preventing bacterial invasion. Benefitting from the polydopamine (PDA) coating-reduced Ag nanoparticles (AgNPs), the hydrogel exhibits high near infrared (NIR) absorption at 808 nm to generate hyperthermia and NIR-enhanced peroxidase (POD-like) activity to produce hydroxyl radicals (•OH), which endows the hydrogel with excellent antibacterial properties when combined with the released Ag+. In addition, the hydrogel presents adhesiveness due to the catechol group on a PDA molecule. The in vivo test results demonstrate that the bilayer hydrogel can accelerate infected skin generation by facilitating collagen deposition, decreasing tumor necrosis factor-α secretion, and promoting vascular endothelial growth factor expression.

The effects on pain, physical function, and quality of life of quadriceps strengthening exercises combined with Baduanjin qigong in older adults with knee osteoarthritis: a quasi-experimental study.

BACKGROUND: Exercise is recommended as a principal treatment for individuals with knee osteoarthritis (KOA). However, the best choice for an optimal exercise program able to promote long-term compliance in KOA patients is not clear. This study aims to compare the effect of combined exercise (CE: quadriceps strengthening exercises (QSE) and Baduanjin qigong training (BDJ)) versus QSE alone and BDJ alone on older adults with KOA. METHODS: A three-arm, quasi-experimental trial with repeated measurements was used. As a cluster randomized trial, participants from three community centers were assigned respectively to QSE group, BDJ group and CE group. We assessed pain intensity, physical function, self-efficacy, and health-related quality-of-life (HRQoL) using standardized instruments at baseline, 3 months and 6 months follow-up. RESULTS: One hundred and twenty-eight participants with KOA aged over 60 completed the study. Over the 6 months, there were significant group interaction effects on pain intensity (F = 28.888, P < 0.001), physical function (F = 26.646, P < 0.001), and self-efficacy (F = 22.359, P < 0.001), and, based on a short form-12 item health survey questionnaire (SF-12), physical component summary (F = 7.470, P < 0.001), and mental component summary (F = 10.207, P < 0.001). Overall, the CE group exhibited significantly greater improvement in all outcomes when compared to the QSE group and the BDJ group. CONCLUSIONS: CE treatment is more effective than QSE and BDJ in pain relief, increasing physical function, improving self-efficacy, and raising quality-of-life in community-dwelling KOA older adults. Moreover, it promotes long-term compliance in KOA community patients. TRIAL REGISTRATION: Chinese Clinical Trails Registry number ChiCTR2000033387 (retrospectively registered). Registered 30 May 2020.

The effect of human-like collagen calcium complex on osteoporosis mice.

The objective of this study was to assess the effect of a modified human-like collagen calcium complex on osteoporosis mice. BHK (Baby Hamster Kidney) cells were used to compare the cytotoxicity of different calcium reagents with the MTT test. Six-week-old male mice (n = 80) were randomly divided into eight groups: a blank group (blank), control group (control), human-like collagen calcium group (HLC-Ca), thiolated human-like collagen calcium group (SH-HLC-Ca), phosphorylated human-like collagen calcium group (Pi-HLC-Ca), gluconate group (Glc-Ca), calcium carbonate group (CaCO3) and D-cal group (B). A systematic analysis of the results available in vivo after 3 months of treatment was presented. The effects of several Ca supplements on osteoporosis mice were investigated by detecting serum calcium, alkaline phosphate activity (ALP), bone hydroxyproline (BHP) and bone mineral density (BMD). The results proved that the BMD and BHP of osteoporosis mice were significantly increased in the Pi-HLC-Ca group, while serum calcium and ALP were decreased. Therefore, Pi-HLC-Ca is likely a good calcium supplement for clinical applications. In this review, the advantage of Pi-HLC-Ca in preventing and delaying osteoporosis is highlighted. In addition to the current progress, further investigations are necessary to reveal the relative influences of collagen and calcium proportions on the long-term clinical effects of osteoporosis.

Anticancer effects of ginsenoside Rk3 on non-small cell lung cancer cells: in vitro and in vivo.

Ginsenoside Rk3 (Rk3) is present in the roots of processed Panax notoginseng herbs and it exerts anti-platelet aggregation, pro-immunogenic and cardioprotective effects. However, little is known regarding the anticancer activities of this compound, especially in lung cancer. This study was designed to investigate the anticancer effects of Rk3 on non-small cell lung cancer (NSCLC) cells and in an H460 xenograft tumor model. Our results showed that Rk3 reduced cell viability, inhibited both cell proliferation and colony formation, and induced G1 phase cell cycle arrest by downregulating the expression of cyclin D1 and CDK4 and upregulating the expression of P21. Rk3 also induced apoptosis in a concentration-dependent manner in H460 and A549 cells by Annexin V/PI staining, TUNEL assay and JC-1 staining, resulting in a change in the nuclear morphology. Moreover, Rk3 induced the activation of caspase-8, -9, and -3, promoted changes in mitochondrial membrane potential, decreased the expression of Bcl-2, increased the expression of Bax, and caused the release of cytochrome c, which indicated that the apoptosis-inducing effects of Rk3 were triggered via death receptor-mediated mitochondria-dependent pathways. Furthermore, Rk3 significantly inhibited the growth of H460 xenograft tumors without an obvious effect on the body weight of the treated mice. Histological analysis indicated that Rk3 inhibited tumor growth by altering the proliferation and morphology of tumor cells. In addition, we confirmed that Rk3 inhibited angiogenesis via CD34 staining and chick embryo chorioallantoic membrane (CAM) assay in vivo. Taken together, our findings revealed not only the anticancer effect of Rk3 on NSCLC cells but also a new promising therapeutic agent for human NSCLC.