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The gut microbiota not only constitutes intestinal microenvironment homeostasis and human health but also exerts indispensable roles in the occurrence and progression of multiple liver diseases, including alcohol-related liver disease, nonalcoholic fatty liver disease, autoimmune liver disease and liver cancer. Given the therapeutic status of these diseases, their prevention and early therapy are crucial, and the detailed mechanism of gut microbiota in liver disease urgently needs to be explored. Meanwhile, multiple studies have shown that various traditional Chinese medicines, such as Si Miao Formula, Jiangzhi Granules, Liushen Capsules, Chaihu-Shugan Power, Cassiae Semen and Gynostemma, as well as some natural products, including Costunolide, Coprinus comatus polysaccharide, Antarctic krill oil, Oridonin and Berberine, can repair liver injury, improve fatty liver, regulate liver immunity, and even inhibit liver cancer through multiple targets, links, and pathways. Intriguingly, the aforementioned effects demonstrated by these traditional Chinese medicines and natural products have been shown to be closely related to the gut microbiota, directly driving the strategy of traditional Chinese medicines and natural products to regulate the gut microbiota as one of the breakthroughs in the treatment of liver diseases. Based on this, this review comprehensively summarizes and discusses the characteristics, functions and potential mechanisms of these medicines targeting gut microbiota during liver disease treatment. Research on the potential effects on gut microbiota and the regulatory mechanisms of traditional Chinese medicine and natural products provides novel insights and significant references for developing liver disease treatment strategies. In parallel, such explorations will enhance the comprehension of traditional Chinese medicine and natural products modulating gut microbiota during disease treatment, thus facilitating their clinical investigation and application.

Osteoporosis (OP) is a chronic bone disease characterized by aberrant microstructure and macrostructure of bone, leading to reduced bone mass and increased risk of fragile fractures. Anti-resorptive drugs, especially, bisphosphonates, are currently the treatment of choice in most developing countries. However, they do have limitations and adverse effects, which, to some extent, helped the development of anabolic drugs such as teriparatide and romosozumab. In patients with high or very high risk for fracture, sequential or combined therapies may be considered with the initial drugs being anabolic agents. Great endeavors have been made to find next generation drugs with maximal efficacy and minimal toxicity, and improved understanding of the role of different signaling pathways and their crosstalk in the pathogenesis of OP may help achieve this goal. Our review focused on recent progress with regards to the drug development by modification of Wnt pathway, while other pathways/molecules were also discussed briefly. In addition, new observations made in recent years in bone biology were summarized and discussed for the treatment of OP.

The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis. Wnt signaling is induced, and β -catenin is activated, associated with the development and progression of renal fibrosis. Wnt/ β -catenin controls the expression of various downstream mediators such as snail1, twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1, transient receptor potential canonical 6, and renin-angiotensin system components in epithelial cells, fibroblast, and macrophages. In addition, Wnt/ β -catenin is usually intertwined with other signaling pathways to promote renal interstitial fibrosis. Actually, given the crucial of Wnt/ β -catenin signaling in renal fibrogenesis, blocking this signaling may benefit renal interstitial fibrosis. There are several antagonists of Wnt signaling that negatively control Wnt activation, and these include soluble Fzd-related proteins, the family of Dickkopf 1 proteins, Klotho and Wnt inhibitory factor-1. Furthermore, numerous emerging small-molecule β -catenin inhibitors cannot be ignored to prevent and treat renal fibrosis. Moreover, we reviewed the knowledge focusing on anti-fibrotic effects of natural products commonly used in kidney disease by inhibiting the Wnt/ β -catenin signaling pathway. Therefore, in this review, we summarize recent advances in the regulation, downstream targets, role, and mechanisms of Wnt/ β -catenin signaling in renal fibrosis pathogenesis. We also discuss the therapeutic potential of targeting this pathway to treat renal fibrosis; this may shed new insights into effective treatment strategies to prevent and treat renal fibrosis.

This study aimed to investigate the ameliorative effect of the polysaccharides of Panax quinquefolius (WQP) on ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in mice and to explore its mechanism. Male C57BL/6J mice were randomly divided into the control group (C), model group (DSS), positive control mesalazine (100 mg/kg, Y) group, and low (50 mg/kg, L), medium (100 mg/kg, M) and high dose (200 mg/kg, H) of WQP groups. The UC model was induced by free drinking water with 2.5% DSS for 7 days. During the experiment, the general condition of the mice was observed, and the disease activity index (DAI) was scored. The conventional HE staining was used to observe pathological changes in mice’s colon, and the ELISA method was used to detect the levels of interleukin-6 (IL-6), IL-4, IL-8, IL-10, IL-1β and tumor necrosis factor-α (TNF-α) in mice’s colon. The changes in gut microbiota in mice were detected by high-throughput sequencing; the concentration of short-chain fatty acids (SCFAs) was determined by gas chromatography; the expression of related proteins was detected by Western blot. Compared with the DSS group, the WQP group showed a significantly lower DAI score of mice and an alleviated colon tissue injury. In the middle- and high-dose polysaccharides groups, the levels of pro-inflammatory cytokines IL-6, IL-8, IL-1β and TNF-α in the colonic tissue were significantly decreased ( P <0.05), while the levels of IL-4 and IL-10 were significantly increased ( P <0.05). The 16S rRNA gene sequencing results showed that different doses of WQP could regulate the composition and diversity of gut microbiota and improve its structure. Specifically, at the phylum level, group H showed an increased relative abundance of Bacteroidetes and a decreased relative abundance of Firmicutes compared with the DSS group, which was closer to the case in group C. At the family level, the relative abundance of Rikenellaceae in L, M and H groups increased significantly, close to that in group C. At the genus level, the relative abundance of Bacteroides , Shigella and Oscillospira in the H group increased significantly, while that of Lactobacillus and Prevotella decreased significantly. The high-dose WQP group could significantly increase the contents of acetic acid, propionic acid, butyric acid, and total SCFAs. Different doses of WQP also increased the expression levels of tight junction proteins ZO-1, Occludin and Claudin-1. To sum up, WQP can regulate the gut microbiota structure of UC mice, accelerate the recovery of gut microbiota, and increase the content of Faecal SCFAs and the expression level of tight junction proteins in UC mice. This study can provide new ideas for the treatment and prevention of UC and theoretical references for the application of WQP.

Dopamine D1 receptor (D1DR) and D2 receptor (D2DR) are closely associated with pain modulation, but their exact effects on neuropathic pain and the underlying mechanisms remain to be identified. Our research revealed that intrathecal administration of D1DR and D2DR antagonists inhibited D1–D2DR complex formation and ameliorated mechanical and thermal hypersensitivity in chronic constriction injury (CCI) rats. The D1–D2DR complex was formed in the rat spinal cord, and the antinociceptive effects of D1DR and D2DR antagonists could be reversed by D1DR, D2DR, and D1–D2DR agonists. Gαq, PLC, and IP3 inhibitors also alleviated CCI-induced neuropathic pain. D1DR, D2DR, and D1–D2DR complex agonists all increased the intracellular calcium concentration in primary cultured spinal neurons, and this increase could be reversed by D1DR, D2DR antagonists and Gαq, IP3, PLC inhibitors. D1DR and D2DR antagonists significantly reduced the expression of p-PKC γ, p-CaMKII, p-CREB, and p-MAPKs. Levo -corydalmine ( l -CDL), a monomeric compound in Corydalis yanhusuo W.T. Wang, was found to obviously suppress the formation of the spinal D1–D2DR complex to alleviate neuropathic pain in CCI rats and to decrease the intracellular calcium concentration in spinal neurons. l- CDL-induced inhibition of p-PKC γ, p-MAPKs, p-CREB, and p-CaMKII was also reversed by D1DR, D2DR, and D1–D2DR complex agonists. In conclusion, these results indicate that D1DR and D2DR form a complex and in turn couple with the Gαq protein to increase neuronal excitability via PKC γ, CaMKII, MAPK, and CREB signaling in the spinal cords of CCI rats; thus, they may serve as potential drug targets for neuropathic pain therapy. Chronic pain: Cutting communication for nerve pain signals Insights into dopamine-mediated neuronal activity in the spinal cord may lead to more effective relief for some chronic pain patients. Up to 10% of adults worldwide live with some form of pain due to nerve damage (neuropathy), and few treatment options are available. The neurotransmitter dopamine is thought to regulate pain-related signaling in the spinal cord, and researchers led by Ji-Hua Liu and Bo-Yang Yu of China Pharmaceutical University, Nanjing, have identified a way to interfere with this signaling. Working with a rat neuropathic pain model, the researchers focused on a protein complex that acts as a receptor for dopamine in spinal neurons. Once activated, this complex initiates cellular processes that mediate the pain response. Chemical agents that block receptor assembly counter these processes, highlighting a promising mechanism to target in neuropathic pain patients.

The objective of the present study was to compare the effects of the immunological activity of various parts (root/stem/leaf/flower/seed) of five-year-old ginseng on the immune system of immunosuppressive mice. Immunosuppression was induced by cyclophosphamide (CTX) in the mouse model, whereas levamisole hydrochloride tablet (LTH) was used for the positive control group. We found that ginseng root (GRT), ginseng leaf (GLF), and ginseng flower (GFR) could relieve immunosuppression by increased viability of NK cells, enhanced immune organ index, improved cell-mediated immune response, increased content of CD4+ and ratio of CD4+/CD8+, and recovery of macrophage function, including carbon clearance, phagocytic rate, and phagocytic index, in immunodeficient mice. However, ginseng stem (GSM) and ginseng seed (GSD) could only enhance the thymus indices, carbon clearance, splenocyte proliferation, NK cell activities, and the level of IL-4 in immunosuppressed mice. In CTX-injected mice, GRT and GFR remarkably increased the protein expression of Nrf2, HO-1, NQO1, SOD1, SOD2, and CAT in the spleen. As expected, oral administration of GRT and GFR markedly enhanced the production of cytokines, such as IL-1β, IL-4, IL-6, IFN-γ, and TNF-α, compared with the CTX-induced immunosuppressed mice, and GRT and GFR did this relatively better than GSM, GLF, and GSD. This study provides a theoretical basis for further study on different parts of ginseng.

It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. ClinicalTrials.gov Identifier: NCT03493048.

Background Pediatric pulmonary hypertension (PH) is a serious and rare disease that is often derived from genetic mutations. Kabuki syndrome (KS) is a chromosomal abnormality disease that has its origin in the mutation of lysine methyltransferase 2D( KMT2D ). Recent evidence has shown that KMT2D mutations are associated with pediatric pulmonary disorders. However, the relationship between the clinical courses of PH and the KMT2D mutation is reported in extremely few cases. Therefore, in this paper, a case was presented and previous literature was reviewed for better understanding of the correlation between pediatric PH and KMT2D mutations. Case presentation A 3-year-old girl was transferred to our center for severe cough, shortness of breath, fatigue and fever. Physical examination revealed facial deformities and growth retardation. Echocardiography showed a small atrial septal defect (ASD), and right heart catheterization indicated a significant increase in pulmonary vascular pressure and resistance. The genetic test suggested that she had a KMT2D gene mutation. The patient was finally diagnosed with KS. She was given targeted drugs to reduce pulmonary vascular pressure, but the effect was unsatisfactory. Conclusions KS can be complicated with multiple organ malformations and dysfunction. With the progress of next generation sequencing, an increasing number of new phenotypes related to KMT2D mutations have been reported. A bold hypothesis is proposed in this article, that is, PH may be a new phenotype associated with KMT2D mutations. It is suggested that KS and PH should be differentiated from each other to avoid delayed diagnosis and treatment in clinical practice. There is no specific drug for KS treatment. The prognosis of children with inherited PH is usually poor, and lung transplantation may increase their survival rates.