Gut microbiota-derived 5-hydroxyindoleacetic acid from pumpkin polysaccharides supplementation alleviates colitis via MAPKs-PPARγ/NF-κB inhibition.

Polysaccharides from Pumpkin (Cucurbita moschata Duchesne) (PPs) have many pharmacological activities, including anti-oxidant, immune, and intestinal microbiota regulation. These activities have provided some reminders of its potential therapeutic effect on ulcerative colitis (UC), but this has not yet been confirmed. This study preliminarily confirmed its significant anti-UC activity superior to Salicylazosulfapyridine. The average molecular weight of PPs was 3.10 × 105 Da, and PPs mainly comprised Mannose, Rhamnose, Galacturonic acid, Galactosamine, Glucose, and Xylose with molar ratios of 1.58:3.51:34.54:1.00:3.25:3.02. PPs (50, 100 mg/kg) could significantly resist dextran sodium sulfate induced UC on C57BL/6 mice by improving gut microbiota dysbiosis, such as the changes of relative abundance of Bacteroides, Culturomica, Mucispirillum, Escherichia-Shigella, Alistipes and Helicobacter. PPs also reverse the abnormal inflammatory reaction, including abnormal level changes of TNF-α, IFN-γ, IL-1ß, IL-4, IL-6, IL-10, and IL-18. Metabolomic profiling showed that PPs supplementation resulted in the participation of PPAR and MAPK pathways, as well as the increase of 5-hydroxyindole acetic acid (5-HIAA) level. 5-HIAA also exhibited individual and synergistic anti-UC activities in vivo. Furthermore, combination of PPs and 5-HIAA could also elevate the levels of PPARγ in nuclear and inhibit MAPK/NF-ĸB pathway in the colon. This study revealed that PPs and endogenous metabolite 5-HIAA might be developed to treat UC.

Phase I, Single-Dose Study to Assess the Pharmacokinetics and Safety of Suramin in Healthy Chinese Volunteers.

Purpose: Suramin is a multifunctional molecule with a wide range of potential applications, including parasitic and viral diseases, as well as cancer. Methods: A double-blinded, randomized, placebo-controlled single ascending dose study was conducted to investigate the safety, tolerability, and pharmacokinetics of suramin in healthy Chinese volunteers. A total of 36 healthy subjects were enrolled. All doses of suramin sodium and placebo were administered as a 30-minute infusion. Blood and urine samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events. Results: After a single dose, suramin maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUClast) increased in a dose-proportional manner. The plasma half-life (t1/2) was dose-independent, average 48 days (range 28-105 days). The cumulative percentages of the dose excreted in urine over 7 days were less than 4%. Suramin can be detected in urine samples for longer periods (more than 140 days following infusion). Suramin was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild in severity. Conclusion: The PK and safety profiles of suramin in Chinese subjects indicated that 10 mg/kg or 15 mg/kg could be an appropriate dose in a future multiple-dose study.

Efficacy and safety of immune checkpoint inhibitors in post-TKI NSCLC patients harboring EGFR mutations.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have been validated in epidermal growth factor receptor (EGFR) wild-type advanced non-small cell lung cancer (NSCLC) patients. However, there exists no evidence regarding NSCLC patients harboring EGFR mutations, experiencing EGFR-TKI (tyrosine kinase inhibitor) treatment failure. We collected clinical information from real world and conducted a time series-based meta-analysis to determine the efficacy and safety of ICIs in patients harboring EGFR mutations and experienced EGFR-TKIs resistance. METHODS: Twenty-two NSCLC patients with EGFR mutations after TKI resistance were included from two hospitals. PubMed, Embase and Cochrane Library were searched for relevant literature published until December 31, 2021. Endpoint outcomes included mortality and progression-free survival (PFS) at different times of follow-up. RESULTS: In total, 22 patients showed that the median PFS was 5.6 months (range 2.0-9.0 months). According to treatment strategies, the median PFS was 2.4 months (range 2.0-5.3 months) in the ICI monotherapy group and 5.9 months (range 2.8-9.0 months) in the ICI combined Chemotherapy group. Additionally, sixteen studies, including 5 trials, 10 controlled cohorts and 1 real-world study, were assessed, involving a total of ICI-treated NSCLC patients with EGFR mutation after TKI failure. The 6-month survival and PFS rate were 0.82 (95% CI 0.36-0.97) and 0.55 (95% CI 0.34-0.74), respectively. ICI combined chemotherapy showed the best survival outcome among these groups, as demonstrated by the 12-month survival rate and PFS. No new safety signals were identified with the combination therapy. The frequency of treatment-related adverse events was similar to that in previously reported studies of chemotherapy combined with checkpoint inhibitors. CONCLUSIONS: The addition of ICIs plus chemotherapy may significantly improve progression-free survival among patients with locally advanced or metastatic non-squamous NSCLC who EGFR-TKIs resistance.

Sanguinarine ameliorates DSS induced ulcerative colitis by inhibiting NLRP3 inflammasome activation and modulating intestinal microbiota in C57BL/6 mice.

BACKGROUND: Sanguinarine (SAN) is an important natural anti-inflammatory constitutes and dietary supplementation with SAN could improve the relative length of the intestine, alter gut microbiota, and enhance growth performance of pigs, broiler chickens, and cattle. However, it is unclear whether it has the therapeutic effect on ulcerative colitis (UC). PURPOSE: This study aimed to investigate the therapeutic effect of SAN on UC and explore its mechanisms of action. STUDY DESIGN AND METHODS: Several efficacy indexes of SAN on dextran sulfate sodium (DSS)-induced C57BL/6 mice were evaluated. ELISA kit and western blot analysis were used to evaluate it's anti-inflammatory effect and the mechanism of action. 16S rDNA sequencing detection was used to determine the impact of SAN on gut microbiota. RESULTS: SAN and Sulfasalazine could significantly improve the colon length, the weight loss, the symptoms and the pathological injury of colon in DSS-induced mice. Meanwhile, SAN could decrease the levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1ß, IL-6, IL-13 and IL-18) and increase the levels of anti-inflammatory cytokines (IL-4 and IL-10) in colon, and suppress DSS-induced high expressions of NLRP3, caspase-1 and IL-1ß. In addition, SAN (0.5, 1 µM) could inhibit the expression level of NLRP3 and the activation of caspase-1 and IL-1ß in lipopolysaccharide-stimulated THP-1 cells in non-cytotoxic doses, which was similar to that of MCC950, a specific inhibitor of NLRP3 inflammasome activation. The abundance changes of many genera such as Muribaculaceae_unclassified, Escherichia-Shigella, Lachnospiraceae_NK4A136_group and Helicobacter were also closely related to the improvement of SAN on intestinal inflammatory response. CONCLUSION: SAN exhibited therapeutic effect on DSS-induced colitis by blocking NLRP3-(Caspase-1)/IL-1ß pathway and improving intestinal microbial dysbiosis. SAN might be developed to treat UC and other disorders associated with microbial dysbiosis.

Disease burden of liver cancer attributable to specific etiologies in China from 1990 to 2019: An age-period-cohort analysis.

Temporal trends of total liver cancer have been well reported in China, especially the trends caused by hepatitis B (HBV); however, the trends of liver cancer attributable to specific etiologies have rarely been reported in China. Thus, this study aims to describe the temporal trends in the incidence, mortality and DALYs of total and etiology-specific liver cancer in China from 1990 to 2019. We extracted the incidence, mortality and disability-adjusted life years (DALYs) of total and etiology-specific liver cancer in China from 1990 to 2019 from global disease burden (GBD) 2019. We plotted the trends in the age-standardized rates for incidence, mortality, and DALYs using locally weighted regression (LOESS)-smoothed data from 1990 to 2019. The age-standardized rate for the incidence of liver cancer was analyzed with an age-period-cohort method. The age-standardized rates for incidence, death, and DALYs decreased by -58.8%, -63.8%, and -65.6%, respectively, between 1990 and 2019. The age-standardized rates of incidence, mortality, and DALYs of total liver cancer showed similar temporal patterns, presenting an overall decline, with the average annual percentage change (AAPC) ranging from -3.3% to -3.8%. People in the period before 2007 had a higher risk, and people after 2007 had a lower risk. The cohort risk ratios (RRs) showed decreasing patterns, with the most rapid decline observed in the 1910 to 1960 cohorts. Our study generally revealed favorable decreasing trends for total and etiology-specific liver cancer in China from 1990 to 2019. Despite the overall decline in liver cancer due to heavy alcohol use and obesity from 1990 to 2019, there have been apparent upward trends since 2006. Planned population-wide interventions targeting heavy alcohol use and obesity may mitigate the increasing trends in liver cancer attributable to alcohol use and NASH.

Hepatitis B and hepatitis C prevalence among people living with HIV/AIDS in China: a systematic review and Meta-analysis.

BACKGROUND: There has been little published data on estimates of HBV and/or HCV coinfection in HIV-positive patients in China or an understanding of how this coinfection varies with different factors. Therefore, this study aimed to determine, through a systematic review and meta-analysis, the prevalence of HBV and/or HCV in HIV-positive patients in China and explore variations in prevalence. METHODS: The Medicine, Web of Science, Chinese Web of Knowledge, and Wanfang databases were searched using a search strategy combining key words and related disease-specific subject terms to identify relevant cohort or cross-sectional studies published up to April 2019. Included articles were assessed for quality. Pooled prevalence and 95% confidence intervals (CIs) were calculated according to study region and other specific characteristics. RESULTS: Our searches identified 7843 records, but only 66 studies were included in our meta-analysis. The pooled HBsAg prevalence in HIV-positive patients was 13.7% (95% CI 12.3-15.3%), with variations found in terms of age and geographic region. The meta-HCV prevalence was 24.7% (95% CI 19.3-30.5%), which varied over the study period and age. The pooled HBV-HCV coinfection prevalence was 3.5% (95% CI 2.4-4.8%), with variations found in terms of age and geographic region. CONCLUSION: Given the high burden of HBV and HCV coinfections in HIV-positive patients, the incorporation of comprehensive screening, treatment, prevention, and vaccination programs into general HIV management in China is imperative.

Lentiviral-mediated overexpression of homeobox A4 by human umbilical cord mesenchymal stem cells repairs full-thickness skin defects.

A number of types of stem cells have been shown to be effective in wound repair. In the present study the effect of homeobox A4 (HOXA4) overexpression by human umbilical cord mesenchymal stem cells (hUMSCs) on full­thickness skin repair was evaluated. Isolated hUMSCs were transfected with a lentivirus expressing HOXA4 and cultured for 21 days. Expression of the epidermal cell­specific markers, cytokeratins 14 and 18, was detected by immunohistochemistry and flow cytometry. Full­thickness skin defects (1.5 cm x 1.5 cm) were made on the backs of 45 nude mice, which were randomly divided into the following three treatment groups: Collagen membrane with lenti­HOXA4 hUMSC seed cells; collagen membrane with lentivirus expressing green fluorescent protein; and collagen membrane alone. On days 7, 14 and 21 following transplantation, tissue samples were harvested and examined by histology and western blot analysis. Flow cytometry showed that the transfection efficiency was 95.41% at a multiplicity of infection of 100, and that the lenti­HOXA4 hUMSCs differentiated into epidermal cells, expressing cytokeratins 14 and 18. In addition, re­epithelialization of wounds treated with lenti­HOXA4 hUMSCs was significantly greater than that in the control groups in the first week. By week three the epidermis was significantly thicker in the lenti­HOXA4 group than the control groups. Thus, transplantation of hUMSCs modified with Ad­HOXA4 promoted wound healing.