Deciphering the pharmacological mechanisms of Shenlingbaizhu formula in antibiotic-associated diarrhea treatment: Network pharmacological analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenlingbaizhu (SLBZ) formula, a classical traditional Chinese medicinal (TCM) formula, has been widely used for treating antibiotic-associated diarrhea (AAD). However, the underlying pharmacological mechanisms have not yet been investigated thoroughly. AIM OF THE STUDY: To explore the remission mechanism of SLBZ in the treatment of AAD, we conducted network pharmacological analysis and experimental validation in vitro and in vivo. MATERIALS AND METHODS: In this study, the main compounds of SLBZ were identified by ultra-high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) and online databases. The targets of the active components and AAD-related targets were predicted by network pharmacology, and the potential targets of SLBZ against AAD were obtained. Then the core targets were recognized after Protein-Protein Interaction (PPI) analysis. Based on these, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analyses were conducted, and the key pathway was screened. Subsequently, molecular docking was performed using Auto Dock Vina to find the key components that played a crucial role in that pathway. Molecular dynamics simulation was performed by Gromacs software to detect the binding mode. Finally, the results were confirmed by in vitro and in vivo experiments. RESULTS: A total of 66 active ingredients of SLBZ were detected by UHPLC-MS, and 128 active ingredients were screened out by network pharmacological analysis. Additionally, 935 drug targets and 1686 AAD-related targets were obtained. Seventy-eight intersected genes were selected as potential therapeutic targets and 19 genes were excavated as core targets. Enrichment analysis revealed PI3K-AKT signaling pathway was the key pathway in SLBZ against AAD. Topological analysis further revealed that JAK2, MTOR, TLR4, and SYK were the key targets affected by SLBZ on the PI3K-AKT pathway, and 52 components of SLBZ were associated with them. Molecular docking and dynamics simulation revealed strong binding affinities between MTOR and diosgenin. Subsequently, after SLBZ treatment, the expression levels of JAK2, MTOR, TLR4, and SYK were found significantly upregulated in the AAD model rats (p < 0.05). The cell experiment further validated the good binding ability between MTOR and diosgenin. CONCLUSION: We demonstrate that the therapeutic effect of SLBZ on AAD was achieved in part by inhibiting the PI3K-AKT pathway.

Gut Microbial Dysbiosis and Changes in Fecal Metabolic Phenotype in Precancerous Lesions of Gastric Cancer Induced With N-Methyl-N'-Nitro-N-Nitrosoguanidine, Sodium Salicylate, Ranitidine, and Irregular Diet.

Background and Aims: Precancerous lesions of gastric cancer (PLGC) are the most important pathological phase with increased risk of gastric cancer (GC) and encompass the key stage in which the occurrence of GC can be prevented. In this study, we found that the gut microbiome changed significantly during the process of malignant transformation from chronic gastritis to GC in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) multiple factors-induced rat model. Accumulating evidence has shown that alterations in gut microbiota and metabolism are potentially linked to chronic inflammation and cancer of the gastrointestinal tract. However, the correlation of gut microbiota and metabolites, inflammatory factors, and the potential mechanism in the formation of PLGC have not yet been revealed. Methods: In this study, multiple factors including MNNG, sodium salicylate drinking, ranitidine feed, and irregular diet were used to establish a PLGC rat model. The pathological state of the gastric mucosa of rats was identified through HE staining and the main inflammatory cytokine levels in the serum were detected by the Luminex liquid suspension chip (Wayen Biotechnologies, Shanghai, China). The microbial composition and metabolites in the stool samples were tested by using 16S ribosomal RNA (rRNA) gene sequencing and non-targeted metabolomics. The correlation analysis of gut microbiota and inflammatory cytokines in the serum and gut microbiota and differential metabolites in feces was performed to clarify their biological function. Results: The results showed that compared to the control group, the gastric mucosa of the model rats had obvious morphological and pathological malignant changes and the serum levels of inflammatory cytokines including interleukin-1ß (IL-1ß), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and macrophage colony-stimulating factor (M-CSF) increased significantly, while the level of chemokine (C-X-C motif) ligand 1 (CXCL1) in serum reduced significantly. There were significant differences in the composition of the gut microbiota and fecal metabolic profiles between the model and control rats. Among them, Lactobacillus and Bifidobacterium increased significantly, while Turicibacter, Romboutsia, Ruminococcaceae_UCG-014, Ruminococcaceae_UCG-005, and Ruminococcus_1 reduced significantly in the model rats compared to the control rats. The metabolites related to the lipid metabolism and peroxisome proliferator-activated receptor (PPAR) signaling pathway have also undergone significant changes. In addition, there was a significant correlation between the changes of the differential inflammatory cytokines in the serum, fecal metabolic phenotypes, and gut microbial dysbiosis in model rats. Conclusion: The activation of the inflammatory response, disturbance of the gut microbiota, and changes in the fecal metabolic phenotype could be closely related to the occurrence of PLGC. This study provides a new idea to reveal the mechanism of risk factors of chronic gastritis and GC from the perspective of inflammation-immune homeostasis, gut microbiota, and metabolic function balance.

Upgrading the school entry vaccination record check strategy to improve varicella vaccination coverage: results from a quasi-experiment study.

BACKGROUND: The school entry vaccination record check strategy (SECS) is an appropriate opportunity to recommend vaccines for students to improve vaccination coverage (VC). However, it is only utilized for providing necessary catch-up vaccination for students who are missing the Expanded Program on Immunization (EPI) vaccines in China. We aimed to address that gap and quantify the relationship between the SECS policy and the increase of coverage in varicella vaccine (VarV). METHODS: We employed a pretest and posttest quasi-experimental design to examine the effect of the upgraded SECS policy on the change of VarV coverage in newly enrolled students in Lu'an, 2019-2020. RESULTS: Eight hundred participants were randomly divided into the control group (C group, 31.8%), the telephone-based intervention group (T group, 31.2%), and the written notification intervention group (W group, 37.0%). Totally, 84 students received VarV during the study period, with a VC of 10.5%. The possibility of vaccination in the T group (RR = 4.9, 95% CI:2.2-10.9) and W group (RR = 5.2, 95% CI:2.4-11.5) was significantly higher than that in the C group (p< .001). CONCLUSIONS: Our study demonstrates that the upgraded SECS produce a positive effect on improving the VC of VarV. This nudge strategy may decrease varicella outbreaks in schools in China, especially in provinces where VarV is not introduced into EPI.

Prediction of per capita water consumption for 31 regions in China.

Considering the shortage of per capita water resources in China, the paper established a fractional order accumulated grey prediction model (FGM(1,1)) to predict per capita water consumption of 31 regions (provinces, municipalities, and autonomous regions) in China from 2019 to 2024. The results show that per capita water consumption varies greatly across the different regions. Among them, per capita water consumption of nine regions (i.e., Beijing, Tianjin, Inner Mongolia, Jiangsu, Henan, Hubei, Guizhou, Yunnan, and Shaanxi) shows an increasing trend, whereas per capita water consumption in other 22 regions shows a downward trend. The predictive results can provide a basis for water resource management in China.

Clinical characteristics and risk factors associated with breakthrough varicella during varicella outbreaks.

BACKGROUND: Although a varicella vaccine has been available in China since 1998 in the private sector, varicella outbreaks and breakthrough varicella (BV) still occur. In 2018, four varicella outbreaks with high BV rate sequentially occurred in four schools in Lu'an, sparking local public health authority's concerns on the varicella vaccine. Therefore, we conducted this investigation to evaluate varicella vaccine effectiveness (VE), characterize BV, and detect potential risk factors associated with BV. METHODS: This was a three-stage study. First, a retrospective cohort study was done in each school to estimate the VEs of varicella vaccine  during outbreaks. Second, a descriptive epidemiological method was used to describe the characteristics of the four outbreaks and to compare the clinical characteristics between the BV cases and unvaccinated varicella cases. To identify the risk factors associated with BV, we conducted an unmatched case-control study in the third stage of the study. RESULTS: A total of 199 cases were identified among four outbreaks, and the overall attack rate was 14%. Of 1203 students with available vaccination information, 822 (68%) were vaccinated at least once. The overall VEs among four outbreaks ranged from 19% to 69%, whereas the VE against moderate or severe varicella ranged from 74% to 90%. Compared with unvaccinated varicella cases, the moderate or severe varicella (p < .001) and fever (p = .029) in the BV group were less common. Besides, BV cases had a shorter duration of disease (p = .007). Children vaccinated more than six years before the outbreak had a higher risk of developing BV compared with those vaccinated within the past six years (OR = 2.4, 95% CI: 1.2-4.8). The risk of developing BV differed by the exposure intensity. Compared with the presence of three or fewer varicella cases in the same class, the OR was 7.8 (95% CI: 3.6-16.9) for four to nine cases in the same class and 25.2 (95% CI: 13.5 -47.2) for that of 10 or more cases. CONCLUSIONS: The overall VE was insufficient to protect varicella infection, and the VE for moderate or severe varicella was only moderate. The manifestations of BV cases were generally milder than those seen in natural varicella infection. The time since vaccination and the intensity of exposure are risk factors for developing BV during an outbreak.

The impact of long-term moderate level of vaccination coverage for epidemiology of varicella in Lu'an, China: should we change immunisation strategy now?

As China implements the voluntary vaccination programme of one-dose of varicella vaccine (VarV) for decades, robust estimates of the impact of voluntary vaccination era on epidemiology of varicella are needed. We estimated the vaccination coverage (VC) of VarV by using surveillance data on immunisation. The descriptive epidemiological method was used to describe the changing epidemiology of varicella from 2007 to 2018. The screening method was used to estimate the vaccine effectiveness (VE) of VarV. The overall VC for VarV was 71.7%, ranged from 47.7% to 79.5% among 2008-2017 birth cohorts. In total, 16 660 varicella cases were reported during 2007-2018, the incidence increased from 10.0 cases per 100 000 population in 2007 to 65.2 cases per 100 000 population in 2018. A shift in age group of varicella was observed since 2012, with the age increased from 5-9 years to 10-14 years. The overall VE was 79.9%, and the VE increased from 60.1% in 2008 birth cohort to 96.2% in 2017 birth cohort. We found that the overall VE for VarV is moderate, but appears highly effective within 5 years after vaccination. In addition, a shift varicella infection to older ages has occurred at the long-term moderate level VC of one-dose VarV. Therefore, to contain the incidence of varicella and prevent any potential shift to older ages, the introduction of VarV into routine immunisation programme is likely needed in Lu'an.

Outbreak of mumps in a student population with high vaccination coverage in China: time for two-dose vaccination.

In 2016, an outbreak of mumps occurred in a primary school in China with a student population having high vaccination coverage. An unmatched case-control study was performed to identify risk factors contributing to this outbreak, and a retrospective cohort study was conducted to evaluate the effectiveness of mumps-containing vaccine (MuCV). A total of 97 cases were identified during the outbreak, and the overall attack rate was 8.2%. Among students with confirmed vaccination status, 90% had received at least one dose of MuCV. Cases were more likely than non-cases to report taking the school bus during the epidemic period (adjusted OR = 2.3, 95% CI: 1.4-3.7). Vaccine effectiveness (VE) was higher for two-dose MuCV (76%, 95% CI:49â€"89%) than for one-dose MuCV (59%, 95% CI: 36â€"74%. The protection afforded by both one-dose and two-dose MuCV waned over time, from 82% among students vaccinated within 5 years to 41% among those vaccinated more than 10 years previously for one-dose VE, and from 90% to 25% over the same time period for two-dose VE. We found that outbreaks of mumps can occur in schools despite high coverage of one-dose MuCV vaccination. Although the VE of both two-dose and one-dose MuCV wanes over time, the overall VE for two-dose MuCV was superior than that of one-dose MuCV. Therefore, a two-dose MuCV schedule through routine services is likely needed in order to control mumps epidemics in China.