3,4-Bis(4-meth­oxy­phen­yl)-2,5-dihydro-1H-pyrrole-2,5-dione

In the title compound, C18H15NO4, the benzene rings form quite different dihedral angles [16.07 (1) and 59.50 (1)°] with the central pyrrole ring, indicating a twisted mol­ecule. Conjugation is indicated between the five- and six-membered rings by the lengths of the C—C bonds which link them [1.462 (3) and 1.477 (3) Å]. The most prominent feature of the crystal packing is the formation of inversion dimers via eight-membered {⋯HNCO}2 synthons

Hesperidin Protects against Acute Alcoholic Injury through Improving Lipid Metabolism and Cell Damage in Zebrafish Larvae

Alcoholic liver disease (ALD) is a series of abnormalities of liver function, including alcoholic steatosis, steatohepatitis, and cirrhosis. Hesperidin, the major constituent of flavanone in grapefruit, is proved to play a role in antioxidation, anti-inflammation, and reducing multiple organs damage in various animal experiments. However, the underlying mechanism of resistance to alcoholic liver injury is still unclear. Thus, we aimed to investigate the protective effects of hesperidin against ALD and its molecular mechanism in this study. We established an ALD zebrafish larvae model induced by 350 mM ethanol for 32 hours, using wild-type and transgenic line with liver-specific eGFP expression Tg (lfabp10α:eGFP) zebrafish larvae (4 dpf). The results revealed that hesperidin dramatically reduced the hepatic morphological damage and the expressions of alcohol and lipid metabolism related genes, including cyp2y3, cyp3a65, hmgcra, hmgcrb, fasn, and fads2 compared with ALD model. Moreover, the findings demonstrated that hesperidin alleviated hepatic damage as well, which is reflected by the expressions of endoplasmic reticulum stress and DNA damage related genes (chop, gadd45αa, and edem1). In conclusion, this study revealed that hesperidin can inhibit alcoholic damage to liver of zebrafish larvae by reducing endoplasmic reticulum stress and DNA damage, regulating alcohol and lipid metabolism

Therapy by physician–pharmacist combination and economic returns for cancer pain management in China: a cost-effectiveness analysis

Objective: To examine whether joint management of cancer pain by physicians and pharmacists in clinics provides economic advantages from the perspective of the Chinese healthcare system.Methods: From February 2018 to March 2020, 100 patients who visited the joint cancer pain clinic at the Xiangya Hospital of Central South University were included. These patients were randomly assigned to either the control or intervention groups. The control group received regular outpatient services from a physician, while the intervention group received regular outpatient services from a physician and medication education provided by a pharmacist. The study considered various direct costs, including drug expenses, physician-pharmacist outpatient services, adverse event management, consultations, examinations, and readmissions. The outcome indicators considered were the cancer pain control rate and the reduction in pain scores. Decision tree modeling, single-factor sensitivity analysis, and probabilistic sensitivity analysis were performed to evaluate the cost-effectiveness of joint physician-pharmacist outpatient services compared to physician-alone outpatient services.Results: The intervention group showed a significantly higher cancer pain control rate than the control group (0.69 vs. 0.39, p = 0.03). In the decision tree model, the intervention group had a significantly lower pain score than the control group (0.23 vs. 0.14). The cost per person in the intervention group was $165.39, while it was$191.1 per person in the control group. The univariate sensitivity analysis showed that the cost of self-management for patients in the control group was identified as the primary sensitivity factor. Probabilistic sensitivity analysis indicated that the joint clinic group had a favorable incremental cost-effectiveness compared to the physician clinic group. In addition, the probabilistic sensitivity analysis demonstrated an absolute advantage in the incremental cost-effectiveness of the joint clinic group over the outpatient physician group.Conclusion: The participation of pharmacists in joint cancer pain clinic services led to improved pain management for patients, demonstrating a clear advantage in terms of cost-effectiveness

BAG3 as a novel prognostic biomarker in kidney renal clear cell carcinoma correlating with immune infiltrates

Abstract Purpose BCL-2-associated athanogene 3 (BAG3) is an anti-apoptotic protein that plays an essential role in the onset and progression of multiple cancer types. However, the clinical significance of BAG3 in kidney renal clear cell carcinoma (KIRC) remains unclear. Methods Using Tumor IMmune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) database, we explored the expression, prognostic value, and clinical correlations of BAG3 in KIRC. In addition, immunohistochemistry (IHC) of HKH cohort further validated the expression of BAG3 in KIRC and its impact on prognosis. Gene Set Cancer Analysis (GSCA) was utilized to scrutinize the prognostic value of BAG3 methylation. Gene Ontology (GO) term analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene set enrichment analysis (GSEA) were used to identify potential biological functions of BAG3 in KIRC. Single-sample gene set enrichment analysis (ssGSEA) was performed to confirm the correlation between BAG3 expression and immune cell infiltration. Results BAG3 mRNA expression and protein expression were significantly downregulated in KIRC tissues compared to normal kidney tissues, associated with adverse clinical–pathological factors and poor clinical prognosis. Multivariate Cox regression analysis indicated that low expression of BAG3 was an independent prognostic factor in KIRC patients. GSEA analysis showed that BAG3 is mainly involved in DNA methylation and the immune-related pathways in KIRC. In addition, the expression of BAG3 is closely related to immune cell infiltration and immune cell marker set. Conclusion BAG3 might be a potential therapeutic target and valuable prognostic biomarker of KIRC and is closely related to immune cell infiltration

Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B

Unfolded protein response (UPR) plays an important role in the pathogenesis of many liver diseases. BMI1 has a liver protection effect, but whether it participates in the regulation of hepatocyte death through UPR is not well defined. Herein, the endoplasmic reticulum stress model was established by inducing hepatocyte line (MIHA) with tunicamycin (TM, 5 µg/ml). Cell counting kit-8 assay and flow cytometry were used to evaluate the viability and apoptosis of hepatocytes. The expression levels of BMI1, KAT2B, and proteins related to UPR (p-eIF2α, eIF2α, ATF4, and ATF6), NF-κB (p65 and p-p65), apoptosis (cleaved caspase-3, bcl-2, and bax) and necroptosis (p-MLKL and MLKL) were determined by Western blot. The relationship between KAT2B and BMI1 was determined by co-immunoprecipitation and ubiquitination assay. The results showed that TM not only promoted UPR, apoptosis, and necroptosis in hepatocytes but also upregulated the expression levels of BMI1 and KAT2B and activated NF-κB pathway. BAY-117082 reversed the effects of TM on viability, apoptosis, NF-κB pathway, and BMI1 but strengthened the effects of TM on KAT2B/MLKL-mediated necroptosis. BMI1 promoted the ubiquitination of KAT2B, and BMI1 overexpression reversed the effects of TM on viability, apoptosis, and KAT2B/MLKL-mediated necroptosis. In summary, overexpression of BMI1 promotes the ubiquitination of KAT2B to block the MLKL-mediated necroptosis of hepatocytes

Histone H3K79 methylation by DOT1L promotes Aurora B localization at centromeres in mitosis

Summary: Centromere localization of the chromosome passenger complex (CPC) is paramount for achieving accurate sister chromosome segregation in mitosis. Although it has been widely recognized that the recruitment of CPC is directly regulated by two histone codes, phosphorylation of histone H3 at threonine 3 (H3T3ph) and phosphorylation of histone H2A at threonine 120 (H2AT120ph), the regulation of CPC localization by other histone codes remains elusive. We show that dysfunction of disruptor of telomeric silencing 1 like (DOT1L) leads to mislocation of the CPC in prometaphase, caused by disturbing the level of H3T3ph and its reader Survivin. This cascade is initiated by over-dephosphorylation of H3T3ph mediated by the phosphatase RepoMan-PP1, whose scaffold RepoMan translocalizes to chromosomes, while the level of H3K79me2/3 is diminished. Together, our findings uncover a biological function of DOT1L and H3K79 methylation in mitosis and give insight into how genomic stability is coordinated by different histone codes

Prevalence, serotype, and antimicrobial resistance profiles of children infected with Salmonella in Guangzhou, southern China, 2016–2021

PurposeSalmonella infection is a key global public health concern and has lead to an increased economic burden on society. We investigated the epidemiological characteristics and antimicrobial resistance profiles of clinically isolated Salmonella strains in Guangzhou Women and Children's Medical Center.Patients and methodsThis was a retrospective study of 1,338 Salmonella strains collected from children in Guangzhou Women and Children's Medical Center during 2016 to 2021.ResultsThe results revealed that 1,338 cases of Salmonella were mainly isolated from feces and blood samples. The age distribution was dominated by infants under 3 years old. The seasonal distribution was high in summer and autumn. 48 serotypes were detected, and S. typhimurium (78.7%) was the predominant serogroup. The results of antimicrobial susceptibility showed that the highest resistance was observed in ampicillin (84.5%), while lower resistance was observed in piperacillin/tazobactam, cefoperazone/sulbactam and ciprofloxacin. The antimicrobial resistance rate of fecal isolates was higher than that of blood isolates. The five-year average detection rate of multi-drug resistant Salmonella was 8.5% (114/1338) and the MDR rate of S. typhimurium was the lowest (6.9%; 73/1053).ConclusionWe concluded that antibacterial treatment should be carefully selected according to serotype and antimicrobial sensitivity results in children. Antimicrobial resistance monitoring for multi-drug resistant Salmonella is still required

Heterostructured Cu/CuO Nanoparticles Embedded within N-Doped Carbon Nanosheets for Efficient Oxygen Reduction Reaction

The development of cost-effective and highly efficient oxygen reduction reaction (ORR) electrocatalysts is an essential component of renewable clean energy technologies, such as fuel cells and metal/air cells, but remains a huge and long-term challenge. Here, novel heterogeneous Cu/CuO nanoparticles embedded within N-doped carbon nanosheets (Cu/CuO@NC-900) are successfully synthesized by combining a facile hydrothermal route with a solid calcination technique. Benefitting from the electronic interaction between Cu and CuO, the generated abundant highly active Cu-Nx active sites and the high conductivity of the N-doped carbon nanosheets, the resulting Cu/CuO@NC-900 material shows superior ORR performance in alkaline media, exhibiting a high half-wave potential of ~0.868 V, and a robust stability and methanol tolerance, even outperforming commercial 20 wt% Pt/C. Our study opens up a new avenue for the rational design and fabrication of efficient and durable noble-metal-free Cu-based electrocatalysts for energy conversion and storage