Discovery of 5-(1-benzyl-1H-imidazol-4-yl)-1,2,4-oxadiazole derivatives as novel RIPK1 inhibitors via structure-based virtual screening.

RIPK1 plays a key role in necroptosis and is associated with various inflammatory diseases. Using structure-based virtual screening, a novel hit with 5-(1-benzyl-1H-imidazol-4-yl)-1,2,4-oxadiazole scaffold was identified as an RIPK1 inhibitor with an IC50 value of 1.3 µM. Further structure-activity relationship study was performed based on similarity research and biological evaluation. The molecular dynamics simulation of compound 2 with RIPK1 indicated that it may act as a type II kinase inhibitor. This study provides a highly efficient way to discover novel scaffold RIPK1 inhibitors for further development.

TP63 truncating mutation causes increased cell apoptosis and premature ovarian insufficiency by enhanced transcriptional activation of CLCA2.

BACKGROUND: Premature ovarian insufficiency (POI) is a severe disorder leading to female infertility. Genetic mutations are important factors causing POI. TP63-truncating mutation has been reported to cause POI by increasing germ cell apoptosis, however what factors mediate this apoptosis remains unclear. METHODS: Ninety-three patients with POI were recruited from Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Whole-exome sequencing (WES) was performed for each patient. Sanger sequencing was used to confirm potential causative genetic variants. A minigene assay was performed to determine splicing effects of TP63 variants. A TP63-truncating plasmid was constructed. Real-time quantitative PCR, western blot analyses, dual luciferase reporter assays, immunofluorescence staining, and cell apoptosis assays were used to study the underlying mechanism of a TP63-truncating mutation causing POI. RESULTS: By WES of 93 sporadic patients with POI, we found a 14-bp deletion covering the splice site in the TP63 gene. A minigene assay demonstrated that the 14-bp deletion variant led to exon 13 skipping during TP63 mRNA splicing, resulting in the generation of a truncated TP63 protein (TP63-mut). Overexpression of TP63-mut accelerated cell apoptosis. Mechanistically, the TP63-mut protein could bind to the promoter region of CLCA2 and activate the transcription of CLCA2 several times compared to that of the TP63 wild-type protein. Silencing CLCA2 using a specific small interfering RNA (siRNA) or inhibiting the Ataxia Telangiectasia Mutated (ATM) pathway using the KU55933 inhibitor attenuated cell apoptosis caused by TP63-mut protein expression. CONCLUSION: Our findings revealed a crucial role for CLCA2 in mediating apoptosis in POI pathogenesis, and suggested that CLCA2 is a potential therapeutic target for POI.

A triple-synergistic small-molecule sulfur cathode promises energetic Cu-S electrochemistry.

Metal-sulfur batteries have received great attention for electrochemical energy storage due to high theoretical capacity and low cost, but their further development is impeded by low sulfur utilization, poor electrochemical kinetics, and serious shuttle effect of the sulfur cathode. To avoid these problems, herein, a triple-synergistic small-molecule sulfur cathode is designed by employing N, S co-doped hierarchical porous bamboo charcoal as a sulfur host in an aqueous Cu-S battery. Expect the enhanced conductivity and chemisorption induced by N, S synergistic co-doping, the intrinsic synergy of macro-/meso-/microporous triple structure also ensures space-confined small-molecule sulfur as high utilization reactant and effectively alleviates the volume expansion during conversion reaction. Under a further joint synergy between hierarchical structure and heteroatom doping, the resulting sulfur cathode endows the Cu-S battery with outstanding electrochemical performance. Cycled at 5 A g-1, it can deliver a high reversible capacity of 2,509.8 mAh g-1 with a good capacity retention of 97.9% after 800 cycles. In addition, a flexible hybrid pouch cell built by a small-molecule sulfur cathode, Zn anode, and gel electrolytes can firmly deliver high average operating voltage of about 1.3 V with a reversible capacity of over 2,500 mAh g-1 under various destructive conditions, suggesting that the triple-synergistic small-molecule sulfur cathode promises energetic metal-sulfur batteries.

Functional foods and dietary supplements in the management of non-alcoholic fatty liver disease: A systematic review and meta-analysis.

Objective: In this systematic review and meta-analysis, we aimed to clarify the overall effects of functional foods and dietary supplements in non-alcoholic fatty liver disease (NAFLD) patients. Methods: Randomized controlled trials (RCTs) published in PubMed, ISI Web of Science, Cochrane library, and Embase from January 1, 2000 to January 31, 2022 were systematically searched to assess the effects of functional foods and dietary supplements in patients with NAFLD. The primary outcomes were liver-related measures, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic fibrosis and steatosis, while the secondary outcomes included body mass index (BMI), waist circumference (WC), triacylglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). These indexes were all continuous variables, so the mean difference (MD) was used for calculating the effect size. Random-effects or fixed-effects models were used to estimate the mean difference (MD). The risk of bias in all studies was assessed with guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions. Results: Twenty-nine articles investigating functional foods and dietary supplements [antioxidants (phytonutrients and coenzyme Q10) = 18, probiotics/symbiotic/prebiotic = 6, fatty acids = 3, vitamin D = 1, and whole grain = 1] met the eligibility criteria. Our results showed that antioxidants could significantly reduce WC (MD: -1.28 cm; 95% CI: -1.58, -0.99, P < 0.05), ALT (MD: -7.65 IU/L; 95% CI: -11.14, -4.16, P < 0.001), AST (MD: -4.26 IU/L; 95% CI: -5.76, -2.76, P < 0.001), and LDL-C (MD: -0.24 mg/dL; 95% CI: -0.46, -0.02, P < 0.05) increased in patients with NAFLD but had no effect on BMI, TG, and TC. Probiotic/symbiotic/prebiotic supplementation could decrease BMI (MD: -0.57 kg/m2; 95% CI: -0.72, -0.42, P < 0.05), ALT (MD: -3.96 IU/L; 95% CI: -5.24, -2.69, P < 0.001), and AST (MD: -2.76; 95% CI: -3.97, -1.56, P < 0.0001) levels but did not have beneficial effects on serum lipid levels compared to the control group. Moreover, the efficacy of fatty acids for treating NAFLD was full of discrepancies. Additionally, vitamin D had no significant effect on BMI, liver transaminase, and serum lipids, while whole grain could reduce ALT and AST but did not affect serum lipid levels. Conclusion: The current study suggests that antioxidant and probiotic/symbiotic/prebiotic supplements may be a promising regimen for NAFLD patients. However, the usage of fatty acids, vitamin D, and whole grain in clinical treatment is uncertain. Further exploration of the efficacy ranks of functional foods and dietary supplements is needed to provide a reliable basis for clinical application. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier: CRD42022351763.

Quadruple therapy with vonoprazan 20 mg daily as a first-line treatment for Helicobacter pylori infection: A single-center, open-label, noninferiority, randomized controlled trial.

BACKGROUND: Although vonoprazan has been proven to be a highly potent drug for Helicobacter pylori eradication, there have been no randomized trials comparing the effectiveness of regimens containing vonoprazan 20 mg daily with alternative standard strategies. We aimed to assess the efficacy, tolerance, and cost-effectiveness of quadruple therapy with vonoprazan 20 mg daily as a first-line therapy for H. pylori eradication. MATERIALS AND METHODS: We conducted a single-center, open-label, noninferiority, randomized controlled study in Zhejiang, China. Treatment-naive H. pylori-positive participants (n = 234) were randomly assigned to three groups in a 1:1:1 ratio: vonoprazan 20 mg daily with amoxicillin 1000 mg, furazolidone 100 mg and colloidal bismuth 200 mg each given twice a day for 10 days (V10) or 14 days (V14), or esomeprazole 20 mg with amoxicillin 1000 mg, furazolidone 100 mg and colloidal bismuth 200 mg each given twice a day for 14 days (E14). The primary endpoint was the eradication rates in each group. The secondary endpoints were the incidence of adverse events (AEs) and compliance. RESULTS: The eradication rates in the V10, V14 and E14 groups were 96.2% (89.2-99.2%), 94.9% (87.4-98.6%), and 93.6% (85.7-97.9%) in the intention-to-treat analysis, and 98.6% (92.7-100.0%), 97.4% (90.8-99.7%), and 94.8% (87.2-98.6%) in the per-protocol analysis, respectively. Quadruple therapy with vonoprazan 20 mg daily was noninferior to the esomeprazole-based regimen (Farrington and Manning test: margin 10%, significance level 2.5%). The adverse event rates were 12.8% versus 3.8% versus 6.4% in the V10, V14, and E14 groups, respectively. All regimens were well tolerated without significant differences (p = 0.096). The cost-effectiveness ratio was 1.32, 1.88, and 3.06 for the V10, V14, and E14 groups in the intention-to-treat analysis, respectively. (NCT04907747). CONCLUSIONS: Vonoprazan (20 mg daily) was as effective as esomeprazole (20 mg twice a day) in quadruple therapies for the eradication of H. pylori, was more economical, and was well tolerated. In addition, the 10-day regimen of vonoprazan (20 mg daily) was comparable to the 14-day regimen.

Tempol modulates lncRNA-miRNA-mRNA ceRNA networks in ovaries of DHEA induced PCOS rats.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in reproductive age women. Our previous results demonstrated that tempol was able to ameliorate PCOS phenotype in rats. However, the exact pathophysiological effect of tempol on PCOS remains largely unknown. To extend this research, deep RNA-sequencing was performed to investigate the long noncoding RNA (lncRNA) associated ceRNA mechanisms in the ovarian tissues of control rats, dehydropiandrosterone (DHEA) induced PCOS rats and tempol treated PCOS rats. Our results identified total 164, 79, and 914 significantly dysregulated lncRNAs, miRNAs, and mRNAs in three groups, respectively. The total of 7 lncRNAs, 8 mRNAs and 5 miRNAs were involved in lncRNA-associated ceRNA networks were constructed. Among them, mRNAs including C1qtnf1, Dipk2a, IL4r and lncRNAs including MSTRG.16751.2, MSTRG.8065.2 had high RNA connectivity in the ceRNA network, which also showed significant alterations in these three groups by using qPCR validation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the involvement of the identified ceRNA networks in regulating the development of PCOS from distinct origins, such as metabolic pathway, immune cell differentiation. The study presents the first systematic dissection of lncRNA-associated ceRNA profiles in tempol treated PCOS rats. The identified ceRNA networks could provide insights that help facilitate PCOS diagnosis and treatment.

LncGSAR Controls Ovarian Granulosa Cell Steroidogenesis via Sponging MiR-125b to Activate SCAP/SREBP Pathway.

Long non-coding RNAs (lncRNAs) have been shown to play important roles in livestock fecundity, and many lncRNAs that affect follicular development and reproductive diseases have been identified in the ovary. However, only a few of them have been functionally annotated and mechanistically validated. In this study, we identified a new lncRNA (lncGSAR) and investigated its effects on the proliferation and steroidogenesis of ovine granulosa cells (GCs). High concentrations of glucose (add 33.6 mM glucose) caused high expression of lncGSAR in GCs by regulating its stability, and lncGSAR overexpression promoted GCs proliferation, estrogen secretion, and inhibited progesterone secretion, whereas interference with lncGASR had the opposite effect. Next, we found that the RNA molecules of lncGSAR act on MiR-125b as competitive endogenous RNA (ceRNA), and SREBP-cleavage-activating protein (SCAP) was verified as a target of MiR-125b. LncGASR overexpression increased the expression of SCAP, SREBP, and steroid hormone-related proteins, which can be attenuated by MiR-125b. Our results demonstrated that lncGSAR can act as a ceRNA to activate SCAP/SREBP signaling by sponging MiR-125b to regulate steroid hormone secretion in GCs. These findings provide new insights into the mechanisms of nutrient-regulated follicle development in ewes.

Development and Validation of the Chinese Frailty Screening Scale: A Study among Community-Dwelling Older Adults in Shanghai.

BACKGROUND: Based on intrinsic capacity (IC) as defined by the World Health Organization, an accelerated decline may be an important precursor of frailty among older adults; however, there is a lack of validated instruments that both screen for frailty and monitor IC. This study aims to develop a comprehensive and acculturative frailty screening scale to determine healthy aging among older Chinese adults. SETTING AND PARTICIPANTS: A cross-sectional and a cohort study both based on community-dwelling older adults aged 65 and older. METHODS: This study mainly consisted of two parts. First, the selection and revision of 20 items related to frailty based on a literature review, expert consultation, and stakeholder analysis; second, a cross-sectional study was conducted to simplify the scale and test the reliability and validity of the new frailty screening tool. The fatigue, resistance, ambulation, illness, and loss of weight (FRAIL) scale, the Tilburg frailty indictor (TFI), and a 49-item Frailty Index (FI) were investigated as criteria. Additionally, a cohort study in Shanghai was conducted to verify the predictive validity of the new screening scale. The disability measured by the activity of daily living (ADL), instrumental activity of daily living (IADL) and all-cause mortality were documented as outcomes. RESULTS: A 10-item Chinese frailty screening scale (CFSS-10) was successfully developed and validated. It presented a Cronbach's α of 0.63 and an intraclass correlation coefficient of 0.73, which indicated good reliability. Taking the other frailty tools as criteria, Kappa values of 0.54-0.58 and an area under the curve of 0.87-0.91 showed good validity. The results of the log-binomial and Poisson models showed a high score, which predicted a higher risk of disability and all-cause mortality. An optimal cut-off point of 5 gave an excellent prediction of one-year disability. CONCLUSIONS: The CFSS-10 has good validity and reliability as a quick and acculturative frailty screening scale for community-dwelling older adults in Shanghai. It may also supplement existing frailty screening tools.

ComABAN: refining molecular representation with the graph attention mechanism to accelerate drug discovery.

An unsolved challenge in developing molecular representation is determining an optimal method to characterize the molecular structure. Comprehension of intramolecular interactions is paramount toward achieving this goal. In this study, ComABAN, a new graph-attention-based approach, is proposed to improve the accuracy of molecular representation by simultaneously considering atom-atom, bond-bond and atom-bond interactions. In addition, we benchmark models extensively on 8 public and 680 proprietary industrial datasets spanning a wide variety of chemical end points. The results show that ComABAN has higher prediction accuracy compared with the classical machine learning method and the deep learning-based methods. Furthermore, the trained neural network was used to predict a library of 1.5 million molecules and picked out compounds with a classification result of grade I. Subsequently, these predicted molecules were scored and ranked using cascade docking, molecular dynamics simulations to generate five potential candidates. All five molecules showed high similarity to nanomolar bioactive inhibitors suppressing the expression of HIF-1α, and we synthesized three compounds (Y-1, Y-3, Y-4) and tested their inhibitory ability in vitro. Our results indicate that ComABAN is an effective tool for accelerating drug discovery.

Association Between Sense of Coherence and Frailty: A Cross-Sectional Study in China.

Purpose: Frailty is an emerging global public health burden. Most existing studies have focused on risk factors for frailty, focusing less on protective factors against frailty. This study aims to examine the association between the sense of coherence (SOC), the most common construct of salutogenesis and frailty status among community-dwelling old adults. Method: A cross-sectional study was conducted among 7,970 old adults aged ≥65 years in three cities in China from June 2019 to October 2020. Frailty was operationalised as the sum of self-reported fatigue, resistance, ambulation, illness, and loss of weight (FRAIL scale). The χ2 test was used to analyse the distribution difference of frailty in demographic, behavioural, and SOC levels. Confounder-adjusted multinomial logistic regression was used to examine the association between SOC and frailty. Results: The prevalence of pre-frailty and frailty was 43.1 and 8.0%, respectively. The results of the confounder-adjusted regression showed that older adults with moderate-level SOC (odds ratio, OR: 0.61, 95% CI: 0.54-0.69) and strong-level SOC (OR: 0.55, 0.48-0.64) had lower odds of being pre-frail compared to those with weak SOC. It also showed that older adults with moderate-level SOC (OR: 0.32, 95% CI: 0.27-0.40) and strong-level SOC (OR: 0.22, 95% CI: 0.16-0.29) had lower odds of being frail compared to those with weak SOC. Conclusion: SOC may be a protective factor against frailty. Improving SOC may be a strategy to prevent frailty among Chinese community-dwelling older adults.

Synergistic dual conversion reactions assisting Pb-S electrochemistry for energy storage.

SignificanceBased on the analysis of three thermodynamic parameters of various M-S systems (solubility of metal sulfides [MxSy] in aqueous solution, volume change of the metal-sulfur [M-S] battery system, and the potential of S/MxSy cathode redox couple), an aqueous Pb-S battery operated by synergistic dual conversion reactions (cathode: S⇄PbS, anode: Pb2+⇄PbO2) has been officially reported. Benefitting from the inherent insolubility of PbS and a conversion-type counter electrode, the aqueous Pb-S battery exhibited two advantages: it is shuttle effect free and has a dendrite-free nature. Moreover, the practical value of the Pb-S battery was further certified by the prototype S|Pb(NO3)2ǁZn(NO3)2|Zn hybrid cell, which afforded an energy density of 930.9 Wh kg-1sulfur.

Association of Serum Amylase Activity and the Copy Number Variation of AMY1/2A/2B with Metabolic Syndrome in Chinese Adults.

PURPOSE: Low serum amylase activity and copy number (CN) variation (CNV) of the salivary amylase gene (AMY1) are reportedly associated with obesity and abnormal glucose metabolism; however, this association remains controversial. We aimed to clarify the relationship between serum amylase activity and the CNV of AMY1/2A/2B with the occurrence of metabolic syndrome (MetS) in Chinese adults. PATIENTS AND METHODS: Anthropometry, metabolic risk factors, and serum amylase activity were assessed in 560 subjects (260 MetS patients; 300 healthy controls). AMY1/2A/2B CNs were evaluated using the highly sensitive droplet digital PCR. RESULTS: The serum total, pancreatic, and salivary amylase activity, but not the AMY1/2A/2B CNs, was significantly lower in MetS patients than that in the control subjects. Patients <45 y had a lower AMY1 CN, compared to that in healthy controls. Low serum amylase activity was significantly associated with high MetS prevalence (p < 0.001). In the receiver operating characteristic curve analysis, serum amylase activity was a significant diagnostic indicator for MetS. The diagnostic value of total amylase was second only to that of γ-glutamyl transpeptidase; it was higher than that of alanine aminotransferase and uric acid. CONCLUSION: Low serum amylase activity was significantly associated with increased risk of MetS in Chinese adults. Therefore, amylase could be a potential biomarker for predicting MetS.

Acetylation of nucleopolyhedrovirus P35 is crucial for its anti-apoptotic activity in silkworm, Bombyx mori.

Apoptosis is a characteristic feature of a nucleopolyhedrovirus infected insect cells. This defensive strategy of the insect cells also affects the viral infectivity. On the contrary, the P35 baculovirus apoptosis inhibitor impedes the insect cell apoptosis induced by viral infection. Our previous investigation of the Bombyx mori nucleopolyhedrovirus (BmNPV) acetylome showed that 3 lysine (K) (70, 127 and 256) sites of P35 were acetylated during infection. How these modifications affect the interaction between the insect cells and BmNPV is still unknown. In order to explore the underlying mechanism of P35 lysine acetylation, mutants with glutamine or arginine substitution were constructed to mimic the acetylated (Q) and deacetylated (R) state. ELISA and DNA fragmentation assay were used to ascertain the acetylation effects on apoptosis. Subsequently the results showed that acetylation of K70 upregulated the anti-apoptotic activity, thereby preventing apoptosis induced by insect cells. Caspase 1 activity assay further confirmed that, acetylated K70 exhibited a strong anti-apoptotic activity in cell lines infected with BmNPV. Intriguingly, an examination with the yeast 2 hybrid (Y2H) assay revealed an interaction with the silkworm caspase 1. Taken together, we demonstrated that acetylation of P35 is crucial for an interaction with caspase 1 and the upregulation of anti-apoptotic activity. Keywords: Bombyx mori; BmNPV; P35; acetylation; anti-apoptotic; caspase 1.

Deacetylation of BmAda3 is required for cell apoptosis caused by Bombyx mori nucleopolyhedrovirus infection.

Silkworm is not only an ideal insect model with a biological significance, but it is also crucially important in sericulture and bioreactors. Bombyx mori nucleopolyhedrovirus (BmNPV) is a principal pathogen of silkworm. However, the molecular mechanism underlying BmNPV invasion is still unclear. Based on our previous acetylome research findings of B. mori after BmNPV infection, here, we focused on silkworm alteration/deficiency in activation-3 (BmAda3). The acetylation of K124 and K128 were significantly reduced (0.66-fold) upon the virus challenge. Due to the interaction between Ada3 and P53, acetylation-mimic K124Q/K128Q and deacetylation-mimic K124R/K128R mutants of BmAda3 were constructed to explore the roles exerted by the acetylation modification of BmAda3 on P53. Yeast two-hybrid and IP results revealed that both BmAda3 and its deacetylation mutants (K124R/K128R) interacted with P53. Interestingly, we found that the deacetylation mutants (K124R/K128R) of BmAda3 significantly promoted the stability of P53. Since P53 is a proapoptotic factor, cell apoptosis was detected. We established that the deacetylation of BmAda3 at K124/K128 facilitated cellular apoptosis during BmNPV infection. Finally, viral proliferation was analyzed, and the results indicated that virus generation was reduced by K124/K128 deacetylation. Our report, based on the deacetylation of two lysine sites 124/128 of BmAda3, shows possible regulatory pathways of BmNPV proliferation and provides novel insights into the development of antiviral agents.

Prussian Blue Analogues in Aqueous Batteries and Desalination Batteries.

In the applications of large-scale energy storage, aqueous batteries are considered as rivals for organic batteries due to their environmentally friendly and low-cost nature. However, carrier ions always exhibit huge hydrated radius in aqueous electrolyte, which brings difficulty to find suitable host materials that can achieve highly reversible insertion and extraction of cations. Owing to open three-dimensional rigid framework and facile synthesis, Prussian blue analogues (PBAs) receive the most extensive attention among various host candidates in aqueous system. Herein, a comprehensive review on recent progresses of PBAs in aqueous batteries is presented. Based on the application in different aqueous systems, the relationship between electrochemical behaviors (redox potential, capacity, cycling stability and rate performance) and structural characteristics (preparation method, structure type, particle size, morphology, crystallinity, defect, metal atom in high-spin state and chemical composition) is analyzed and summarized thoroughly. It can be concluded that the required type of PBAs is different for various carrier ions. In particular, the desalination batteries worked with the same mechanism as aqueous batteries are also discussed in detail to introduce the application of PBAs in aqueous systems comprehensively. This report can help the readers to understand the relationship between physical/chemical characteristics and electrochemical properties for PBAs and find a way to fabricate high-performance PBAs in aqueous batteries and desalination batteries.

Copper niobate nanowires boosted by a N, S co-doped carbon coating for superior lithium storage.

With the development of electric vehicles, more and more attention has been paid to the kinetic performance of batteries, which is related to rapid charge/discharge and safety issues. To improve this aspect, Cu2Nb34O87 nanowires covered by nitrogen and sulfur co-doped carbon (Cu2Nb34O87/NSC nanowires) are prepared by electrospinning combined with surface coating. As-prepared Cu2Nb34O87/NSC nanowires present a high ion diffusion coefficient and electronic conductivity, showing good a kinetic performance. Specifically, they deliver a splendid capacity of 311.2 mA h g-1 at 1 C and a superior cycling stability with a capacity fading of 0.031% per cycle upon 1000 cycles. At the same time, the electrochemical and structural reversibility is fully discussed and demonstrated by ex situ XRD, ex situ SEM and ex situ XPS based on the redox couples of Cu2+/Cu+, Nb5+/Nb4+, and Nb4+/Nb3+. Contributing to peculiar physico-chemical properties, Cu2Nb34O87/NSC nanowires are expected to be a candidate material for the anode in lithium-ion batteries.

Expeditious Approach to Indoloquinazolinones via Double Annulations of o-Aminoacetophenones and Isocyanates.

A novel procedure for a one-pot cascade reaction of o-aminoacetophenones and aryl/aliphatic isocyanates catalyzed/oxidized by the [Pd]/[Ag] system was developed. The reaction involves two C-N bond and one C-C bond formations during the double annulation process and the desired indoloquinazolinones and derivatives were afforded up to 81% yields from readily available substrates with a tolerance of a broad variety.