Revealing the key role of cuproptosis in osteoporosis via the bioinformatic analysis and experimental validation of cuproptosis-related genes.

The incidence of osteoporosis has rapidly increased owing to the ageing population. Cuproptosis, a novel mechanism that regulates cell death, may be a new therapeutic approach. However, the relevance of cuproptosis in the immune microenvironment and osteoporosis immunotherapy is still unknown. We intersected the differentially expressed genes from osteoporotic samples with 75 cuproptosis-related genes to identify 16 significantly expressed cuproptosis genes. We further explored the connection between the cuproptosis pattern, immune microenvironment, and immunotherapy. The weighted gene co-expression network analysis algorithm was used to identify cuproptosis phenotype-associated genes, and we used quantitative real-time PCR and immunohistochemistry in mouse femur tissues to verify hub gene (MAP2K2, FDX1, COX19, VEGFA, CDKN2A, and NFE2L2) expression. Six hub genes and 59 cuproptosis phenotype-associated genes involved in immunisation were identified among the osteoporosis and control groups, and the majority of these 59 genes were enriched in the inflammatory response, as well as in signal transducers, Janus kinase, and transcription pathway activators. In addition, two different clusters of cuproptosis were found, and immune infiltration analysis showed that gene Cluster 1 had a greater immune score and immune infiltration level. Further analysis revealed that three key genes (COX19, MAP2K2, and FDX1) were highly correlated with immune cell infiltration, and external experiments validated the association of these three genes with the prognosis of osteoporosis. We used the three key mRNAs COX19, MAP2K2, and FDX1 as a classification model that may systematically elucidate the complex connection between cuproptosis and the immune microenvironment of osteoporosis. New insights into osteoporosis pathogenesis and immunotherapy prospects may be gained from this study.

Meta-analysis of pulsed-field ablation versus cryoablation for atrial fibrillation.

PURPOSE: The available data on the treatment strategy of pulsed field ablation (PFA) for patients with atrial fibrillation (AF) is limited. This study aims to provide a comparative analysis of the efficacy, safety, and procedural efficiency between PFA and cryoballoon ablation (CBA) for AF. METHODS: We conducted a comprehensive search of the EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov databases to identify trials comparing PFA with CBA for AF from their inception until December 2023. The odds ratio (OR) and mean difference (MD), along with a 95% confidence interval (CI), were utilized as measures of treatment effect. RESULTS: The analysis included 15 eligible trials with a total enrollment of 1880 patients. No significant differences were found in recurrent atrial arrhythmia (OR 0.83, 95% CI 0.64, 1.07) or periprocedural complications (OR 0.78, 95% CI 0.46, 1.30) between the two ablation techniques examined in this study. However, the PFA technique demonstrated a significantly shorter procedure time (MD -7.17, 95% CI -13.60, -0.73), but a longer fluoroscopy time (MD 2.53, 95% CI 0.87, 4.19). Similarly, PFA was found to be significantly associated with a decreased incidence of phrenic nerve palsy (OR 0.20, 95% CI 0.07, 0.59), but an increased incidence of cardiac tamponade (OR 4.07, 95% CI 1.15, 14.39). Moreover, there was a significantly higher release of troponin with PFA compared to CBA (MD 470.28, 95% CI 18.89, 921.67), while the increase in S100 protein and heart rate was significantly lower with PFA than with CBA (MD -64.41, 95% CI -105.46, -17.36), (MD -8.76, 95% CI -15.12, -2.40). CONCLUSION: The utilization of PFA provides a safer, time-saving, and tissue-specific procedure compared to CBA, while maintaining comparable success rates. This has the potential to enhance procedural efficiency and optimize resource utilization in clinical practice. These findings underscore the feasibility and promise of PFA as an alternative technique for PVI in patients with AF.

Molecularly Imprinted Electrochemical Sensors Based on Ti3C2Tx-MXene and Graphene Composite Modifications for Ultrasensitive Cortisol Detection.

The increasing pressure and unhealthy lifestyle are gradually eroding the physical and mental health of modern people. As a key hormone responsible for maintaining the normal functioning of human systems, cortisol plays a vital role in regulating physiological activities. Moreover, cortisol can serve as a marker for monitoring psychological stress. The development of cortisol detection sensors carries immense potential, as they not only facilitate timely adjustments and treatments by detecting abnormal physiological indicators but also provide comprehensive data for conducting research on the correlation between cortisol and several potential diseases. Here, we report a molecularly imprinted polymer (MIP) electrochemical biosensor that utilizes a porous composite (MXG) modified electrode. MXG composite is prepared by combining Ti3C2Tx-MXene sheets and graphene (Gr). MXG composite material with high conductive properties and large electroactive surface area promotes the charge transfer capability of the electrode surface, expands the effective surface area of the sensor, and increases the content of cortisol-imprinted cavities on the electrode, thereby improving the sensing ability of the sensor. By optimizing the preparation process, the prepared sensor has an ultralow lower limit of detection of 0.4 fM, a wide detection range of 1 fM-10 µM, and good specificity for steroid hormones and interfering substances with similar cortisol structure. The ability of the sensor to detect cortisol in saliva was also confirmed experimentally. This highly sensitive and selective cortisol sensor is expected to be widely used in the fields of physiological and psychological care.

Th17 Cell-Related Gene Biomarkers in Osteoporosis: Comprehensive Bioinformatics Analysis and In Vivo Validation.

The interaction between the bone and immune systems has a major role in osteoporosis regulation. However, the infiltration of T helper 17 (Th17) cells and their associated genes in osteoporosis remains unclear. The GSE35959 dataset was obtained from the Gene Expression Omnibus (GEO) database, and the Immune Cell Abundance Identifier (ImmuCellAI) program was used to evaluate the abundance of 24 immune cell types, including Th17 cells. Differential analysis and relevance analysis were performed to identify differentially expressed Th17 cell-related genes (DETh17RGs) in osteoporosis. The potential functions of DETh17RGs were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment. Hub DETh17RGs were obtained through comprehensive analysis using Weighted Gene Co-Expression Network Analysis (WGCNA) and the CytoHubba plug-in algorithm. The expression levels of hub genes were validated using additional osteoporosis datasets. Additionally, the transcript levels of Hub genes in a mice model of osteoporosis were examined using quantitative PCR (qPCR). 464 DETh17RGs were identified in this study, with 421 genes showing positive associations and 43 genes showing negative associations. Among these, seven genes (CD44, TGFB1, ACTN4, ARHGDIA, ESR1, TLN1, FLNA) were considered as Hub DETh17RGs. The qPCR transcript levels of hub DETh17RGs in a mice model of osteoporosis exhibited consistent expression trends with the bioinformatics analysis. This research enhances our understanding of the molecular mechanisms involving Th17 cells in the development of osteoporosis and contributes to the discovery of potential biomarkers.

Indirect Comparison of Cryoablation and Radiofrequency Ablation as Initial Therapy for Symptomatic Paroxysmal Atrial Fibrillation: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Data on first-line ablation treatment for patients with symptomatic atrial fibrillation (AF) are scarce. This study indirectly compared the efficacy and safety of cryoballoon ablation (CBA) versus radiofrequency ablation (RFA) as initial therapy for symptomatic AF. METHODS: We searched the EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov databases for randomized controlled trials (RCTs) that compared CBA or RFA with antiarrhythmic drugs (AADs) as first-line treatment for AF from the time of database establishment up to December 2021. The odds ratio (OR) with a 95% confidence interval (CI) was used as a measure of the treatment effect. RESULTS: Six RCTs (3 CBA, 3 RFA) that enrolled a total of 1,215 patients were included in this analysis. There were no significant differences in atrial arrhythmia (AA) (OR 0.993, 95% CI: 0.602-1.638), symptomatic AA (OR 0.638, 95% CI: 0.344-1.182), or serious adverse events (OR 1.474, 95% CI: 0.404-5.376) between the two ablation techniques. The incidences of additional CBA therapy (OR 2.693, 95% CI: 1.277-5.681) and patients who crossed over to AAD therapy (OR 0.345, 95% CI: 0.179-0.664) in the CBA group were significantly lower than those in the RFA group. CONCLUSION: Among patients with paroxysmal AF receiving initial therapy, CBA and RFA share a similar efficacy and safety profile. When pulmonary vein isolation is performed by CBA, study crossover and the need for additional ablation are substantially lower.

Single nucleotide polymorphisms (SNPs) and indels identified from whole-genome re-sequencing of four Chinese donkey breeds.

This paper represents the fundamental report of the survey of genome-wide changes of four Chinese indigenous donkey breeds, Dezhou (DZ), Guangling (GL), North China (NC), and Shandong Little donkey (SDL), and the findings will prove usefully for identification of biomarkers that perhaps predict or characterize the growth and coat color patterns. Three genomic regions in CYP3A12, TUBGCP5, and GSTA1 genes, were identified as putative selective sweeps in all researched donkey populations. The loci of candidate genes that may have contributed to the phenotypes in body size (ACSL4, MSI2, ADRA1B, and CDKL5) and coat color patterns (KITLG and TBX3) in donkey populations would be found in underlying strong selection signatures when compared between large and small donkey types, and between different coat colors. The results of the phylogenetic analysis, FST, and principal component analysis (PCA) supported that each population cannot clearly deviate from each other, showing no obvious population structure. We can conclude from the population history that the formation processes between DZS and NC, GL, and SDL are completely different. The genetic variants discovered here provide a rich resource to help identify potential genomic markers and their associated molecular mechanisms that impact economically important traits for Chinese donkey breeding programs.

CKM intron: an appropriate marker for the determination of the genetic relationships among horse populations and breeds.

To date, the origins, domestication, and genetic structure of Chinese Mongolian horses (CMH) are poorly understood. Furthermore, there have been sparse reports on the genetic differences between CMH and Thoroughbred. In order to determine their genetic structure, understand their genetic relationships, and explore their domestication processes, we performed an extensive survey of creatine kinase (muscle isoenzyme; CKM) variations among six populations of indigenous CMH, cultivated Sanhe horses, and imported Thoroughbred. Twenty-three single-nucleotide polymorphisms were found among the 343 horse sequences. From these, 40 haplotypes were inferred. Haplotype diversity (H) values differed from 0.6424 to 0.7881 and nucleotide diversity (π) values ranged from 0.00150 to 0.00211. The differences between Thoroughbred population and other Chinese horse populations were large, but only small differences were observed among Chinese horse populations with respect to CKM intron sequences suggesting that the domestication history, breeding measures, and origins of these horse populations are completely different. Results suggest that Sanhe and CMH are very closely related and the introgression (interbreeding) between them is serious. Our results suggest that Sanhe and Wushen require prompt and powerful protection. Overall, CKM intron was an appropriate marker for the determination of genetic relationships among horse populations and breeds.

A Therapeutic DNA Vaccine Targeting HPV16 E7 in Combination with Anti-PD-1/PD-L1 Enhanced Tumor Regression and Cytotoxic Immune Responses.

Persistent infection of high-risk human papillomavirus (HPV) and the expression of E6 and E7 oncoproteins are the main causes of cervical cancer. Several prophylactic HPV vaccines are used in the clinic, but these vaccines have limited efficacy in patients already infected with HPV. Since HPV E7 is vital for tumor-specific immunity, developing a vaccine against HPV E7 is an attractive strategy for cervical cancer treatment. Here, we constructed an HPV16 E7 mutant that loses the ability to bind pRb while still eliciting a robust immune response. In order to build a therapeutic DNA vaccine, the E7 mutant was packaged in an adenovirus vector (Ad-E7) for efficient expression and enhanced immunogenicity of the vaccine. Our results showed that the Ad-E7 vaccine effectively inhibited tumor growth and increased the proportion of interferon-gamma (IFN-γ)-secreting CD8+ T cells in the spleen, and tumor-infiltrating lymphocytes in a mouse cervical cancer model was achieved by injecting with HPV16-E6/E7-expressing TC-1 cells subcutaneously. Combining the Ad-E7 vaccine with the PD-1/PD-L1 antibody blockade significantly improved the control of TC-1 tumors. Combination therapy elicited stronger cytotoxic T lymphocyte (CTL) responses, and IFN-γ secretion downregulated the proportion of Tregs and MDSCs significantly. The expressions of cancer-promoting factors, such as TNF-α, were also significantly down-regulated in the case of combination therapy. In addition, combination therapy inhibited the number of capillaries in tumor tissues and increased the thickness of the tumor capsule. Thus, Ad-E7 vaccination, in combination with an immune checkpoint blockade, may benefit patients with HPV16-associated cervical cancer.

Meta-analysis of medical management versus catheter ablation for atrial fibrillation.

Several observational studies have shown a survival benefit for patients with atrial fibrillation (AF) who are treated with catheter ablation (CA) rather than medical management (MM). However, data from randomized controlled trials (RCTs) are uncertain. Therefore, we performed a meta-analysis of RCTs that compared the benefits of CA and MM in treatment of AF. We searched the Cochrane Library, PubMed, and EMBASE databases for RCTs that compared AF ablation with MM from the time of database establishment up to January 2020. The risk ratio (RR) with a 95% confidence interval (CI) was used as a measure treatment effect. Twenty-six RCTs that enrolled a total of 5788 patients were included in the meta-analysis. In this meta-analysis, the effect of AF ablation depended on the baseline level of left ventricular ejection fraction (LVEF) in the heart failure (HF) patients. AF ablation appears to be of benefit to patients with a lesser degree of advanced HF and better LVEF by reducing mortality. Meanwhile, this mortality advantage was manifested in long-term follow-up. CA increased the risk for hospitalization when it was used as first-line therapy and decreased the risk when used as second-line therapy. CA reduced recurrence of atrial arrhythmia for different types of AF (paroxysmal or persistent AF) and CA-related complications were non-negligible. There was no convincing evidence for a reduction in long-term stroke risk after AF ablation, and additional high quality RCTs are needed to address that issue.

First detection and genetic characterization of a novel kirkovirus from a dead thoroughbred mare in northern Xinjiang, China, in 2018.

BACKGROUND: In May 2018, a 8 year old thoroughbred mare died at an equestrian club in Changji, Xinjiang, China. The horse had been imported from the United States in 2013. She became pregnant in December 2016 but, after foaling, gradually lost weight and died in May 2018. This study aim to identify the pathogen, who cause of horse death, using virome. RESULTS: We have identified an Equ1-like virus from the fecal virome of a dead thoroughbred mare in China. Full genomic sequencing and phylogenetic analysis of the virus, tentatively named "kirkovirus Cj-7-7", showed that it was closely related to kirkovirus Equ1 and clustered together with po-circo-like viruses 21, 22, 41, and 51, suggesting that it should be assigned to the proposed family "Kirkoviridae". An epidemiological investigation showed that kirkovirus Cj-7-7 circulates in horses of northern Xinjiang and may specifically infect intestinal cells. CONCLUSIONS: Our findings demonstrate the genetic diversity and geographic distribution of Kirkoviruses, and the prevalence of Kirkovirus Cj-7-7 in Xinjiang, China.

sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway.

Doxorubicin (Dox) is an effective chemotherapy drug against a wide range of cancers, including both hematological and solid tumors. However, the serious cardiotoxic effect restricted its clinical application. We previously have illuminated the protective role of canonical Wnt/ß-catenin signaling in Dox-induced cardiotoxicity. Secreted frizzled-related protein 1 (sFRP1) is one of the endogenous inhibitors of both canonical and noncanonical Wnt signaling. In this study, we investigated the relationship between sFRP1 and noncanonical Wnt/PCP-JNK (Wnt/planar cell polarity-c-Jun N-terminal kinase) pathway in Dox-induced cardiotoxicity in vitro and in vivo. We showed that treatment of H9c2 cardiac myoblasts with Dox (1 µM) time-dependently suppressed cell viability accompanied by significantly decreased sFRP1 protein level and increased Wnt/PCP-JNK signaling. Pretreatment with SP600125, the Wnt/PCP-JNK signaling inhibitor, attenuated Dox-induced apoptosis of H9c2 cells. Overexpression of sFRP1 protected H9c2 cells from Dox-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. After intraperitoneal injection of a cumulative dose of 15 mg/kg Dox, rats displayed significant cardiac dysfunction; their heart showed inhibited Wnt/ß-catenin signaling and activated Wnt/PCP-JNK signaling. These results suggest that sFRP1 may be a novel target for Dox-induced cardiotoxicity.

Empirical prediction model based process optimization for droplet size and spraying angle during pharmaceutical fluidized bed granulation.

The objective of this study was to predict the droplet size and the spraying angle during the process of binder atomization in pharmaceutical fluidized bed granulation using an empirical model. The effects of the binder viscosity, the atomization pressure, and the spray rate on the droplet size and the spraying angle were investigated using a response surface central composite design and analysis of variance. Prediction models for droplet size and spraying angle were then established using stepwise regression analysis and were validated by comparing the measured and predicted values. The results showed that the droplet size model and the spraying angle model were well established, with an R2 of 0.93 (p < 0.0001) and a root mean square error (RMSE) of 10.10, and an R2 of 0.82 (p < 0.0001) and an RMSE of 3.69, respectively. The error between the measured and predicted values of the droplet size and the spraying angle were less than 10%, indicating that the established models were accurate. The results of the present study were significant in predicting the droplet size and spraying angle in the process of pharmaceutical fluidized bed granulation.

Enhanced Oral Bioavailability of Chlormadinone Acetate through a Self-Microemulsifying Drug Delivery System for a Potential Dose Reduction.

Chlormadinone acetate (CMA) is a derivative of the naturally secreted hormone progesterone and exhibits reliable contraceptive and non-contraceptive benefits. Although the marketed product of CMA as oral tablets under the trade name Belara® has been highly successful, there is still room for further improvements in oral bioavailability and a reduction in the clinical dose to decrease related adverse effects. In the current study, a CMA-based self-microemulsifying drug delivery system (SMEDDS) was developed using 32% ethyl oleate as an oil phase, 40% Tween-80 as a surfactant, and 12% Transcutol P combined with 16% PEG400 as a cosurfactant, resulting in spherical droplets with a z-average particle size of 38.92 nm and an average zeta potential of - 3.18 mv. The in vitro release rate of CMA from CMA-SMEDDS in different media (distilled water, HCl solution at pH 1.2, phosphate buffers at pH 4.5 and pH 6.8) was significantly faster than that from Belara® in the first 15 min. A pharmacokinetic study in rats showed that the Cmax and AUC of CMA-SMEDDS were significantly higher (P < 0.01) than those of Belara®, with a 1.98-fold increase in oral bioavailability. In comparison with Belara®, the developed CMA-SMEDDS showed promising release profiles both in vitro and in vivo, which could potentially be useful in enhancing oral bioavailability and reducing the clinical dose of CMA.

(-)-Meptazinol-melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-ß aggregation with high antioxidant potency for Alzheimer's therapy.

The multifactorial pathogenesis of Alzheimer's disease (AD) implicates that multi-target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-ß (Aß) aggregation and oxidative stress, two prominent neuropathological hallmarks in patients, play crucial roles in the neurotoxic cascade of this disease. In the present study, a series of novel (-)-meptazinol-melatonin hybrids were designed, synthesized and biologically characterized as potential MTDLs against AD. Among them, hybrids 7-7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound 7c could effectively inhibit Aß self-aggregation, showed favorable safety and the blood-brain barrier (BBB) permeability. Therefore, 7c may serve as a valuable candidate that is worthy of further investigations in the treatment of AD.

Enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7.

UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation conjugation reaction plays an important role in the elimination of many important clinical drugs and endogenous substances. The present study aims to investigate the enantioselective inhibition of carprofen towards UGT isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation mixture was used to screen the inhibition potential of (R)-carprofen and (S)-carprofen towards multiple UGT isoforms. The results showed that (S)-carprofen exhibited stronger inhibition potential than (R)-carprofen towards UGT2B7. However, no significant difference was observed for the inhibition of (R)-carprofen and (S)-carprofen towards other UGT isoforms. Furthermore, the inhibition kinetic behavior was compared for the inhibition of (S)-carprofen and (R)-carprofen towards UGT2B7. A Lineweaver-Burk plot showed that both (S)-carprofen and (R)-carprofen exhibited competitive inhibition towards UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameter (Ki ) was calculated to be 7.0 µM and 31.1 µM for (S)-carprofen and (R)-carprofen, respectively. Based on the standard for drug-drug interaction, the threshold for (S)-carprofen and (R)-carprofen to induce a drug-drug interaction is 0.7 µM and 3.1 µM, respectively. In conclusion, enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7 was demonstrated in the present study. Using the in vitro inhibition kinetic parameter, the concentration threshold of (S)-carprofen and (R)-carprofen to possibly induce the drug-drug interaction was obtained. Therefore, clinical monitoring of the plasma concentration of (S)-carprofen is more important than (R)-carprofen to avoid a possible drug-drug interaction between carprofen and the drugs mainly undergoing UGT2B7-catalyzed metabolism.

Regulation profile of phosphatidylcholines (PCs) and lysophosphatidylcholines (LPCs) components towards UDP-glucuronosyltransferases (UGTs) isoforms.

1.Endogenous compounds have been reported to be the regulators of UDP-glucuronosyltransferases (UGTs) isoforms. This study aims to investigate the regulatory effects of the activity of UGT isoforms by two important lipid components phosphatidylcholine (PC) and lysophosphatidylcholines (LPC) using in vitro incubation system. 2.UGTs supersomes-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as the probe reaction to evaluate the inhibition of compounds towards UGT isoforms except UGT1A4, and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation reaction was utilized to phenotype the activity of UGT1A4. 3.About 50 µM of LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0 exhibited inhibition towards more than 90% activity of UGT isoforms, and other LPC and PC components showed negligible inhibitory potential towards all the UGT isoforms. UGT1A6 and UGT1A8 were identified to be the most sensitive UGT isoforms susceptible for the inhibition by LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0, indicating the strong influence of these LPC and PC components towards UGT1A6 and UGT1A8-catalyzed metabolic reaction when the concentrations of these components increased.

Gut microbiota and oral cavity cancer: a two-sample bidirectional Mendelian randomization study.

This study employs a two-sample bidirectional Mendelian randomization (MR) approach to systematically evaluate the causal relationship between gut microbiota and oral cavity cancer (OCC). Objective: To address the challenge in establishing the causal relationship between gut microbiota and OCC, we applied a systematic MR analysis. Methods: Utilizing GWAS data from the MiBioGen consortium (18,340 individuals) and UK Biobank (n = 264,137), we selected instrumental variables and employed MR-Egger, weighted median, IVW, and weighted mode analyses. Heterogeneity and pleiotropy were assessed using Cochran's Q test and MR-Egger intercept test. Results: Our findings indicate, at the order level, Bacteroidales (OR = 0.9990, 95% CI = 0.9980-1.0000, P = 0.046), Burkholderiales (OR = 1.0009, 95% CI = 1.0001-1.0018, P = 0.033), and Victivallales (OR = 0.9979, 95% CI = 0.9962-0.9995, P = 0.037) exhibit causality on OCC in the Weighted median, IVW, and MR-Egger analyses, respectively. At the family level, Alcaligenaceae (OR = 1.0012, 95% CI = 1.0004-1.0019, P = 0.002) and Clostridiaceae1 (OR = 0.9970, 95% CI = 0.9948-0.9992, P = 0.027) show causality on OCC in IVW and MR-Egger analyses. At the genus level, Clostridiumsensustricto1 (IVW, OR = 0.9987, 95% CI = 0.9980-0.9995, P = 0.001; MR-Egger, OR = 0.9978, 95% CI = 0.9962-0.9995, P = 0.035), Desulfovibrio (IVW, OR = 1.0008, 95% CI = 1.0001-1.0015, P = 0.016), Eggerthella (IVW, OR = 0.9995, 95% CI = 0.9990-1.0000, P = 0.048), Eubacterium fissicatena group (IVW, OR = 1.0005, 95% CI = 1.0000-1.0009, P = 0.032), and Holdemanella (IVW, OR = 0.9994, 95% CI = 0.9989-0.9999, P = 0.018) are implicated in causing OCC in related analyses. Conclusion: Our study identifies Burkholderiales order, Alcaligenaceae family, Desulfovibrio genus, and Eubacterium fissicatena group as causally increasing OCC risk. In contrast, Bacteroidales order, Victivallales order, Clostridiaceae1 family, Clostridiumsensustricto1 genus, Eggerthella genus, and Holdemanella genus are causally associated with a decreased OCC risk. However, further investigations are essential to delineate an optimal gut microbiota composition and unravel the underlying mechanisms of specific bacterial taxa in OCC pathophysiology.

Innate Immune Evasion of PRRSV nsp11 through Degradation of the HDAC2 by Its Endoribonuclease Activity.

Porcine reproductive and respiratory syndrome virus (PRRSV), a member of the Arteriviridae family, represents a persistent menace to the global pig industry, causing reproductive failure and respiratory disease in pigs. In this study, we delved into the role of histone deacetylases (HDAC2) during PRRSV infection. Our findings revealed that HDAC2 expression is downregulated upon PRRSV infection. Notably, suppressing HDAC2 activity through specific small interfering RNA led to an increase in virus production, whereas overexpressing HDAC2 effectively inhibited PRRSV replication by boosting the expression of IFN-regulated antiviral molecules. Furthermore, we identified the virus's nonstructural protein 11 (nsp11) as a key player in reducing HDAC2 levels. Mutagenic analyses of PRRSV nsp11 revealed that its antagonistic effect on the antiviral activity of HDAC2 is dependent on its endonuclease activity. In summary, our research uncovered a novel immune evasion mechanism employed by PRRSV, providing crucial insights into the pathogenesis of this virus and guiding the development of innovative prevention strategies against PRRSV infection.

Arbidol exhibits strong inhibition towards UDP-glucuronosyltransferase (UGT) 1A9 and 2B7.

The aim of the present study was to investigate arbidol's inhibition towards UDP-glucuronosyltransferase (UGT) 1A9 and 2B7. The nonspecific probe substrate 4-methylumbelliferone (4-MU) and recombinant UGT enzymes (UGT1A9, UGT2B7) were firstly used to evaluate the inhibition of arbidol towards UGT1A9 and UGT2B7. Furthermore, specific substrates of UGT1A9 and UGT2B7 propofol and zidovudine (AZT) were used to determine the inhibition of arbidol towards UGT1A9 and UGT2B7. Inhibition type and inhibition kinetic parameters (Ki) were determined. In vitro-in vivo extrapolation (IV-IVE) was performed to predict in vivo DDI magnitude induced by arbidol. Arbidol was demonstrated to exhibit competitive inhibition towards UGT1A9 and UGT2B7 without substate-dependent behaviour. The inhibition kinetic parameters (Ki) were calculated to be 0.5 microM, 3.5 microM, 2.8 microM, 29.7 microM for UGT2B7-mediated 4-MU glucuronidation, UGT1A9-mediated 4-MU glucuronidation, UGT2B7-mediated AZT glucuronidation, and UGT1A9-mediated propofol glucuronidation, respectively. Using these parameters, the in vivo alteration of area under of concentration-time curve (AUC) was calculated to be 156%, 22%, 28% and 2.6%, respectively. Given that arbidol exhibits strong inhibition towards UGT1A9 and UGT2B7, clinical monitoring should be given when arbidol was co-administered with drugs mainly undergoing UGT1A9, UGT2B7-mediated metabolism.