Discovery and evaluation of HW161023 as a potent and orally active AAK1 inhibitor.

AAK1, also known as AP2-associated protein kinase 1, is an enzyme that belongs to the family of serine/threonine protein kinases. It regulates the assembly and disassembly of clathrin-coated pits and thereby protein endocytosis, by phosphorylating the µ2 subunit of the AP2 complex, which is a key component of clathrin-coated vesicles. LX9211 is currently the only selective small molecule AAK1 inhibitor at the clinical trial stage for diabetic peripheral neuropathic pain, which was found to be safe and well tolerated in healthy participants in phase I clinical trials. The present manuscript described a series of fused-ring derivatives as a novel class of potent AAK1 inhibitors, resulting in the discovery of compound 5, namely HW161023, which showed high inhibitory potency against AAK1 enzyme and satisfactory oral pharmacokinetic profile with weaker HepG2 cell toxicity and hERG inhibition than LX9211.

A NIR fluorescent probe based on tricyanofuran for the detection of ß-galactosidase in living ovarian tumor cells and in vivo.

ß-Galactosidase (ß-Gal) as an important glycoside hydrolase plays an important role in the early diagnosis of ovarian cancer. It is important to accurately and conveniently detect ß-Gal in organisms. In this study, we developed a fluorescent probe TCF-GAL based on the tricyanofuran structure, which is linked to ß-galactose through ether bonds for ß-Gal detection. Probe TCF-GAL exhibited satisfactory selectivity and sensitivity toward ß-Gal with the calculated LOD of 1.45 × 10-4 U/mL. Moreover, it can be applied to image endogenous ß-Gal in living SKOV3 cells with low cytotoxicity. Importantly, probe TCF-GAL was successfully employed in monitoring ß-Gal in the mouse subcutaneous model of ovarian cancer. These results indicated that this probe had great potential for diagnosing ß-Gal related diseases.

Kidney injury: An overlooked manifestation in autoimmune encephalitis.

AIM: To investigate the prevalence and clinical features of kidney injury in patients with autoimmune encephalitis (AE). METHODS: Kidney injury was suspected in kidney-involving group due to persistent abnormal in urinary protein and serum albumin. Data on demographics and clinical features were compared between kidney-involving group and kidney-sparing group (patients without kidney injury) using Wilcoxon rank-sum test or chi-square test. Renal biopsy was conducted to identify the type of kidney injury. RESULTS: Approximate 30 % (32 of 108) patients with AE were suspicious of kidney injury. Nine patients further tested 24 h urine total protein, and seven of them had an elevated urine protein higher than 150 mg. The predominantly patterns of kidney injury were elevated urine protein, decreased serum albumin and normal kidney function. Compared to kidney-sparing group, the spectrum of AE antibodies in kidney-involving group was different, manifested as less anti-N-methyl-d-aspartate receptor antibodies (50 % vs. 72.4 %, p = 0.025) and more anti-contactin-associated protein like 2 antibodies (18.8 % vs. 1.3 %, p = 0.003). Definite pathological changes indicative of IgA nephropathy and membranous nephropathy in renal biopsy of two cases provided evidence of autoimmune attacks. DISCUSSION: Kidney injury occurred in considerable proportion of patients with AE. An in-depth screening for nephropathy could be essential for AE.

Metagenomics reveals the characteristics and potential spread of microbiomes and virulence factor genes in the dairy cattle production system.

Virulence factor genes (VFGs) pose a potential threat to ecological security and animal health, and have attracted increasing attention in the livestock industry. As one of the primary livestock types, dairy cattle may be an important source of VFG transmission. However, the distribution, transmission, and evolution of VFGs in the gastrointestinal tract and surrounding environment of dairy cattle remain unclear. In the present study, a total of 263 samples were collected from cows, calves, colostrum, farm wastewater, and soil. Metagenomics was conducted to analyze changes in the microbiome and VFGs characteristics in these ecological niches. The VFGs of the cows showed distinct differences between the rumen and feces, and were influenced by the region. The dominant VFG hosts was regulated by their microbial structure. Colostrum administration of cows increased VFG abundance in their newborn calf feces sharply and Enterobacteriaceae became the primary host. While diet was the primary driving force for the temporal variation in calf VFGs. For samples of the surrounding environment, water and soil had higher VFG concentrations and were more structurally stable. Moreover, extensive interactions between the mobile genetic elements and VFGs and gene mobile analysis map based on metagenomic binning both displayed the potential horizontal transfer ability of VFGs in the cows and environment. Our study revealed the prevalence, diffusion, and regulatory factors of VFGs in dairy cattle production systems, providing novel insights into reducing livestock VFGs and limiting their spread.

Nomogram to Predict Nodal Recurrence-Free Survival in Early Oral Squamous Cell Carcinoma.

OBJECTIVE: This study aimed to develop and internally validate a prognostic nomogram for predicting nodal recurrence-free survival (NRFS) in patients with early-stage oral squamous cell carcinoma (OSCC) with clinically negative neck lymph nodes. MATERIALS AND METHODS: The management of early-stage oral cancer patients with clinically negative neck lymph nodes (cN0) remains controversial, especially concerning the need for elective neck dissection. Data from a single institution spanning 2010 to 2020 were utilized to develop and evaluate the nomogram. The nomogram was constructed using multivariable Cox regression and LASSO regression analyses to identify independent risk factors for lymph node metastasis. Internal validation was performed using bootstrap resampling to assess the nomogram's predictive accuracy. RESULTS: A total of 930 cN0 patients with T1 and T2 stage OSCC were randomly divided into training and validation cohorts (8:2 ratio). Independent risk factors for lymph node metastasis included tumor pathological grade (well: reference, moderate/poor: OR 1.69), cT (cT1: reference, cT2: OR 2.01), history of drinking (never: reference, current/former: OR 1.72), and depth of invasion (0 mm < DOI ≤ 5 mm: reference, 5 mm < DOI ≤ 10 mm: OR 1.31). The nomogram, incorporating these variables, demonstrated good predictive accuracy with a C-index of 0.67 (95% CI: 0.58-0.76) in the validation set. In both training and validation groups, the nomogram effectively stratified patients into low-risk and high-risk groups for occult cervical nodal metastases (p < 0.05). CONCLUSIONS: The nomogram enables risk stratification and improved identification of occult cervical nodal metastases in clinically node-negative OSCC patients by incorporating tumor-specific and patient-specific risk factors.

Maternal gastrointestinal microbiome shapes gut microbial function and resistome of newborns in a cow-to-calf model.

BACKGROUND: The maternal gut microbiome is the direct and important source of early colonization and development of the neonatal gut microbiome. However, differences in unique and shared features between mothers with different physiological phenotypes and their newborns still lack exhaustive investigation. Here, using a cow-to-calf model, a comprehensive investigation was conducted to elucidate the pattern and characterization of microbial transfer from the maternal source to the offspring. RESULTS: The microbiota in the rumen and feces of dairy cows were divided into two clusters via enterotype analysis. The cows from the enterotype distinguished by Prevotella in the rumen had better production performance, whereas no difference was observed in the cows classified by feces enterotype. Furthermore, through a pairwise combination of fecal and ruminal enterotypes, we screened a group of dairy cows with excellent phenotypes. The gastrointestinal microbiomes of cows with different phenotypes and their offspring differed significantly. The rumen was a more important microbial source for meconium than feces. Transmission of beneficial bacteria from mother to offspring was observed. Additionally, the meconium inherits advantageous metabolic functions of the rumen. The resistome features of the rumen, feces, and meconium were consistent, and resistome abundance from cows to calves showed an expanding trend. The interaction between antibiotic-resistance genes and mobile genetic elements from the rumen to meconium was the most remarkable. The diversity of core metabolites from cows to calves was stable and not affected by differences in phenotypes. However, the abundance of specific metabolites varied greatly. CONCLUSIONS: Our study demonstrates the microbial taxa, metabolic function, and resistome characteristics of maternal and neonatal microbiomes, and reveals the potential vertical transmission of the microbiome from a cow-to-calf model. These findings provide new insights into the transgenerational transmission pattern of the microbiome. Video Abstract.

A novel model of post-burn hypertrophic scarring in rat tail with a high success rate and simple methodology.

BACKGROUND: Hypertrophic scars present a serious concern after surgeries and trauma, particularly with the highest risk following burn injury. The current modeling methods usually involve relatively complicated surgical operations and special equipment, and have unstable reproducibility and reliability. This study aimed to establish a simple and reliable model of post-burn hypertrophic scarring in the rat tail. METHODS: Wet gauze saturated with hot water (94-98 °C) was applied to the dorsal side of the rat tail for varying durations to induce burn injury. Wounds were left exposed until completely healed, and the optimal duration for scalding treatment was determined based on gross examination. Thereafter, the optimal scalding duration was used again to evaluate scar formation over time, which was tracked through hematoxylin-eosin (HE) and Masson staining, immunohistochemistry of scar-related proteins and number/distribution of vascular endothelial cells, and picrosirius red staining to measure the quantities and proportion of type I and III collagen. RESULTS: The scalding duration which led to optimal post-burn scarring was 15 s, with an overall success rate of 87.5 %. Complete healing of the wound occurred after roughly 30 days, leading to the formation of scars grossly red in appearance, tough to the touch and raised compared to the surrounding skin. Microscopically, the epidermis and dermis of the scar were significantly thicker than normal rat tail skin, and the dermis of scar contained a large number of disorganized bundles of fine filamentous collagen. We also observed a significant increase in the number of TGF-ß1-positive cells and capillaries in the dermis (p < 0.05). Picrosirius red staining showed that compared to type III collagen, the expression of type I collagen was more dominant in scar tissue, and was more finely distributed than in normal rat tail skin. CONCLUSION: We successfully established a model for post-burn hypertrophic scarring, utilizing reliable and simple techniques and materials, which could simulate the biological characteristics of post-burn scarring. Our innovative model has the potential to facilitate the study of post-burn wound healing and scar formation.

Fibroblast Growth Factor 21 Suppressed Neutrophil Extracellular Traps Induced by Myocardial Ischemia/Reperfusion Injury via Adenosine Monophosphate-Activated Protein Kinase.

Background: Previous investigations have established the anti-inflammatory properties of fibroblast growth factor 21 (FGF21). However, the specific mechanism through which FGF21 mitigates myocardial ischemia/reperfusion (I/R) injury by inhibiting neutrophil extracellular traps (NETs) remains unclear. Methods: A mice model of myocardial I/R injury was induced, and myocardial tissue was stained with immunofluorescence to assess NETs. Serum NETs levels were quantified using a PicoGreen kit. In addition, the expression levels of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and FGF21 were evaluated by Wes fully automated protein blotting quantitative analysis system. Moreover, a hypoxia/reoxygenation (H/R) model was established using AMPK inhibitor and agonist pretreated H9c2 cells to further explore the relationship between FGF21 and AMPK. Results: Compared with the control group, serum NETs levels were significantly higher in I/R mice, and a large number of NETs were formed in myocardial tissues (97.63 ± 11.45 vs. 69.65 ± 3.33, P < 0.05). However, NETs levels were reversed in FGF21 pretreated mice (P < 0.05). Further studies showed that FGF21 enhanced AMPK expression, which was significantly increased after inhibition of AMPK and decreased after promotion of AMPK (P < 0.05). Conclusions: FGF21 may exert cardioprotective effects by inhibiting I/R injury-induced NETs via AMPK.

Targeted NO-Releasing L-arginine-Induced Hesperetin Self-Assembled Nanoparticles for Ulcerative Colitis Intervention.

Overproduction of reactive oxygen species (ROS) plays a crucial role in initiating and advancing ulcerative colitis (UC), and the persistent cycle between ROS and inflammation accelerates disease development. Therefore, developing strategies that can effectively scavenge ROS and provide targeted intervention is crucial for the management of UC. In this study, we synthesized natural carrier-free nanoparticles (HST-Arg NPs) using the Mannich reaction and π-π stacking for the intervention of UC. HST-Arg NPs are an oral formulation that exhibits good antioxidant capabilities and gastrointestinal stability. Benefiting from the negatively charged characteristics, HST-Arg NPs can specifically accumulate in positively charged inflamed regions of the colon. Furthermore, in the oxidative microenvironment of colonic inflammation, HST-Arg NPs respond to ROS by releasing nitric oxide (NO). In mice model of UC induced by dextran sulfate sodium (DSS), HST-Arg NPs significantly mitigated colonic injury by modulating oxidative stress, lowering pro-inflammatory cytokines, and repairing intestinal barrier integrity. In summary, this convenient and targeted oral nanoparticle can effectively scavenge ROS at the site of inflammation and achieve gas intervention, offering robust theoretical support for the development of subsequent oral formulations in related inflammatory interventions. STATEMENT OF SIGNIFICANCE: Nanotechnology has been extensively explored in the biomedical field, but the application of natural carrier-free nanotechnology in this area remains relatively rare. In this study, we developed a natural nanoparticle system based on hesperetin (HST), L-arginine (L-Arg), and vanillin (VA) to scavenge ROS and alleviate inflammation. In the context of ulcerative colitis (UC), the synthesized nanoparticles exhibited excellent intervention effects, effectively protecting the colon from damage. Consequently, these nanoparticles provide a promising and precise nutritional intervention strategy by addressing both oxidative stress and inflammatory pathways simultaneously, demonstrating significant potential for application.

Research progress on correlative prediction factors and prediction models of endometriosis associated ovarian carcinoma.

BACKGROUND: Endometriosis is a common benign disease in women of childbearing age, with a malignant change rate of about 1%. Endometriosis associated ovarian cancer (EAOC), which usually occurs in the ovaries, is a serious threat to women's health. Early identification of high-risk groups of EMs malignant transformation is of great significance for the prevention and treatment of EAOC. However, there is still a lack of specific and sensitive prediction factors. In recent years, scholars at home and abroad have used traditional statistical methods and machine learning to explore EAOC related prediction factors and prediction models. This paper mainly reviews and evaluates the diagnosis and prediction model of EAOC. METHODS: Studies were identified by searching the CNKI, PubMed and Web of Science Core Collection, (WOSCC) till 2023, Data which met the inclusion criteria of clinical studies were evaluated about the quality. This paper analyzes and summarizes the prediction factors and prediction models in the literature. RESULTS: After screening, 7 relevant studies were finally obtained. Prediction factors included: age, menstruation, menopausal status, course of disease, infertility associated with endometriosis, history of single estrogen use during menopause, serological indexes: human epididymis protein 4, carbohydrate antigen 125(CA125), ovarian malignancy risk algorithm, indications for ultrasound examination: cyst shape, structure and blood flow signal, etc. Prediction models: Alignment diagram, Multivariate logistic regression model, Gail model, Gradient Boosting Decision Tree and Lasso-logistics regression. CONCLUSION: Related models were in good agreement with the actual situation, and have good sensitivity and specificity. The relevant prediction factors and prediction models were summarized to provide reference and new thinking for the research of prediction models in the field of EAOC, in order to develop standardized long-term management strategies for high-risk groups of EAOC and realize the advance of the diagnosis threshold of patients with EAOC.

The Assembly of Cerium(III)-Containing Silicotungstate with Lewis Acid-Base Sites Enables the Selective C3-Alkenylation of Oxindole.

A cerium(III)-containing silicotungstate, [H2N(CH3)2]10NaK[KCe(SiW11O39)2(H2O)]·18.5H2O (CeSiW), was successfully synthesized and characterized. Structure analysis reveals that CeSiW is composed of two {SiW11O39} units connected by one cerium(III) cation to form a typical 1:2 sandwich structure, which is further expanding into a 1D chain linked by K+ ions. The oxygen-enriched surfaces of {SiW11O39} units and open cerium sites provide abundant Lewis base and acid sites in CeSiW. As a result, CeSiW efficiently catalyzed the C3-alkenylation of oxindoles with aldehydes through the simultaneous activation of both reaction substrates on its crystal framework. Various 3-benzylidene-oxindoles are synthesized with excellent yields and high E-selectivity under solvent-free conditions.

C/EBPδ deficiency delays infection-induced preterm birth.

BACKGROUND: Parturition is an inflammation process. Exaggerated inflammatory reactions in infection lead to preterm birth. Although nuclear factor kappa B (NF-κB) has been recognized as a classical transcription factor mediating inflammatory reactions, those mediated by NF-κB per se are relatively short-lived. Therefore, there may be other transcription factors involved to sustain NF-κB-initiated inflammatory reactions in gestational tissues in infection-induced preterm birth. METHODS: Cebpd-deficient mice were generated to investigate the role of CCAAT enhancer-binding protein δ (C/EBPδ) in lipopolysaccharide (LPS)-induced preterm birth, and the contribution of fetal and maternal C/EBPδ was further dissected by transferring Cebpd-/- or WT embryos to Cebpd-/- or WT dams. The effects of C/EBPδ pertinent to parturition were investigated in mouse and human myometrial and amnion cells. The interplay between C/EBPδ and NF-κB was examined in cultured human amnion fibroblasts. RESULTS: The mouse study showed that LPS-induced preterm birth was delayed by Cebpd deficiency in either the fetus or the dam, with further delay being observed in conceptions where both the dam and the fetus were deficient in Cebpd. Mouse and human studies showed that the abundance of C/EBPδ was significantly increased in the myometrium and fetal membranes in infection-induced preterm birth. Furthermore, C/EBPδ participated in LPS-induced upregulation of pro-inflammatory cytokines as well as genes pertinent to myometrial contractility and fetal membrane activation in the myometrium and amnion respectively. A mechanistic study in human amnion fibroblasts showed that C/EBPδ, upon induction by NF-κB, could serve as a supplementary transcription factor to NF-κB to sustain the expression of genes pertinent to parturition. CONCLUSIONS: C/EBPδ is a transcription factor to sustain the expression of gene initiated by NF-κB in the myometrium and fetal membranes in infection-induced preterm birth. Targeting C/EBPδ may be of therapeutic value in the treatment of infection-induced preterm birth.

ApCarE4 and ApPOD3 participate in the adaptation of pea aphids to different alfalfa varieties.

The adaptability of insects to hosts has long been a focal point in the study of insect-plant interactions. The pea aphid (Acythosiphon pisum), a significant pest of numerous leguminous crops, not only inflicts direct economic losses but also disseminates various plant viruses. To understand how pea aphids adapt to diverse alfalfa varieties. We analyzed the differentially expressed genes (DEGs) of pea aphids in distinct alfalfa varieties using transcriptome sequencing, and subsequently conducted functional validation of these genes. Comparative analysis between pea aphids feeding on susceptible and resistant strains revealed that DEGs in aphids feeding on resistant strains were primarily associated with transcriptional enrichment in the sugar, amino acid, protein, and lipid metabolism pathways. Fourteen DEGs related to adaptation of the pea aphid to alfalfa were chosen, including five carboxylesterases (CarE), four cytochrome P450s, three glutathione S-transferases, and two peroxidases (POD). RT-qPCR results indicated significant up-regulation of two carboxylesterase genes and two peroxidase genes after 24 h of feeding resistant alfalfa (Gannong 5, GN5) compared to the susceptible varieties (Hunter River, LRH), particularly highlighting the high expression levels of ApCarE4 and ApPOD3. Simultaneously, RNAi-induced knockdown of ApCarE4 and ApPOD3 led to a higher mortality of pea aphids in the alfalfa Hunter River. These results indicate that ApPOD3 and ApCarE4 are involved in the detoxification of metabolic functions in the adaptation of pea aphids to host switching. These findings contribute to the understanding of pea aphid adaptation to host plants and lay a foundation for further exploration of the physiological roles of carboxylesterase and peroxidase genes in pea aphids.

Clinical and CT characteristics for predicting lymph node metastasis in patients with synchronous multiple primary lung adenocarcinoma.

PURPOSE: This study aims to investigate the risk factors for lymph node metastasis (LNM) in synchronous multiple primary lung cancer (sMPLC) using clinical and CT features, and to offer guidance for preoperative LNM prediction and lymph node (LN) resection strategy. MATERIALS AND METHODS: A retrospective analysis was conducted on the clinical data and CT features of patients diagnosed with sMPLC at the Third Affiliated Hospital of Kunming Medical University from January 1, 2018 to December 31, 2022. Patients were classified into two groups: the LNM group and the non-LNM (n-LNM) group. The study utilized univariate analysis to examine the disparities in clinical data and CT features between the two groups. Additionally, multivariate analysis was employed to discover the independent risk variables for LNM. The diagnostic efficacy of various parameters was evaluated using the receiver operating characteristic (ROC) curve. RESULTS: Among the 688 patients included in this study, 59 exhibited LNM. Univariate analysis revealed significant differences between the LNM and n-LNM groups in terms of gender, smoking history, CYFRA21-1 level, CEA level, NSE level, lesion type, total lesion diameter, main lesion diameter, spiculation sign, lobulation sign, cavity sign, and pleural traction sign. Logistic regression identified CEA level (OR = 1.042, 95%CI: 1.009-1.075), lesion type (OR = 9.683, 95%CI: 3.485-26.902), and main lesion diameter (OR = 1.677, 95%CI: 1.347-2.089) as independent predictors of LNM. The regression equation for the joint prediction was as follows: logit(p)= -7.569+0.041*CEA level +2.270* lesion type +0.517* main lesion diameter.ROC curve analysis showed that the AUC for CEA level was 0.765 (95% CI, 0.694-0.836), for lesion type was 0.794 (95% CI, 0.751-0.838), for main lesion diameter was 0.830 (95% CI, 0.784-0.875), and for the combine predict model was 0.895 (95% CI, 0.863-0.928). CONCLUSION: The combination of clinical and imaging features can better predict the status of LNM of sMPLC, and the prediction efficiency is significantly higher than that of each factor alone, and can provide a basis for lymph node management decision.

[Comparison of Three Remote Sensing Indices in Revealing the Vegetation Growth Dynamics in Nepal from 2000 to 2020].

Remote sensing indices have been widely used to monitor the vegetation growth dynamics induced by climate change and human activities, and yet the consistency of the vegetation dynamics revealed by different remote sensing indices in mountains is unclear. Using Nepal as a case study, this study explored the spatial-termporal consistencies of the three widely-used remote sensing indices （i.e., normalized difference vegetation index （NDVI）, leaf area index （LAI）, and net primary production （NPP）） in quantifying the vegetation growth dynamics in mountainous regions. The results indicated that the spatial distributions of the multi-year mean estimates varied greatly by remote sensing index, especially in the low-altitude regions. The maximum NDVI, LAI, and NPP occurred in the low, medium, and high mountain regions, respectively. Although all three indices showed an overall increasing tendency from a long-term perspective, the area percentage of the lands with a significant trend was obviously larger in NDVI （82%） than that in NPP （58%） and LAI （56%）. In addition, the land area percentages with vegetation growth enhancement decreased gradually by the rise of altitude for both the NDVI and LAI indices but decreased after an increase for the NPP index. Only 9.6% of the lands showed consistent long-term trends （with the same change directions and significant levels） in the three indices on a per-pixel basis. Our findings highlight the large uncertainties of remote sensing indices in monitoring vegetation growth dynamics in mountainous areas, and the importance of developing reinforced remote sensing products in future efforts.

Dietary Probiotic Pediococcus acidilactici GKA4, Dead Probiotic GKA4, and Postbiotic GKA4 Improves Cisplatin-Induced AKI by Autophagy and Endoplasmic Reticulum Stress and Organic Ion Transporters.

BACKGROUND/OBJECTIVES: Acute kidney injury (AKI) syndrome is distinguished by a quick decline in renal excretory capacity and usually diagnosed by the presence of elevated nitrogen metabolism end products and/or diminished urine output. AKI frequently occurs in hospital patients, and there are no existing specific treatments available to diminish its occurrence or expedite recovery. For an extended period in the food industry, Pediococcus acidilactici has been distinguished by its robust bacteriocin production, effectively inhibiting pathogen growth during fermentation and storage. METHODS: In this study, the aim is to assess the effectiveness of P. acidilactici GKA4, dead probiotic GKA4, and postbiotic GKA4 against cisplatin-induced AKI in an animal model. The experimental protocol involves a ten-day oral administration of GKA4, dead probiotic GKA4, and postbiotic GKA4 to mice, with a cisplatin intraperitoneal injection being given on the seventh day to induce AKI. RESULTS: The findings indicated the significant alleviation of the renal histopathological changes and serum biomarkers of GKA4, dead probiotic GKA4, and postbiotic GKA4 in cisplatin-induced nephrotoxicity. GKA4, dead probiotic GKA4, and postbiotic GKA4 elevated the expression levels of HO-1 and decreased the expression levels of Nrf-2 proteins. In addition, the administration of GKA4, dead probiotic GKA4, and postbiotic GKA4 significantly reduced the expression of apoptosis-related proteins (Bax, Bcl-2, and caspase 3), autophagy-related proteins (LC3B, p62, and Beclin1), and endoplasmic reticulum (ER) stress-related proteins (GRP78, PERK, ATF-6, IRE1, CHOP, and Caspase 12) in kidney tissues. Notably, GKA4, dead probiotic GKA4, and postbiotic GKA4 also upregulated the levels of proteins related to organic anion transporters and organic cation transporters. CONCLUSIONS: Overall, the potential therapeutic benefits of GKA4, dead probiotic GKA4, and postbiotic GKA4 are significant, particularly after cisplatin treatment. This is achieved by modulating apoptosis, autophagy, ER stress, and transporter proteins to alleviate oxidative stress.

Circulating levels of micronutrients and the risk of benign paroxysmal positional vertigo: A Mendelian randomization study.

Background: Benign paroxysmal positional vertigo (BPPV) is a typical vestibular disease characterized by recurrent episodes of vertigo. The role of micronutrients in BPPV pathogenesis has not been extensively studied, prompting this investigation into the relationship between circulating micronutrients and BPPV risk. This research aimed to explore the relationship between blood micronutrient levels and BPPV risk via Mendelian randomization (MR) analysis, a robust method for inferring causality from observational data. Methods: A total of 15 circulating micronutrients were assessed for their association with BPPV risk. MR analysis was conducted via the following methods: MR‒Egger, weighted median, simple model, inverse variance weighting (IVW), and weighted mode. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. A multivariate MR analysis was also conducted, incorporating potential confounders such as trauma, chronic otitis media, hearing loss, peripheral atherosclerosis, ageing, and osteoporosis. Results: MR analysis revealed an obvious association between selenium and BPPV risk (OR 1.074, 95 % CI 1.005 to 1.148; P = 0.035). Folate was negatively related (OR 0.694, 95 % CI 0.501 to 0.962, P = 0.028) but was excluded because of inconsistent OR values across methods. Sensitivity analysis supported the IVW results, and there was no evidence of significant heterogeneity among the selenium-related instrumental variables included in the study, nor was horizontal pleiotropy detected among the instrumental variables. Multivariate MR analysis confirmed that selenium was an independent risk factor for BPPV (OR 1.22, 95 % CI 1.059 to 1.406, P = 0.006), with no significant associations observed for other micronutrients or exposure factors. Conclusion: This study provides evidence that blood selenium levels are positively associated with the risk of BPPV, suggesting a potential role for selenium in the pathogenesis of this disorder. These findings are robust to various sensitivity analyses and support the use of MR analysis to identify novel risk factors for BPPV. The identification of selenium as an independent risk factor for BPPV has implications for the development of preventive strategies and targeted interventions. It is necessary to analyse the biological mechanisms of this association and determine the therapeutic value of limiting selenium intake for BPPV to provide support for the treatment of such patients.

The mixture of non-persistent endocrine-disrupting chemicals in relation to endometriosis.

Non-persistent endocrine-disrupting chemicals (EDCs) are of significant concern due to their reproductive toxicity. Previous research reported a relationship between a single type of EDCs and endometriosis. Yet, evidence regarding mixed exposure of multiple categories of EDCs is scarce. Between 2014 and 2018, our hospital-based case-control study recruited 238 endometriosis cases diagnosed by laparoscopy and 296 normal controls in China. Seventeen non-persistent EDCs (phthalates and bisphenols) were measured in urine. The association of single EDC with endometriosis was estimated using logistic regression, while the association between EDC mixture and endometriosis was modeled by Bayesian kernel machine regression (BKMR), quantile-based g-computation (q-gcomp), and principal component analysis (PCA). Consistent results were observed in both single and mixture models where phthalates and bisphenols were associated with increased risk of endometriosis (mixture effect: adjusted odds ratio (aOR)=1.44, 1.22-1.70) and the major contributors were bisphenol A (BPA) and the metabolites of di(2-ethylhexyl) phthalate (DEHP). Interaction analysis showed that bisphenols exhibited significant synergistic interactions with phthalates. Our results suggest that non-persistent EDCs are associated with endometriosis but the underlying mechanisms remain to be elucidated. Our finding may have important public health implications in preventing endometriosis.

Putative Dual Roles of Bone Morphogenetic Protein 8B (BMP8B) in Disease Progression of Gastric Cancer.

Background/Aim: Increased expression of bone morphogenetic protein 8B (BMP8B) in bone marrow and primary tumors of patients with gastric cancer (GC) is associated with disease progression and poor prognosis. However, a reduced expression has also been seen in GCs due to histone acetylation. This study aimed to evaluate BMP8B transcript levels in a large GC cohort and its impact on cellular functions. Materials and Methods: BMP8B transcripts were determined in 319 gastric tumors and compared with 182 adjacent normal tissues using real time PCR, with a further analysis conducted in the TCGA database. Kaplan-Meier plotter analysis was performed to evaluate the correlation between BMP8B and prognosis of the disease. BMP8B knockdown model was employed to determine the effect of BMP8B on the function of GC cells (HGC27). Results: BMP8B mRNA levels were significantly up-regulated in the GC tissues compared with adjacent normal tissues in both TCGA database and our own database from Beijing Cancer Hospital, and high BMP8B expression was associated with poor prognosis. BMP8B is most likely to be involved in the differentiation of GC. Poorly differentiated GC samples presented a significantly reduced BMP8B expression in relation to well-differentiated and moderately differentiated GC. BMP8B knockdown inhibited proliferation of GC cells, while promoted invasion and migration of cancer cells. Conclusion: BMP8B was reduced in GCs, whereas higher BMP8B expression was associated with poor prognosis. BMP8B knockdown inhibited proliferation of GC cells, and promoted invasion and migration. Our results suggest that BMP8B plays dual roles in GC.

Association between obstructive sleep apnea and 24-h urine protein quantification in patients with hypertension.

The association between obstructive sleep apnea (OSA) and proteinuria is undetermined, with few studies on hypertension, a high-risk group for renal impairment. Therefore, we aimed to explore whether OSA is an independent risk factor for proteinuria in patients with hypertension. We investigated the cross-sectional association between OSA and proteinuria. Participants were divided into groups by apnea hypopnea index (AHI) category. Multivariable Logistic regression analysis was used to evaluate the association between OSA severity, objectively measured sleep dimensions, and proteinuria which is mainly defined by 24-h urine protein quantification > 300 mg/24 h. Sensitivity analyses were performed by excluding those with comorbidities (primary aldosteronism and homocysteine ≥ 15 µmol/L). Of the 2106 participants, the mean age was 47.57 ± 10.50 years, 67.2% were men, and 75.9% were OSA patients. In total participants, compared with those without OSA, patients with mild OSA, moderate OSA, and severe OSA showed 1.09 (95% CI 0.80-1.40), 1.24 (95% CI 0.89-1.74) and 1.47 (95% CI 1.04-2.08) fold risk for proteinuria with a trend test P trend < 0.05. Each 10-unit increase in the AHI, oxygen desaturation index (ODI), and time spent with oxygen saturation < 90% (T90) was found to be associated with 13%, 10%, and 2% higher likelihood of proteinuria in the crude model, significant in adjusted models. The more severe the OSA is, the higher the risk of proteinuria. AHI and T90 are independently associated with a higher risk of structural renal damage in the population with hypertension.