Association Between Neck Circumference and Bone Mineral Loss: A Cross-sectional Study in Sichuan Province in China.

BACKGROUND: The associations of fat distribution with bone health are debatable. We aimed to investigate the associations between neck circumference (NC) and bone mineral loss among the adult Chinese population in Sichuan province. METHODS: We examined overall NC size and NC stratums (≤35cm, 3538cm) with bone mineral density (BMD) at the femoral neck, lumbar spine, total hip skeletal sites in 135 men and 479 women respectively, and assessed whether adiposity, lipids, and calcium and phosphorus levels, might have a biased role in the relationship of NC and bone mineral loss with linear regression, logistic regression, and restricted cubic spline models. RESULTS: The overall NC size is not independently associated with BMD at all sites. However, stratification for NC revealed that the positive correlation between NC and BMD at all sites were significant in the NC stratum 1 (≤35cm) in women (all p<0.05) and NC stratum 2 (3538cm) compared with NC stratum 1 using logistic regression. However, in women, no statistically significant association was observed between NC stratum 1 and BMD values after adjustment for the same confounders. CONCLUSIONS: Our findings suggest a NC stratum-specific association between NC size and bone mineral loss in men in Sichuan province in China, but not in women.

Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine.

Antimicrobial peptides (AMPs), ancient scavengers of bacteria, are very poorly induced in macrophages infected by Mycobacterium tuberculosis (M. tuberculosis), but the underlying mechanism remains unknown. Here, we report that L-alanine interacts with PRSS1 and unfreezes the inhibitory effect of PRSS1 on the activation of NF-κB pathway to induce the expression of AMPs, but mycobacterial alanine dehydrogenase (Ald) Rv2780 hydrolyzes L-alanine and reduces the level of L-alanine in macrophages, thereby suppressing the expression of AMPs to facilitate survival of mycobacteria. Mechanistically, PRSS1 associates with TAK1 and disruptes the formation of TAK1/TAB1 complex to inhibit TAK1-mediated activation of NF-κB pathway, but interaction of L-alanine with PRSS1, disables PRSS1-mediated impairment on TAK1/TAB1 complex formation, thereby triggering the activation of NF-κB pathway to induce expression of AMPs. Moreover, deletion of antimicrobial peptide gene ß-defensin 4 (Defb4) impairs the virulence by Rv2780 during infection in mice. Both L-alanine and the Rv2780 inhibitor, GWP-042, exhibits excellent inhibitory activity against M. tuberculosis infection in vivo. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses its own alanine dehydrogenase to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.

Effect of electroacupuncture stimulation of "Sibai"(ST2) and "Quanliao"(SI18) on excitatory neurons of sensorimotor cortex in mice. / 电针"四白"和"颧髎"æ¿€æ´»å°é¼ èº¯ä½“æ„Ÿè§‰è¿åŠ¨çš®å±‚çš„å ´å¥‹æ€§ç¥žç»å ƒ.

OBJECTIVES: To observe the activation state and neuronal types of somatosensory cortex and the primary motor cortex induced by electroacupuncture (EA) stimulation of "Sibai" (ST2) and "Quanliao" (SI18) acupoints in mice. METHODS: Male C57BL/6J mice were randomly divided into blank control and EA groups, with 6 mice in each group. Rats of the EA group received EA stimulation (2 Hz, 0.6 mA) at ST2 and SI18 for 30 minutes. Samples were collected after EA intervention, and immunofluorescence staining was performed to quantify the expression of the c-Fos gene (proportion of c-Fos positive cells) in the somatosensory cortex and primary motor cortex. The co-labelled cells of calcium/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) and gamma-aminobutyric acid (GABA) in the somatosensory cortex and primary motor cortex were observed and counted by using microscope after immunofluorescence staining. Another 10 mice were used to detect the calcium activity of excitatory neurons in the somatosensory cortex and primary motor cortex by fiber photometry. RESULTS: In comparison with the blank control group, the number of c-Fos positive cells, and the proportion of c-Fos and CaMKⅡ co-labelled cells in both the somatosensory cortex and primary motor cortex were significantly increased after EA stimulation (P<0.05). No significant changes were found in the proportion of c-Fos and GABA co-labeled cells in both the somatosensory cortex and primary motor cortex after EA. Results of fiber optic calcium imaging technology showed that the spontaneous calcium activity of excitatory neurons in both somatosensory cortex and primary motor cortex were obviously increased during EA compared with that before EA (P<0.01), and strikingly reduced after cessation of EA compared with that during EA (P<0.05). CONCLUSIONS: Under physiological conditions, EA of ST2 and SI18 can effectively activate excitatory neurons in the somatosensory cortex and primary motor cortex.

Protective effect of phospholipids in lipoproteins against diabetic kidney disease: A Mendelian randomization analysis.

BACKGROUND: The etiology of diabetic kidney disease is complex, and the role of lipoproteins and their lipid components in the development of the disease cannot be ignored. However, phospholipids are an essential component, and no Mendelian randomization studies have yet been conducted to examine potential causal associations between phospholipids and diabetic kidney disease. METHODS: Relevant exposure and outcome datasets were obtained through the GWAS public database. The exposure datasets included various phospholipids, including those in LDL, IDL, VLDL, and HDL. IVW methods were the primary analytical approach. The accuracy of the results was validated by conducting heterogeneity, MR pleiotropy, and F-statistic tests. MR-PRESSO analysis was utilized to identify and exclude outliers. RESULTS: Phospholipids in intermediate-density lipoprotein (OR: 0.8439; 95% CI: 0.7268-0.9798), phospholipids in large low- density lipoprotein (OR: 0.7913; 95% CI: 0.6703-0.9341), phospholipids in low- density lipoprotein (after removing outliers, OR: 0.788; 95% CI: 0.6698-0.9271), phospholipids in medium low- density lipoprotein (OR: 0.7682; 95% CI: 0.634-0.931), and phospholipids in small low-density lipoprotein (after removing outliers, OR: 0.8044; 95% CI: 0.6952-0.9309) were found to be protective factors. CONCLUSIONS: This study found that a higher proportion of phospholipids in intermediate-density lipoprotein and the various subfractions of low-density lipoprotein, including large LDL, medium LDL, and small LDL, is associated with a lower risk of developing diabetic kidney disease.

Radiomic signatures associated with tumor immune heterogeneity predict survival in locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The prognostic value of traditional clinical indicators for locally recurrent nasopharyngeal carcinoma (lrNPC) is limited due to their inability to reflect intratumor heterogeneity. We aimed to develop a radiomic signature to reveal tumor immune heterogeneity and predict survival in lrNPC. METHODS: This multicenter, retrospective study included 921 patients with lrNPC. A machine learning signature and nomogram based on pretreatment MRI features were developed for predicting overall survival (OS) in a training cohort and validated in two independent cohorts. A clinical nomogram and an integrated nomogram were constructed for comparison. Nomogram performance was evaluated by concordance index (C-index) and receiver operating characteristic curve analysis. Accordingly, patients were classified into risk groups. The biological characteristics and immune infiltration of the signature were explored by RNA sequencing (RNA-seq) analysis. RESULTS: The machine learning signature and nomogram demonstrated comparable prognostic ability to a clinical nomogram, achieving C-indexes of 0.729, 0.718, and 0.731 in the training, internal, and external validation cohorts, respectively. Integration of the signature and clinical variables significantly improved the predictive performance. The proposed signature effectively distinguished patients between risk groups with significantly distinct OS rates. Subgroup analysis indicated the recommendation of local salvage treatments for low-risk patients. Exploratory RNA-seq analysis revealed differences in interferon response and lymphocyte infiltration between risk groups. CONCLUSIONS: An MRI-based radiomic signature predicted OS more accurately. The proposed signature associated with tumor immune heterogeneity may serve as a valuable tool to facilitate prognostic stratification and guide individualized management for lrNPC patients.

The safety and efficacy of neoadjuvant immunochemotherapy following laparoscopic gastrectomy for gastric cancer: a multicenter Real-world clinical study.

BACKGROUND: The safety and efficacy of neoadjuvant immunochemotherapy (nICT) for locally advanced gastric cancer (LAGC) remain controversial. METHODS: Patients with LAGC who received either nICT or neoadjuvant chemotherapy (nCT) at 3 tertiary referral teaching hospitals in China between January 2016 and October 2022 were analysed. After propensity-score matching (PSM), comparing the radiological response, pathological response rate, perioperative outcomes, and early recurrence between the two groups. RESULTS: After PSM, 585 patients were included, with 195 and 390 patients comprising the nICT and nCT groups, respectively. The nICT group exhibited a higher objective response rate (79.5% versus [vs.] 59.0%; P<0.001), pathological complete response rate (14.36% vs. 6.41%; P=0.002) and major pathological response rate (39.49% vs. 26.15%; P=0.001) compared with the nCT group. The incidence of surgical complications (17.44% vs. 16.15%, P=0.694) and proportion of perioperative textbook outcomes (80.0% vs. 81.0%; P=0.767) were similar in both groups. The nICT group had a significantly lower proportion of early recurrence than the nCT group (29.7% vs. 40.8%; P=0.047). Furthermore, the multivariable logistic analysis revealed that immunotherapy was an independent protective factor against early recurrence (odds ratio 0.62 [95% CI 0.41-0.92]; P=0.018). No significant difference was found in neoadjuvant therapy drug toxicity between the two groups (51.79% vs. 45.38%; P=0.143). CONCLUSIONS: Compared with nCT, nICT is safe and effective, which significantly enhanced objective and pathological response rates, and reduced the risk for early recurrence among patients with LAGC. TRIAL REGISTRATION: Clinical Trials.gov.

Towards an actionable One Health approach.

BACKGROUND: Despite the increasing focus on strengthening One Health capacity building on global level, challenges remain in devising and implementing real-world interventions particularly in the Asia-Pacific region. Recognizing these gaps, the One Health Action Commission (OHAC) was established as an academic community for One Health action with an emphasis on research agenda setting to identify actions for highest impact. MAIN TEXT: This viewpoint describes the agenda of, and motivation for, the recently formed OHAC. Recognizing the urgent need for evidence to support the formulation of necessary action plans, OHAC advocates the adoption of both bottom-up and top-down approaches to identify the current gaps in combating zoonoses, antimicrobial resistance, addressing food safety, and to enhance capacity building for context-sensitive One Health implementation. CONCLUSIONS: By promoting broader engagement and connection of multidisciplinary stakeholders, OHAC envisions a collaborative global platform for the generation of innovative One Health knowledge, distilled practical experience and actionable policy advice, guided by strong ethical principles of One Health.

Nanoparticles targeting mutant p53 overcome chemoresistance and tumor recurrence in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) shows high drug resistance and leads to low survival due to the high level of mutated Tumor Protein p53 (TP53). Cisplatin is a first-line treatment option for NSCLC, and the p53 mutation is a major factor in chemoresistance. We demonstrate that cisplatin chemotherapy increases the risk of TP53 mutations, further contributing to cisplatin resistance. Encouragingly, we find that the combination of cisplatin and fluvastatin can alleviate this problem. Therefore, we synthesize Fluplatin, a prodrug consisting of cisplatin and fluvastatin. Then, Fluplatin self-assembles and is further encapsulated with poly-(ethylene glycol)-phosphoethanolamine (PEG-PE), we obtain Fluplatin@PEG-PE nanoparticles (FP NPs). FP NPs can degrade mutant p53 (mutp53) and efficiently trigger endoplasmic reticulum stress (ERS). In this study, we show that FP NPs relieve the inhibition of cisplatin chemotherapy caused by mutp53, exhibiting highly effective tumor suppression and improving the poor NSCLC prognosis.

Gigantol ameliorates DSS-induced colitis via suppressing ß2 integrin mediated adhesion and chemotaxis of macrophage.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium, recognized as "Shihu" in traditional Chinese medicine, holds a rich history of medicinal utilization documented in the Chinese Pharmacopoeia. Ancient texts like "Shen Nong Ben Cao Jing" extol Dendrobium's virtues as a superior herbal medicine fortifying "Yin" and invigorating the five viscera. Dendrobium is extensively employed for the treatment of gastrointestinal inflammatory disorders, showcasing significant therapeutic efficacy, particularly against ulcerative colitis (UC), within the realm of Chinese ethnopharmacology. Dendrobium plays crucial pharmacological roles due to its rich content of polysaccharides, alkaloids, phenanthrenes, and bibenzyls. Gigantol, a prominent bibenzyl compound, stands out as one of the most vital active constituents within Dendrobium, the gigantol content of Dendrobium leaves can reach approximately 4.79 µg/g. Its significance lies in being recognized as a noteworthy anti-inflammatory compound derived from Dendrobium. AIM OF THE STUDY: Given the pivotal role of gigantol as a primary active substance in Dendrobium, the therapeutic potential of gigantol for gastrointestinal diseases remains enigmatic. Our present investigation aimed to evaluate the therapeutic effects of gigantol on dextran sulfate sodium (DSS)-induced colitis and reveal its potential mechanism in countering UC activity. MATERIALS AND METHODS: The protective efficacy of gigantol against colitis was assessed by examining the histopathological changes and conducting biochemical analyses of colon from DSS-challenged mice. Assessments focused on gigantol's impact on improving the intestinal epithelial barrier and its anti-inflammatory effects in colonic tissues of colitis mice. Investigative techniques included the exploration of the macrophage inflammatory signaling pathway via qPCR and Western blot analyses. In vitro studies scrutinized macrophage adhesion, migration, and chemotaxis utilizing transwell and Zigmond chambers. Furthermore, F-actin and Rac1 activation assays detailed cellular cytoskeletal remodeling. The potential therapeutic target of gigantol was identified and validated through protein binding analysis, competitive enzyme-linked immunosorbent assay (ELISA), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assay. The binding sites between gigantol and its target were predicted via molecular docking. RESULTS: Gigantol ameliorated symptoms of DSS-induced colitis, rectified damage to the intestinal barrier, and suppressed the production of pro-inflammatory cytokines in colonic tissues. Intriguingly, gigantol significantly curtailed NF-κB signaling activation in the colons of DSS-induced colitis mice. Notably, gigantol impaired the ß2 integrin-dependent adhesion and migratory capacity of RAW264.7 cells. Moreover, gigantol notably influenced the cytoskeleton remodeling of RAW264.7 cells by suppressing Vav1 phosphorylation and Rac1 activation. Mechanistically, gigantol interacted with ß2 integrin, subsequently diminishing binding affinity with intercellular adhesion molecule-1 (ICAM-1). CONCLUSIONS: In conclusion, these findings elucidate that gigantol ameliorates DSS-induced colitis by antagonizing ß2 integrin-mediated macrophage adhesion, migration, and chemotaxis, thus it may impede macrophage recruitment and infiltration into colonic tissues. This study suggests that gigantol shows promise as a viable candidate for clinical colitis therapy.

Characteristics and influencing factors of demoralization in patients with lung cancer: A latent class analysis.

OBJECTIVE: Demoralization has garnered increasing attention in recent years as a significant psychological distress. This study aims to identify latent classes of demoralization in lung cancer patients using Latent Class Analysis (LCA) from a person-centered perspective and to explore the factors influencing the latent classes of demoralization. METHODS: A cross-sectional study using convenience sampling was conducted among 567 lung cancer patients in three tertiary hospitals in China. LCA was employed to classify heterogeneous classes of demoralization. Multinomial logistic regression analyses were performed to explore the associations between demographic and clinical characteristics, as well as physical symptoms, resilience, family function, and coping strategies, with class membership in the identified heterogeneous subgroups of lung cancer patients. RESULTS: Three latent classes of demoralization were identified: the high demoralization group (Class 1, 14.8%), the moderate demoralization-distress and helplessness group (Class 2, 37.2%), and the low demoralization group (Class 3, 48.0%). In comparison to Class 3, lung cancer patients with hypertension, higher core symptom burden, poorer resilience, dysfunctional family dynamics, and resignation coping were more likely to belong to Class 1 and Class 2. CONCLUSIONS: The demoralization patterns in lung cancer patients were varied. Targeted intervention should be developed based on the characteristics of each class, and timely attention should be paid to high-risk patients.

Triterpenoids from Juglans mandshurica with anti-hyaluronidase activities.

Phytochemical study on 90% ethanol extract from the green walnut husks of Juglans mandshurica Maxim. resulted into the isolation of three undescribed triterpenoids, juglansmanoids A-C (1-3). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated components were evaluated in vitro for anti-hyaluronidase activities. As a result, triterpenoid 1 exhibited potent anti-hyaluronidase activity (IC50 = 9.78 µg/ml) three times more than the positive control drug oleanolic acid (IC50 = 40.12 µg/ml).

Serum secreted phosphoprotein 1 level is associated with plaque vulnerability in patients with coronary artery disease.

Background: Vulnerable plaque was associated with recurrent cardiovascular events. This study was designed to explore predictive biomarkers of vulnerable plaque in patients with coronary artery disease. Methods: To reveal the phenotype-associated cell type in the development of vulnerable plaque and to identify hub gene for pathological process, we combined single-cell RNA and bulk RNA sequencing datasets of human atherosclerotic plaques using Single-Cell Identification of Subpopulations with Bulk Sample Phenotype Correlation (Scissor) and Weighted gene co-expression network analysis (WGCNA). We also validated our results in an independent cohort of patients by using intravascular ultrasound during coronary angiography. Results: Macrophages were found to be strongly correlated with plaque vulnerability while vascular smooth muscle cell (VSMC), fibrochondrocyte (FC) and intermediate cell state (ICS) clusters were negatively associated with unstable plaque. Weighted gene co-expression network analysis showed that Secreted Phosphoprotein 1 (SPP1) in the turquoise module was highly correlated with both the gene module and the clinical traits. In a total of 593 patients, serum levels of SPP1 were significantly higher in patients with vulnerable plaques than those with stable plaque (113.21 [73.65 - 147.70] ng/ml versus 71.08 [20.64 - 135.68] ng/ml; P < 0.001). Adjusted multivariate regression analysis revealed that serum SPP1 was an independent determinant of the presence of vulnerable plaque. Receiver operating characteristic curve analysis indicated that the area under the curve was 0.737 (95% CI 0.697 - 0.773; P < 0.001) for adding serum SPP1 in predicting of vulnerable plaques. Conclusion: Elevated serum SPP1 levels confer an increased risk for plaque vulnerability in patients with coronary artery disease.

Interfacial Tuning of Electrocatalytic Ag Surfaces for Fragment-Based Electrophile Coupling.

Construction of C‒C bonds in medicinal chemistry frequently draws on the reductive coupling of organic halides with ketones or aldehydes. Catalytic C(sp3)‒C(sp3) bond formation, however, is constrained by the competitive side reactivity of radical intermediates following sp3 organic halide activation. Here, an alternative paradigm deploys catalytic Ag surfaces for reductive fragment-based electrophile coupling compatible with sp3 organic halides. We use in-situ spectroscopy, electrochemical analyses, and simulation to uncover the catalytic interfacial structure and guide reaction development. Specifically, Mg(OAc)2 outcompetes the interaction between Ag and the aldehyde, thereby tuning the Ag surface for selective product formation. Data are consistent with an increased population of Mg-bound aldehyde facilitating the addition of a carbon-centered radical (product of Ag-electrocatalyzed organic halide reduction) to the carbonyl. Electron transfer from Ag to the resultant alkoxy radical yields the desired alcohol. Molecular interfacial tuning at reusable catalytic electrodes will accelerate development of sustainable organic synthetic methods.

Global burden of early-onset osteoarthritis, 1990-2019: results from the Global Burden of Disease Study 2019.

OBJECTIVES: Early-onset osteoarthritis (OA) is an emerging health issue amidst the escalating prevalence of overweight and obesity. However, there are scant data on its disease, economic burden and attributable burden due to high body mass index (BMI). METHODS: Using data from the Global Burden of Diseases Study 2019, we examined the numbers of incident cases, prevalent cases, years lived with disability (YLDs) and corresponding age-standardised rates for early-onset OA (diagnosis before age 55) from 1990 to 2019. The case definition was symptomatic and radiographically confirmed OA in any joint. The average annual percentage changes (AAPCs) of the age-standardised rates were calculated to quantify changes. We estimated the economic burden of early-onset OA and attributable burden to high BMI. RESULTS: From 1990 to 2019, the global incident cases, prevalent cases and YLDs of early-onset OA were doubled. 52.31% of incident OA cases in 2019 were under 55 years. The age-standardised rates of incidence, prevalence and YLDs increased globally and for countries in all Sociodemographic Index (SDI) quintiles (all AAPCs>0, p<0.05), with the fastest increases in low-middle SDI countries. 98.04% of countries exhibited increasing trends in all age-standardised rates. Early-onset OA accounts for US$46.17 billion in healthcare expenditure and US$60.70 billion in productivity loss cost in 2019. The attributable proportion of high BMI for early-onset OA increased globally from 9.41% (1990) to 15.29% (2019). CONCLUSIONS: Early-onset OA is a developing global health problem, causing substantial economic costs in most countries. Targeted implementation of cost-effective policies and preventive intervention is required to address the growing health challenge.

Efficacy and safety of cadonilimab in previously treated recurrent or metastatic nasopharyngeal carcinoma(COMPASSION-06): A phase II multicenter study.

OBJECTIVE: This study was designed to assess the efficacy and safety of cadonilimab monotherapy, a first-in-class, bi-specific PD-1/CTLA-4 antibody, in patients with previously treated recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). PATIENTS AND METHODS: This multicenter, open-label, single-arm, phase II clinical trial enrolled patients with R/M-NPC who had failed first-line platinum-based chemotherapy and second-line single agent or combined chemotherapy, and immunotherapy-naive. Patients received cadonilimab for 6 mg/kg once every 2 weeks (Q2W). The primary endpoint was objective response rate (ORR) in full analysis set (FAS) assessed by investigators according to RECIST v.1.1. The secondary endpoint included progression-free survival (PFS), overall survival (OS), duration of response (DoR), time to response (TTR) and safety. RESULTS: A total of 23 patients were assessed. The median time from first dose to data cutoff was 16.56 (range, 0.8-25.2) months. ORR was 26.1 % (95 %CI:10.2-48.4). The ORR were 44.4 % (95 %CI: 13.7-78.8) and 14.3 % (95 %CI:1.8-42.8) in patients with tumor PD-L1 expression ≥50 % and <50 %, respectively. ORR was achieved in 40.0 % (95 %CI:12.2-73.8) of patients with EBV-DNA level <4000 IU/ml (n = 10) and 15.4 % (95 %CI:1.9-45.4) of those with ≥4000 IU/ml. The median PFS was 3.71 months (95 %CI: 1.84-9.30). respectively. Median OS was not reached, and the 12-month OS rate was 79.7 % (95 % CI:54.5-91.9). Only two patients (8.3 %) experienced Grade ≥3 treatment-related adverse events (TRAEs) with hypothyroidism (30.4 %), rash (21.7 %) and pruritus (21.7 %) being the most prevalent TRAEs. CONCLUSION: Cadonilimab monotherapy demonstrated a promising efficacy and manageable toxicity in patients with previously treated R-M/NPC and provide an efficacious salvage treatment option.

Network pharmacology combined with Mendelian randomization analysis to identify the key targets of renin-angiotensin-aldosterone system inhibitors in the treatment of diabetic nephropathy.

Background: Diabetic Nephropathy (DN) is one of the microvascular complications of diabetes. The potential targets of renin-angiotensin-aldosterone system (RAAS) inhibitors for the treatment of DN need to be explored. Methods: The GSE96804 and GSE1009 datasets, 729 RAAS inhibitors-related targets and 6,039 DN-related genes were derived from the public database and overlapped with the differentially expressed genes (DN vs. normal) in GSE96804 to obtain the candidate targets. Next, key targets were screened via the Mendelian randomization analysis and expression analysis. The diagnostic nomogram was constructed and assessed in GSE96804. Additionally, enrichment analysis was conducted and a 'core active ingredient-key target-disease pathway' network was established. Finally, molecular docking was performed. Results: In total, 60 candidate targets were derived, in which CTSC and PDE5A were screened as the key targets and had a causal association with DN as the protective factors (P < 0.05, OR < 1). Further, a nomogram exhibited pretty prediction efficiency. It is indicated that Benadryl hydrochloride might play a role in the DN by affecting the pathways of 'cytokine cytokine receptor interaction', etc. targeting the CTSC. Moreover, PDE5A might be involved in 'ECM receptor interaction', etc. for the effect of NSAID, captopril, chlordiazepoxide on DN. Molecular docking analysis showed a good binding ability of benadryl hydrochloride and CTSC, NSAID and PDE5A. PTGS2, ITGA4, and ANPEP are causally associated with acute kidney injury. Conclusion: CTSC and PDE5A were identified as key targets for RAAS inhibitors in the treatment of DN, which might provide some clinical significance in helping to diagnose and treat DN. Among the targets of RAAS inhibitors, PTGS2, ITGA4 and ANPEP have a causal relationship with acute kidney injury, which is worthy of further clinical research.

PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg-1·d-1, i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 µM) significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3ß/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.

Incidence and warning signs for complications of human brucellosis: a multi-center observational study from China.

BACKGROUND: Brucellosis is a severe zoonotic disease that is often overlooked, particularly in impoverished countries. Timely identification of focal complications in brucellosis is crucial for improving treatment outcomes. However, there is currently a lack of established indicators or biomarkers for diagnosing these complications. Therefore, this study aimed to investigate potential warning signs of focal complications in human brucellosis, with the goal of providing practical parameters for clinicians to aid in the diagnosis and management of patients. METHODS: A multi-center cross-sectional study was conducted in China from December 2019 to August 2021. The study aimed to investigate the clinical characteristics and complications of patients with brucellosis using a questionnaire survey and medical record system. The presence of warning signs for complications was assessed using univariate and multivariate logistic regression models. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used for variable screening and model evaluation. RESULTS: A total of 880 participants diagnosed with human brucellosis were enrolled. The median age of the patients was 50 years [interquartile range (IQR): 41.5-58.0], and 54.8% had complications. The most common organ system affected by complications was the osteoarticular system (43.1%), with peripheral arthritis (30.0%), spondylitis (16.6%), paravertebral abscess (5.0%), and sacroiliitis (2.7%) being the most prevalent. Complications in other organ systems included the genitourinary system (4.7%), respiratory system (4.7%), and hematologic system (4.6%). Several factors were found to be associated with focal brucellosis. These factors included a long delay in diagnosis [odds ratio (OR) = 3.963, 95% confidence interval (CI) 1.906-8.238 for > 90 days], the presence of underlying disease (OR = 1.675, 95% CI 1.176-2.384), arthralgia (OR = 3.197, 95% CI 1.986-5.148), eye bulging pain (OR = 3.482, 95% CI 1.349-8.988), C-reactive protein (CRP) > 10 mg/L (OR = 1.910, 95% CI 1.310-2.784) and erythrocyte sedimentation rate (ESR) elevation (OR = 1.663, 95% CI 1.145-2.415). The optimal cutoff value in ROC analysis was > 5.4 mg/L for CRP (sensitivity 73.4% and specificity 51.9%) and > 25 mm/h for ESR (sensitivity 47.9% and specificity 71.1%). CONCLUSIONS: More than 50% of patients with brucellosis experienced complications. Factors such as diagnostic delay, underlying disease, arthralgia, eye pain, and elevated levels of CRP and ESR were identified as significant markers for the development of complications. Therefore, patients presenting with these conditions should be closely monitored for potential complications, regardless of their culture results and standard tube agglutination test titers.

Fecal Microbiota Transplantation: A Prospective Treatment for Type 2 Diabetes Mellitus.

Purpose of Review: The aim of this review is to summarize the role of gastrointestinal microbiome (GM) in the development of type 2 diabetes mellitus (T2DM). Besides, we discuss the feasibility of applying FMT in the treatment of T2DM and propose a series of processes to refine the use of FMT in the treatment of T2DM. Recent Findings: T2DM is a metabolic disease which is connected with the GM. According to many researches, GM can produce a variety of metabolites such as bile acid, short chain fatty acids, lipopolysaccharides and trimethylamine oxide which play an important role in metabolism. FMT is a method to regulate GM and has been observed to be effective in the treatment of metabolic diseases such as T2DM in some mouse models and people. However, there is still a lack of direct evidence for the use of FMT in the treatment of T2DM, and the process of FMT is not standardized. Summary: Dysregulation of GM is closely related to the development of T2DM. Promoting the conversion of GM in T2DM patients to normal population through FMT can reduce insulin resistance and lower their blood glucose level, which is an optional treatment for T2DM patients in the future. At present, the feasibility and limitations of applying FMT to the treatment of T2DM need to be further studied.

Septin9 DNA methylation is associated with breast cancer recurrence or metastasis.

OBJECTIVE: We aimed to explore the prognostic value of Septin9 DNA methylation in breast cancer. METHODS: Breast cancer patients with and without recurrence or metastasis and matched non-breast cancer patients were screened retrospectively from 2014 to 2016. Bisulfite conversion and fluorescence quantitative methylation-specific polymerase chain reaction were used to detect the Septin9 methylation status and distribution levels in patient breast tissues. RESULTS: Septin9 DNA methylation was more frequent in breast cancer tissues than in non-breast cancer tissues, but was not significantly correlated with any relevant breast cancer patient clinicopathological characteristic. Septin9 methylation rates were higher in patients with recurrence or metastasis. Septin9 methylation, tumor size, lymph node status, and progesterone receptor (PR) expression could influence prognosis. Septin9 methylation was significantly associated with worse disease-free survival in breast cancer patients, with receiver operating characteristic curve analysis indicating that it had good prognostic ability, with an area under the curve (AUC) value of 0.719. The AUC values increased when Septin9 methylation was combined with tumor size, lymph node status, and PR to predict prognosis. CONCLUSIONS: Septin9 DNA methylation was an independent predictors of breast cancer prognostic risk. This could possibly help improve comprehensive prognosis prediction methods when combined with other risk factors.