Correlations between the modification patterns mediated by pyroptosis-related genes, tumor microenvironment, and immunotherapy in soft tissue sarcoma.

Soft tissue sarcoma (STS) incidence, progression, and metastasis are tightly linked to the tumor microenvironment (TME). The modification patterns mediated by pyroptosis-related genes (PRGs) in STS are unknown regarding the immune cell infiltration landscape of TME, immunotherapy effect, and prognostic value. First, we downloaded STS samples from the Cancer Genome Atlas (TCGA) and gene-expression omnibus (GEO) databases. Based on 52 PRGs, 2 pyroptosis modification patterns were analyzed, and the associations of pyroptosis modification patterns with immune cell infiltration in the TME were elucidated systematically. To quantify PRG modification patterns in STS patients, we generated a pyroptosis scoring system using principal component analysis (PCA). We identified 2 distinct pyroptosis modification patterns in STS. Compared to PRG cluster A, the prognosis of cluster B was better. These 2 pyroptosis modification patterns corresponded to different characteristics of immune cell infiltration in the TME and biological behaviors. In the pyroptosis scoring system, a high pyroptosis score was connected to higher immune cell infiltration, stronger immune surveillance, immune-killing effects on tumor cells, and better clinical benefits. The results from 3 anti-PD1/PD-L1-treated immune cohorts demonstrated that higher pyroptosis scores are also closely connected to better immunotherapy results. We demonstrated that pyroptosis modification is essential to the STS microenvironment. Moreover, the pyroptosis score is a reliable and independent prognostic factor in STS patients, enabling a richer understanding of the STS microenvironment and the screening of immunotherapy candidates, predicting the immunotherapeutic effects for individual STS patients, and guiding the use of chemotherapy drugs.

Isoptericola luteus sp. nov., a novel yellow bacterium isolated from soil.

An aerobic, non-motile, Gram-stain-positive bacterium, designated strain NEAU-Y5T, was isolated from a soil sample collected from Northeast Agricultural University, Heilongjiang province. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NEAU-Y5T belonged to the genus and showed high 16S rRNA sequence similarity to Isoptericola variabilis (98.9 %), Isoptericola nanjingensis (98.9 %), Isoptericola cucumis (98.5 %), Isoptericola hypogeus (98.5 %), Isoptericola dokdonensis (98.5 %), Isoptericola jiangsuensis (98.3 %), and Isoptericola halalbus (98.1 %), followed by other members of the genus Isoptericola (<98 %), and phylogenetically clustered with I. dokdonensis and I. jiangsuensis. Strain NEAU-Y5T was found to grow at 4-40 °C (optimum, 28 °C), pH 6.0-12.0 (optimum, pH 7.0), and tolerated 0-6 % NaCl (w/v). The cell-wall peptidoglycan type was l-Lys-d-Asp. The whole-cell hydrolysates contained glucose, galactose, and ribose. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, hydroxyphosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside, and glucosamine unknown phospholipid. Major fatty acids were anteiso-C15 : 0 and anteiso-C17 : 0. The predominant menaquinone was MK-9(H4). The DNA G+C content was 73.4 mol%. The digital DNA-DNA hybridization and average nucleotide identity values between strain NEAU-Y5T and the type strains of the genus Isoptericola ranged from 18.6 to 23.5 % and from 77.3 to 81.6 %, respectively. Based on morphological, physiological, chemotaxonomic, and phylogenetic data, as well as digital DNA-DNA hybridization and average nucleotide identity values, the novel strain NEAU-Y5T could be differentiated from its closest relatives. Therefore, the strain represents a novel species of the genus Isoptericola, for which the name Isoptericola luteus sp. nov. is proposed. The type strain is NEAU-Y5T (=CCTCC AA 2019087T=DSM 110637T).

The crosstalk between macrophages and cancer cells potentiates pancreatic cancer cachexia.

With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.

Dietary vitamin C and vitamin E with the risk of aortic aneurysm and dissection: A prospective population-based cohort study.

BACKGROUND AND AIMS: The associations between dietary vitamin C (VC), vitamin E (VE) intake and aortic aneurysm and dissection (AAD) remain unclear. This study aimed to prospectively investigate the associations between dietary VC and VE with the incident risk of AAD. METHODS AND RESULTS: A total of 139 477 participants of UK Biobank cohort were included in the analysis. Dietary VC and VE consumptions were acquired through a 24-h recall questionnaire. Cox proportional regression models were used to examine the associations between VC, VE intake and the risk of AAD. Incident AAD was ascertained through hospital inpatient records and death registers. During a median follow-up of 12.5 years, 962 incident AAD events were documented. Both dietary VC [adjusted hazard ratio (HR), 0.77; 95 % confidence intervals (CI), 0.63-0.93; P-trend = 0.008] and VE (adjusted HR, 0.70; 95 % CI, 0.57-0.87; P-trend = 0.002) were inversely associated with incident AAD when comparing the participants in the highest quartile with those in the lowest. In subgroup analyses, the associations were more pronounced in participants who were over 60 years old, participants with smoking history, hypertension or hyperlipidemia, who were under the high risk of AAD. CONCLUSION: Higher dietary VC and VE intakes are associated with reduced risk of AAD. Our study emphasizes the importance of diet adjustment strategies targeted on VC and VE to lower the incidence rate of AAD especially in the high-risk population.

Pullulan-Based Spray-Dried Mucoadhesive Microparticles for Sustained Oromucosal Drug Delivery.

Mucoadhesive microparticles for oromucosal drug delivery offer several advantages, including intimate contact with the mucosa, delivery to less accessible regions, extended residence time, sustained drug release, reduced irritation, and improved patient compliance. In this study, pullulan was used to prepare mucoadhesive spray-dried microparticles for delivering benzydamine hydrochloride (BZH) to oral mucosa. The BZH-pullulan spray-dried microparticles had a mean size of <25 µm with an angle of repose values between 25.8-36.6°. Pullulan markedly extended drug-release time to >180 min, ~9 times greater than the duration (i.e., 20 min) reportedly achieved by chitosan. Kinetic analysis showed the drug-release rate was concentration dependent and jointly controlled by drug diffusion and polymer chain relaxation. Further, pullulan was mucoadhesive and was able to retain up to 78.8% w/w of microencapsulated gold nanoparticle probes at the mucosal membrane. These data strongly suggest that BZH-pullulan microparticles have great potential for oromucosal drug delivery, by providing elongated residence time in situ and sustained drug release for the treatment of local diseases.

Sleep Patterns and Traditional Cardiovascular Health Metrics: Joint Impact on Major Adverse Cardiovascular Events in a Prospective Cohort Study.

BACKGROUND: This study examines the association between traditional cardiovascular health (CVH) metrics and major adverse cardiovascular events (MACE) incidence in individuals with diverse sleep patterns. METHODS AND RESULTS: We analyzed data from 208 621 participants initially free of cardiovascular disease (CVD) in the UK Biobank study. Sleep patterns were assessed using scores for chronotype, duration, insomnia, snoring, and daytime dozing. Traditional CVH scores were derived from the Life's Simple 7 metrics. Cox proportional hazards multivariate regression assessed associations between distinct combinations of CVH and sleep scores and MACE, including nonfatal myocardial infarction, nonfatal stroke, and CVD mortality. Over a mean follow-up of 12.73 years, 9253 participants experienced incident MACE. Individuals with both a healthy sleep pattern and ideal CVH levels had the lowest MACE risk compared with those with a poor sleep pattern and poor CVH levels (hazard ratio, 0.306 [95% CI, 0.257-0.365]; P<0.001). Elevated CVH scores were associated with a reduced risk of MACE across different sleep patterns. Similar trends were observed for individual MACE components, heart failure, and all-cause mortality. These findings remained robust in sensitivity analyses and across various subgroups. CONCLUSIONS: In individuals without known CVD, maintaining a favorable sleep pattern and achieving optimal CVH levels, as measured by traditional metrics, were associated with the lowest MACE risk. Enhanced CVH significantly reduced CVD risk, even in individuals with a poor sleep pattern. These results emphasize the importance of considering multiple dimensions of sleep health alongside CVH to mitigate CVD risk. REGISTRATION: URL: https://www.ukbiobank.ac.uk; Unique identifier: 91090.

Efficacy observation, complications and nursing of enteral nutrition suspension in patients with acute ischemic stroke.

OBJECTIVE: This study focuses on exploring the efficacy observation, complications and nursing aspects of using enteral nutrition suspension in patients with acute ischemic stroke. METHODS: This study retrospectively analyzed clinical data from 188 patients with acute ischemic stroke treated in the Neurology Department of our hospital from October 2022 to September 2023. Patients who received intermittent enteral nutrition and nursing interventions were included in the control group (n=96), while patients who received continuous enteral nutrition and nursing interventions were included in the treatment group (n=92). Relevant indicators data changes before and after treatment were recorded for each patient, along with the occurrence of complications in both groups, and statistical analysis was conducted. RESULTS: The treatment group had fewer days in the ICU and total hospitalization days compared to the control group, with p < .05. Patients in the treatment group had higher levels of serum albumin and serum prealbumin than those in the control group, with p < .05. The occurrence of abdominal pain, diarrhea, constipation, bloating and acid reflux in the treatment group was lower than in the control group, with p < .05. There was no significant difference in the occurrence of adverse outcomes at discharge, death at discharge, cerebral hemorrhage, lung infection and gastrointestinal bleeding between the two groups (p > .05). CONCLUSION: The application of enteral nutrition suspension in patients with acute ischemic stroke effectively provides the necessary nutrients, maintains nutritional balance, promotes tissue repair and recovery and reduces the length of hospital stay.

Immunotherapy for depression: Recent insights and future targets.

Depression stands as a prominent contributor to global disability, entailing an elevated risk of suicide. Substantial evidence supports the notion that immune dysregulation may play a role in the development of depression and impede responses to antidepressant treatments. Immune dysregulation may cause depression in susceptible individuals through raising inflammatory responses. Differences in immune cell types and the release of pro-inflammatory mediators are observed in the blood and cerebrospinal fluid of patients with major depressive disorder, which is associated with neuroimmune dysfunction. Therefore, the interaction of peripheral and central immune targets in depression needs to be understood. Urgent attention is required for the development of innovative therapeutics directed at modulating immune responses for the treatment of depression. This review delineates the immune mechanisms involved in the pathogenesis of depression, assesses the therapeutic potential of immune system targeting for depression treatment, and deliberates on the merits and constraints of employing immunotherapy in the management of depression.

Evaluating the causal effect of atherosclerosis on the risk of intervertebral disc degeneration.

Background: Intervertebral disc degeneration (IDD) and atherosclerosis are two common age-related conditions that can cause significant morbidity. While previous studies have suggested an association between the two conditions, the nature of this association remains unclear. Methods: We used Mendelian randomization (MR) to investigate the causal relationship between IDD and atherosclerosis. We identified genetic variants associated with IDD using summary statistics from a large genome-wide association study (GWAS). These variants were then used as instrumental variables to infer causal relationships with atherosclerosis in summary statistics from a separate GWAS. Results: Our MR analysis provided evidence for a causal relationship between IDD and atherosclerosis. We found that the genetic predisposition to atherosclerosis was associated with a higher risk of IDD (odds ratio [OR] = 3.55, 95% confidence interval [CI]: 1.07-11.74, p = 0.04). The IVW estimates were consistent with the observational findings and other robust MR methods. Sensitivity analyses suggested that our findings were robust to potential sources of bias. Conclusions: Our study provides evidence for a causal link between IDD and atherosclerosis, suggesting that interventions targeting atherosclerosis could have potential benefits for reducing the risk of IDD. Further research is needed to explore the underlying mechanisms that link these two conditions and to investigate potential therapeutic interventions.

CircZCCHC2 (hsa_circ_0000854) promotes hepatocellular carcinoma progression through modulating miR-936/BTBD7 axis and activating Rho/ROCK2 pathway.

Hepatocellular carcinoma (HCC) is one of the most aggressive and refractory cancers due to its high propensity to metastasize and the unavailability of efficacious treatments. Circular RNAs (circRNAs) participate in diverse biological activities in human cancers. Here, we detected the upregulation of a novel circRNA, circZCCHC2 (hsa_circ_0000854), in HCC samples and cells. The upregulation indicated an unfavorable prognosis in HCC patients. CircZCCHC2 accelerated cell growth and metastasis in vitro and tumorigenicity in vivo. Mechanistic investigations revealed that circZCCHC2 regulated BTBD7 expression by sponging miR-936. Moreover, the suppression of malignancy caused by circZCCHC2 knockdown could be sufficiently reversed by miR-936 inhibition. Additionally, the suppressed Rho/ROCK2 pathway conferred by circZCCHC2 knockdown could be restored by inhibiting miR-936 expression. Collectively, our findings reveal that circZCCHC2 plays an oncogenic role of in HCC progression by modulating the miR-936/BTBD7/Rho/ROCK2 pathway.

Dual-monomer solvatochromic probe system (DSPS) for effectively differentiating lipid raft cholesterol and active membrane cholesterol in the inner-leaflet plasma membrane.

Monitoring active membrane cholesterol and lipid raft cholesterol in the inner leaflet of the plasma membrane is significant for understanding the membrane function and cellular physiopathological processes. Limited by existing methods, it is difficult to differentiate active membrane cholesterol and lipid raft cholesterol. A novel dual-monomer solvatochromic probe system (DSPS) that targets two types of cholesterol was developed. Acrylodan-BG/SNAP-D4 composed of SNAP-D4 cholesterol-recognizing monomers and solvatochromic acrylodan-BG-sensing monomers exhibits excellent cholesterol detecting properties in terms of selectivity, accuracy, convenience and economic benefits. Cell imaging revealed that lipid raft cholesterol emitted blue fluorescence, whereas active membrane cholesterol (which partially bobbed in aqueous cytosol) displayed green fluorescence; both the fluorescence emissions increased or decreased in a cholesterol-dependent manner. This system provides a new technology for the determination of two types of cholesterol, which is beneficial for the further study of membrane function, intracellular cholesterol trafficking, and cell signaling.

A retrospective cohort study of clinical characteristics and outcomes of type 2 diabetic patients with kidney disease.

Background: Type 2 diabetes mellitus (T2DM) with chronic kidney disease (CKD) poses a serious health threat and becomes a new challenge. T2DM patients with CKD fall into three categories, diabetic nephropathy (DN), non-diabetic kidney disease (NDKD), and diabetic nephropathy plus non-diabetic kidney disease (DN + NDKD), according to kidney biopsy. The purpose of our study was to compare the clinical characteristics and kidney outcomes of DN, NDKD, and DN + NDKD patients. Methods: Data on clinical characteristics, pathological findings, and prognosis were collected from June 2016 to July 2022 in patients with previously diagnosed T2DM and confirmed DN and or NDKD by kidney biopsy at Tongji Hospital in Wuhan, China. The endpoint was defined as kidney transplantation, dialysis, or a twofold increase in serum creatinine. Results: In our 6-year retrospective cohort research, a total of 268 diabetic patients were admitted and categorized into three groups by kidney biopsy. The 268 patients were assigned to DN (n = 74), NDKD (n = 109), and DN + NDKD (n = 85) groups. The most frequent NDKD was membranous nephropathy (MN) (n = 45,41.28%). Hypertensive nephropathy was the most common subtype in the DN+NDKD group (n = 34,40%). A total of 34 patients (12.7%) reached the endpoint. The difference between the Kaplan-Meier survival curves of the DN, NDKD, and DN + NDKD groups was significant (p < 0.05). Multifactorial analysis showed that increased SBP [HR (95% CI): 1.018(1.002-1.035), p = 0.025], lower Hb [HR(95% CI): 0.979(0.961-0.997), p = 0.023], higher glycosylated hemoglobin [HR(95% CI): 1.338(1.080-1.658), p = 0.008] and reduced serum ALB [HR(95% CI): 0.952(0.910-0.996), p = 0.032] were risk factors for outcomes in the T2DM patients with CKD. Conclusions: This research based on a Chinese cohort demonstrated that the risk of endpoint events differed among DN, NDKD, and DN+NDKD patients. In T2DM patients with CKD, DN patients displayed worse kidney prognosis than those with NDKD or DN + NDKD. Increased SBP, higher glycosylated hemoglobin, lower Hb, and decreased serum ALB may be correlated with adverse kidney outcomes in T2DM patients.

Removal of strontium by nanofiltration: Role of complexation and speciation of strontium with organic matter.

Strontium (Sr) removal from water is required because excessive naturally occurring Sr exposure is hazardous to human health. Climate and seasonal changes cause water quality variations, in particular quality and quantity of organic matter (OM) and pH, and such variations affect Sr removal by nanofiltration (NF). The mechanisms for such variations are not clear and thus OM complexation and speciation require attention. Sr removal by NF was investigated with emphasis on the role of OM (type and concentration) and pH (2-12) on possible removal mechanisms, specifically size and/or charge exclusion as well as solute-solute interactions. The filtration results show that the addition of various OM (10 types) and an increase of OM concentration (2-100 mgC.L-1) increased Sr removal by 10-15%. The Sr-OM interaction was enhanced with increasing OM concentration, implying enhanced size exclusion via Sr-OM interaction as the main mechanism. Such interactions were quantified by asymmetric flow field-flow fractionation (FFFF) coupled with an inductively coupled plasma mass spectrometer (ICP-MS). Both extremely low and high pH increased Sr removal due to the enhanced charge exclusion and Sr-OM interactions. This work elucidated and verified the mechanism of OM and pH on Sr removal by NF membranes.

Efficacy and Safety of Antidiabetic Agents for Major Depressive Disorder and Bipolar Depression: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials.

BACKGROUND: This meta-analysis aimed to determine the efficacy and safety of antidiabetic agents in the treatment of major depressive disorder and bipolar depression. METHODS: Randomized controlled trials (RCTs) of antidiabetic agents in major depressive disorder or bipolar depression were searched in three electronic databases and three clinical trial registry websites from their inception up to October 2023. The differences in changes in the depression rating scale scores from baseline to endpoint or pre-defined sessions, response rate, remission rate, rate of side effects and dropout rate between antidiabetic agents and placebo were meta-analyzed. RESULTS: Six RCTs involving 399 participants were included in the final meta-analysis, which did not find that antidiabetics outperformed the placebo in reducing depressive symptoms. The standardized mean difference (SMD) in the depression scores from baseline to endpoint was 0.25 (95% CI -0.1, 0.61). However, a subgroup analysis found a significant difference between antidiabetics and placebos in reducing depressive symptoms in Middle Eastern populations, with an SMD of 0.89 (95% CI 0.44, 1.34). CONCLUSIONS: The current meta-analysis does not support the efficacy of antidiabetics being superior to the placebo in the treatment of unipolar and bipolar depression. However, a subgroup analysis indicates that patients from the Middle East may benefit from adding an antidiabetic medication to their ongoing medication(s) for their depression. Larger studies with good-quality study designs are warranted.

Role of sleep in asthenospermia induced by di (2-ethyl-hexyl) phthalate.

Di (2-ethyl-hexyl) phthalate (DEHP) mainly enters the human body through the digestive tract, respiratory tract, and skin. At the same time, it has reproductive and developmental toxicity, neurotoxicity, and so on, which can cause the decrease of sperm motility. Asthenospermia is also known as low sperm motility, and the semen quality of men in some areas of China is declining year by year. Interestingly, previous studies have shown that sleep disorders can also lead to asthenospermia. However, the relationship between sleep, DEHP, and asthenospermia is still unclear. Analysis of the National Health and Nutrition Examination Survey (NHANES) population database showed that DEHP was associated with sleep disorders, and subsequent experiments in mice and Drosophila indicated that DEHP exposure had certain effects on sleep and asthenospermia. Furthermore, we analyzed the Comparative Toxicogenomics Database (CTD) to find out the common signaling pathway among the three: hypoxia-inducible factor 1(HIF-1). Then Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) was used to screen out the proteins that DEHP affected the HIF-1 pathway: glyceraldehyde-3-phosphate dehydrogenase (GAPDH), serine/threonine-protein kinase (AKT1), epidermal growth factor receptor (EGFR), and finally Western blot analysis was used to detect the expression levels of the three proteins. Compared with the control group, DEHP decreased the protein expression levels of GAPDH and AKT1 in the HIF-1 pathway, and caused sleep disorders and decreased sperm motility. This study provides preliminary evidence for exploring the mechanism among DEHP, sleep disorders, and asthenospermia.

New cassane-type alkaloids and diterpenoids from the pericarps of Caesalpinia bonduc.

The phytochemical investigation of the pericarps of Caesalpinia bonduc led to the isolation and identification of five new cassane-type alkaloids: caesalminines C - G (1-5) and six new diterpenoids: caesalbonducin K - P (6-11), along with seven known compounds (12-18). Compounds 1-5 were identified as a group of rare alkaloids possessing a tetracyclic cassane-type diterpenoid skeleton with a lactam D-ring instead of a typical furan or lactone moiety. The structures of 1-11 were elucidated on the basis of 1D and 2D NMR including HSQC, HMBC, COSY and NOESY, and other spectroscopic analyses. The cytotoxic activities of the isolated compounds were evaluated in the A431, A549 and U87MG cancer cell lines.

The peripheral immune cell counts and mouth ulcers: A two-sample Mendelian randomization study.

Objective: This study explored the causal association of peripheral immune cell counts with mouth ulcers (MUs) by two-sample Mendelian Randomization. Design: The counts of 12 circulating immune cell types (leukocytes, lymphocytes, monocytes, eosinophils, neutrophils, basophils, CD4+ cells, CD8+ cells, unswitched memory B cells, NK cells, B cells and a derived ratio (CD4+/CD8+)) were determined as the exposure. MUs were the outcome. The analysis was conducted mostly using the inverse-variance weighted (IVW) approach. MR Egger, weighted median, weighted mode and simple mode were used to detect the horizontal pleiotropy. Results: The IVW results for leukocytes and lymphocyte counts were OR = 0.93, 95 % CI = 0.88-0.98, p = 0.0115 and OR = 0.91, 95 % CI: 0.84-0.98, p = 0.0150, respectively. The Wald ratio result for CD4+ cell and CD8+ cell counts were OR = 0.70, 95 % CI: 0.65-0.75, p = 1.05 × 10-20 and OR = 1.25, 95 % CI: 1.19-1.31, p = 9.99 × 10-21, respectively. Conclusions: This study supports a causal effect of peripheral immune cell counts on MUs. Higher leukocyte, lymphocyte and CD4+ cell counts can protect against MUs, but higher CD8+ cell counts enhance the risk of MUs. This finding confirms host immune factors play a crucial role in the aetiology of MUs.

Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission.

Fibroblast activation and proliferation is an essential phase in the progression of renal fibrosis. Despite the recognized significance of glutamine metabolism in cellular growth and proliferation, its precise pathophysiological relevance in renal fibrosis remains uncertain. Therefore, this study aims to investigate the involvement of glutamine metabolism in fibroblast activation and its possible mechanism. Our findings highlight the importance of glutamine metabolism in fibroblast activation and reveal that patients with severe fibrosis exhibit elevated serum glutamine levels and increased expression of kidney glutamine synthetase. Furthermore, the deprivation of glutamine metabolism in vitro and in vivo could inhibit fibroblast activation, thereby ameliorating renal fibrosis. It was also detected that glutamine metabolism is crucial for maintaining mitochondrial function and morphology. These effects may partially depend on the metabolic intermediate α-ketoglutaric acid. Moreover, glutamine deprivation led to upregulated mitochondrial fission in fibroblasts and the activation of the mammalian target of rapamycin / mitochondrial fission process 1 / dynamin-related protein 1 pathway. Thus, these results provide compelling evidence that the modulation of glutamine metabolism initiates the regulation of mitochondrial function, thereby facilitating the progression of renal fibrosis. Consequently, targeting glutamine metabolism emerges as a novel and promising avenue for therapeutic intervention and prevention of renal fibrosis.

The non-causative role of abnormal serum uric acid in intervertebral disc degeneration: A Mendelian randomization study.

Background: Intervertebral disc degeneration (IDD) is a common musculoskeletal disorder that contributes significantly to disability and healthcare costs. Serum urate concentration has been implicated in the development of various musculoskeletal conditions. While previous observational studies have suggested an association between the two conditions, it might confound the effect of serum urate concentrations on IDD. This Mendelian randomization (MR) study aimed to investigate the causal relationship between serum urate concentration and IDD. Methods: We performed a two-sample MR analysis using summary-level data from genome-wide association studies (GWAS) of serum urate concentration (n = 13 585 994 European ancestry) and IDD (n = 16 380 337 European ancestry). Single nucleotide polymorphisms (SNPs) significantly associated with serum urate concentration (p < 5 × 10-8) were selected as instrumental variables. The associations between genetically predicted serum urate concentration and IDD were estimated using the inverse-variance weighted (IVW) method, with sensitivity analyses employing the weighted median, MR-Egger, and MR-PRESSO approaches to assess the robustness of the findings. Results: In the primary IVW analysis, genetically predicted serum urate concentration was unrelated associated with IDD (odds ratio [OR] = 1.00, 95% confidence interval (CI): 1.00-1.00, p = 0.17)). The results remained consistent across the sensitivity analyses, and no significant directional pleiotropy was detected (MR-Egger intercept: p = 0.15). Conclusions: This MR study provides evidence that there is no causal relationship between serum urate concentration and IDD. It suggests previous observational associations may be confounded. Serum urate levels are unlikely to be an important contributor to IDD.