Metabolic Factors Research Articles

FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma.

Cholesterol metabolism is vital for multiple cancer progression, while how cholesterol affects lung, a low-cholesterol tissue, for cancer metastasis and the underlying mechanism remain unclear. In this study, we found that metastatic lung adenocarcinoma cells acquire cellular dehydrocholesterol and cholesterol by endogenous cholesterol biosynthesis, instead of uptake upon cholesterol treatment. Besides, we demonstrated that exogenous cholesterol functions as signaling molecule to induce FOXA3, a key transcription factor for lipid metabolism via GLI2. Subsequently, ChIP-seq analysis and molecular studies revealed that FOXA3 transcriptionally activated Hmgcs1, an essential enzyme of cholesterol biosynthesis, to induce endogenous dehydrocholesterol and cholesterol level for membrane composition change and cell migration. Conversely, FOXA3 knockdown or knockout blocked cholesterol biosynthesis and lung adenocarcinoma metastasis in mice. In addition, the potent FOXA3 inhibitor magnolol suppressed metastatic gene programs in lung adenocarcinoma patient-derived organoids (PDOs). Altogether, our findings shed light onto unique cholesterol metabolism and FOXA3 contribution to lung adenocarcinoma metastasis.

The Role of Bacterial Extracellular Membrane Nanovesicles in Atherosclerosis: Unraveling a Potential Trigger.

In this review, we explore the intriguing and evolving connections between bacterial extracellular membrane nanovesicles (BEMNs) and atherosclerosis development, highlighting the evidence on molecular mechanisms by which BEMNs can promote the athero-inflammatory process that is central to the progression of atherosclerosis. Atherosclerosis is a chronic inflammatory disease primarily driven by metabolic and lifestyle factors; however, some studies have suggested that bacterial infections may contribute to the development of both atherogenesis and inflammation in atherosclerotic lesions. In particular, the participation of BEMNs in atherosclerosis pathogenesis has attracted special attention. We provide some general insights into how the immune system responds to potential threats such as BEMNs during the development of atherosclerosis. A comprehensive understanding of contribution of BEMNs to atherosclerosis pathogenesis may lead to the development of targeted interventions for the prevention and treatment of the disease.

Unraveling the relationship between histone methylation and nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) poses a significant health challenge in modern societies due to shifts in lifestyle and dietary habits. Its complexity stems from genetic predisposition, environmental influences, and metabolic factors. Epigenetic processes govern various cellular functions such as transcription, chromatin structure, and cell division. In NAFLD, these epigenetic tendencies, especially the process of histone methylation, are intricately intertwined with fat accumulation in the liver. Histone methylation is regulated by different enzymes like methyltransferases and demethylases and influences the expression of genes related to adipogenesis. While early-stage NAFLD is reversible, its progression to severe stages becomes almost irreversible. Therefore, early detection and intervention in NAFLD are crucial, and understanding the precise role of histone methylation in the early stages of NAFLD could be vital in halting or potentially reversing the progression of this disease.

Risk Factors for Pelvic Organ Prolapse: Wide-Angled Mendelian Randomization Analysis.

We hypothesized that some metabolic factors, lifestyle factors, and socioeconomic factors may have a causal effect on pelvic organ prolapse (POP). We selected instruments from corresponding genome-wide association studies (GWAS), which identified independent single nucleotide polymorphisms strongly associated with 12 potential risk factors. Summary statistics for POP were derived from two GWAS datasets, serving for discovery and replication stage. The primary analysis involved the use of the inverse-variance weighting mendelian randomization (MR) method, with additional sensitivity MR analyses conducted. The univariable mendelian randomization (UVMR) analysis in both the discovery and replication stage provided evidence for significant causal effects between higher waist-to-hip ratio adjusted for body mass index (WHRadjBMI) levels, lower high-density lipoprotein cholesterol (HDL-C) levels, and lower educational attainment and higher POP risk, as well as a suggestive positive causal effect between triglycerides and POP. The multivariable mendelian randomization (MVMR)analysis showed that only HDL-C among the three blood lipid fractions could reduce the risk of POP. Mediation analysis indicated that HDL-C may partially mediate the effect of WHRadjBMI on POP risk, and the causal effect between educational attainment and POP may be mediated through WHRadjBMI and HDL-C. Our study's evidence supported a causal relationship between WHRadjBMI, triglycerides, HDL-C, educational attainment, and POP risk. This highlights that clinicians may guide the general female population to control obesity and blood lipid levels to reduce the risk of POP.

Genetically predicted N-methylhydroxyproline levels mediate the association between naive CD8+ T cells and allergic rhinitis: a mediation Mendelian randomization study

BackgroundAllergic rhinitis (AR), a prevalent chronic inflammatory condition triggered by immunoglobulin E (IgE), involves pivotal roles of immune and metabolic factors in its onset and progression. However, the intricacies and uncertainties in clinical research render current investigations into their interplay somewhat inadequate.ObjectiveTo elucidate the causal relationships between immune cells, metabolites, and AR, we conducted a mediation Mendelian randomization (MR) analysis.MethodsLeveraging comprehensive publicly accessible summary-level data from genome-wide association studies (GWAS), this study employed the two-sample MR research method to investigate causal relationships among 731 immune cell phenotypes, 1400 metabolite levels, and AR. Additionally, employing the mediation MR approach, the study analyzed potential mediated effect of metabolites in the relationships between immune cells and AR. Various sensitivity analysis methods were systematically employed to ensure the robustness of the results.ResultsFollowing false discovery rate (FDR) correction, we identified three immune cell phenotypes as protective factors for AR: Naive CD8br %CD8br (odds ratio (OR): 0.978, 95% CI = 0.966–0.990, P = 4.5×10–4), CD3 on CD39+ activated Treg (OR: 0.947, 95% CI = 0.923–0.972, P = 3×10–5), HVEM on CD45RA- CD4+ (OR: 0.967, 95% CI = 0.948–0.986, P = 4×10–5). Additionally, three metabolite levels were identified as risk factors for AR: N-methylhydroxyproline levels (OR: 1.219, 95% CI = 1.104–1.346, P = 9×10–5), N-acetylneuraminate levels (OR: 1.133, 95% CI = 1.061–1.211, P = 1.7×10–4), 1-stearoyl-2-arachidonoyl-gpc (18:0/20:4) levels (OR: 1.058, 95% CI = 1.029–1.087, P = 5×10–5). Mediation MR analysis indicated a causal relationship between Naive CD8br %CD8br and N-methylhydroxyproline levels, acting as a protective factor (OR: 0.971, 95% CI = 0.950–0.992, P = 8.31×10–3). The mediated effect was -0.00574, accounting for 26.1% of the total effect, with a direct effect of -0.01626. Naive CD8+ T cells exert a protective effect on AR by reducing N-methylhydroxyproline levels.ConclusionOur study, delving into genetic information, has substantiated the intricate connection between immune cell phenotypes and metabolite levels with AR. This reveals a potential pathway to prevent the onset of AR, providing guiding directions for future clinical investigations.

#1316 Sirtuin 3 promotes renal gluconeogenesis in fibrotic kidneys

Abstract Background and Aims Decreased renal gluconeogenesis is currently identified as a hallmark of chronic kidney disease (CKD), which may contribute to renal fibrosis. Sirt3 is a crucial metabolic sensor that regulates ATP generation, mitochondrial adaptive response to stress, and glucose metabolism. It has been shown that Sirt3 is renal protective in fibrotic kidneys, however its underlying mechanisms is not completely known. In this study, we aimed to investigated whether Sirt3 inhibits CKD associated renal fibrosis through restoring renal gluconeogenesis. Method 1. Animal model of renal fibrosis (in vivo) For unilateral ureter obstructed (UUO) mouse model, a. Twenty-eight C57 mice were divided into four groups: sham + Vehicle, UUO + Vehicle, UUO + 3-TYP and UUO + HKL group. Mice were treated with saline or 20 mg/kg 3-TYP, an inhibitor of SIRT3 or 1 mg/kg HKL, an activator of SIRT3 daily (i.p.). b. Fourteen C57 mice were divided into two groups: Ad-Sirt 3 or Ad-LacZ (0.5 × 109 pfu/100 μL) was injected into the left renal artery before the UUO operation. Systemic glucose metabolism was evaluated by insulin and glucose tolerance tests. 7 or 14 days after operation, kidney tissues were collected and performed histopathological and molecular examination. 2. Primary murine renal tubules fibrosis (ex vivo) Primary renal tubules were isolated from C57 mouse of 4 weeks of age. 5 ng/mL TGF-β was added to culture medium for inducing fibrosis. After this Sirt3 was inhibited by 3-TYP (25 μm) or activated by HKL (2 μm) or overexpressed by adenovirus for different time periods (1, 3, 24, 48 hours). Protein or RNA samples were taken to evaluate renal fibrosis and gluconeogenesis. 3. Human renal epithelial (HK2) cells culture and treatment (in vitro) TGF-β stimulated HK2 cells were used as an in vitro model. Sirt3 was inhibited by 3-TYP or activated by HKL or overexpressed by adenovirus. Protein and RNA samples were taken to evaluate renal fibrosis and gluconeogenesis. Glucose and lactate were measured in supernatant of culture medium. Results In vivo, Masson staining showed that 3-TYP treatment increased the tubulointerstitial collagen deposition of UUO kidneys (Fig. 1A). WB results indicated that 3-TYP enhanced the increased expression of fibrotic marks (Fibronectin, Collagen-I, Vimentin) (Fig. 1B), and further reduced the expression of gluconeogenesis limitation enzyme (PCK1, FBP1) and transcription factors (PGC-1α and FOXO1) 14 days after UUO operation (Fig. 1C). Conversely, HKL treatment or overexpression of Sirt3 in UUO kidney reduced expression of fibrotic marks, increased the expression of gluconeogenesis markers (Fig. 1D-E). 3-TYP increased the lactate concentration in UUO kidneys (Fig. 1F). Insulin sensitivity and glucose clearance tests showed that treatment with 3-TYP further damaged the glucose homeostasis in UUO mice (Fig. 1G-J). Ex vivo, q-PCR results showed that the mRNA of Sirt3 was significantly decreased by time after TGF-β stimulation while the mRNA of FN, Snail was up-regulated and PCK1 and FBP1 were down-regulated (Fig. 2A-D). WB showed that 3-TYP treatment inhibited the expression of PCK1, FBP1 and PGC-1α, FOXO1 (Fig. 2E), however, HKL treatment or overexpressed of Sirt3 by adenovirus increased the expression of gluconeogenesis markers respectively in primary renal tubules (Fig. 2F). In vitro, WB showed that transfection of Sirt3 increased the expression of gluconeogenesis markers and decreased the expression of fibrotic marks of HK2 cells in a fibrotic condition (Fig. 3A-B). Moreover, 3-TYP treatment further decreased the mRNA expression of PCK1 and FBP1 in TGF-β stimulated HK2 cells (Fig. 3C-D). The increased lactate concentration and decreased glucose concentration in the culture medium of TGF-β stimulated HK2 cells were further escalated after 3-TYP treatment (Fig. 3E-F) while reversed after overexpression of Sirt3 (Fig. 3G-H). Conclusion Sirt 3 promotes renal gluconeogenesis in fibrotic kidneys through up-regulation of renal gluconeogenic enzyme PCK1 and FBP1 expression, which is associated with activation of renal metabolic transcription factors PGC-1α and FOXO1.

#1372 Association of plasma beta-2-microglobulin with risk of cardiovascular disease in patients with chronic kidney disease

Abstract Background and Aims In patients with chronic kidney disease(CKD), beta 2 microglobulin (B2MG) can be used to assess renal function, and predialysis serum B2MG levels can predict mortality risk. In addition to the kidney, B2MG regulates the expression of interleukin 1 and tumor necrosis factor, participates in the pathogenesis of vascular damage, and is a marker that can detect the formation of amyloid, therefore it is important in the diagnosis of cardiovascular disease (CVD). To assess the correlation of serum B2MG levels with some metabolic and cardiovascular function factors in patients with chronic kidney disease. Method 119 people with chronic kidney disease and 52 healthy control groups were selected as a case-control study and blood samples were analyzed for creatinine, urea, cholesterol, triglycerides, LDL, calcium, phosphorus, albumin, total protein, and B2MG with Cobas 6000 fully automatic analyzer and echocardiography was performed. Renal function was evaluated by CKD EPI crea-cys combined calculation. In the group with CKD, a person with eGFR <90 ml/min/1.73 m² was not included in the study due to the study exclusion criteria. Results The average age of the group with CKD was 54.92, and the average age of the healthy group was 50.66. B2MG has a significantly higher (P < 0.000) statistically significant correlation in the group with CKD compared to the control group. B2MG was significantly associated with creatinine (g = 0.516, P < 0.000), phosphorus (g = 0.342, P < 0.000), cystatin C (g = 0.700, P < 0.000), urea (g = 0.326, P < 0.000), and echocardiography with directly indicators LVMI(g = 0.113, P < 0.000), LVESD (r = 0.265, P < 0.000), thus BMI (g = −0.274, P < 0.000), tTSH (r = −0.516, P < 0.000), calcium ( g = −0.137, P < 0.000), albumin (g = −0.180, P < 0.000), total protein (r = −0.080, P < 0.000), cholesterol (g = −0.215, P < 0.000), BNLP (r = −0.163, P < 0.000), triglycerides (g = −0.142, P < 0.000), and EV of echocardiography (g = −0.292, P < 0.000) have inverse statistical significance. Conclusion B2MG levels have been shown to predict CVD risk and CVD-related mortality in all stages of chronic kidney disease. According to our study, B2MG is directly related to kidney function biomarkers, phosphorus, LVMI, and LVESD indicators of cardiac echocardiography, and inversely correlated with parameters of eGFR, protein, triglycerides, calcium, and cardiac echocardiogram EV indicators, which is similar to studies conducted in other countries. Therefore, B2MG can be used to detect the risk of CVD in people with severe CKD. Figure: Will be uploaded on our poster if accepted.

Sex-Dimorphic Effects of Hypoglycemia on Metabolic Sensor mRNA Expression in Ventromedial Hypothalamic Nucleus-Dorsomedial Division (VMNdm) Growth Hormone-Releasing Hormone Neurons.

Growth hormone-releasing hormone (Ghrh) neurons in the dorsomedial ventromedial hypothalamic nucleus (VMNdm) express the metabolic transcription factor steroidogenic factor-1 and hypoglycemia-sensitive neurochemicals of diverse chemical structures, transmission modes, and temporal signaling profiles. Ghrh imposes neuromodulatory control of coexpressed transmitters. Multiple metabolic sensory mechanisms are employed in the brain, including screening of the critical nutrient glucose or the energy currency ATP. Here, combinatory laser-catapult-microdissection/single-cell multiplex qPCR tools were used to investigate whether these neurons possess molecular machinery for monitoring cellular metabolic status and if these biomarkers exhibit sex-specific sensitivity to insulin-induced hypoglycemia. Data show that hypoglycemia up- (male) or downregulated (female) Ghrh neuron glucokinase (Gck) mRNA; Ghrh gene silencing decreased baseline and hypoglycemic patterns of Gck gene expression in each sex. Ghrh neuron glucokinase regulatory protein (Gckr) transcript levels were respectively diminished or augmented in hypoglycemic male vs female rats; this mRNA profile was decreased by Ghrh siRNA in both sexes. Gene transcripts encoding catalytic alpha subunits of the energy monitor 5-AMP-activated protein kinase (AMPK), i.e., Prkaa1 and 2, were increased by hypoglycemia in males, yet only the former mRNA was hypoglycemia-sensitive in females. Ghrh siRNA downregulated baseline and hypoglycemia-associated Prkaa subunit mRNAs in males but elicited divergent changes in Prkaa2 transcripts in eu- vs hypoglycemic females. Results provide unique evidence that VMNdm Ghrh neurons express the characterized metabolic sensor biomarkers glucokinase and AMPK and that the corresponding gene profiles exhibit distinctive sex-dimorphic transcriptional responses to hypoglycemia. Data further document Ghrh neuromodulation of baseline and hypoglycemic transcription patterns of these metabolic gene profiles.

Nuclear export is a limiting factor in eukaryotic mRNA metabolism.

The eukaryotic mRNA life cycle includes transcription, nuclear mRNA export and degradation. To quantify all these processes simultaneously, we perform thiol-linked alkylation after metabolic labeling of RNA with 4-thiouridine (4sU), followed by sequencing of RNA (SLAM-seq) in the nuclear and cytosolic compartments of human cancer cells. We develop a model that reliably quantifies mRNA-specific synthesis, nuclear export, and nuclear and cytosolic degradation rates on a genome-wide scale. We find that nuclear degradation of polyadenylated mRNA is negligible and nuclear mRNA export is slow, while cytosolic mRNA degradation is comparatively fast. Consequently, an mRNA molecule generally spends most of its life in the nucleus. We also observe large differences in the nuclear export rates of different 3'UTR transcript isoforms. Furthermore, we identify genes whose expression is abruptly induced upon metabolic labeling. These transcripts are exported substantially faster than average mRNAs, suggesting the existence of alternative export pathways. Our results highlight nuclear mRNA export as a limiting factor in mRNA metabolism and gene regulation.

The effects of grape seed extract supplementation on cardiovascular risk factors, liver enzymes and hepatic steatosis in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study.

Despite the high antioxidant potential of grape seed extract (GSE), very limited studies have investigated its effect on non-alcoholic fatty liver disease (NAFLD). Therefore, this study was conducted with the aim of investigating the effect of GSE on metabolic factors, blood pressure and steatosis severity in patients with NAFLD. In this double-blind randomized clinical trial study, 50 NAFLD patients were divided into two groups of 25 participants who were treated with 520mg/day of GSE or the placebo group for 2 months. The parameters of glycemic, lipid profile, blood pressure and steatohepatitis were measured before and after the intervention. The GSE group had an average age of 43.52 ± 8.12 years with 15 women and 10 men, while the placebo group had an average age of 44.88 ± 10.14 years with 11 women and 14 men. After 2 months of intervention with GSE, it was observed that insulin, HOMA-IR, TC, TG, LDL-c, ALT, AST, AST/ALT, SBP, DBP and MAP decreased and QUICKi and HDL-c increased significantly (p-value for all < 0.05). Also, before and after adjustment based on baseline, the average changes indicated that the levels of insulin, HOMA-IR, TC, TG, LDL-c, SBP, DBP, MAP in the GSE group decreased more than in the control group (p for all < 0.05). Furthermore, the changes in HDL-c were significantly higher in the GSE group (p < 0.05). The between-groups analysis showed a significant decrease in the HOMA-β and AST before and after adjustment based on baseline levels (p < 0.05). Moreover, the changes in QUICKi after adjustment based on baseline levels were higher in the GSE group than in the control group. Also, between-groups analysis showed that the severity of hepatic steatosis was reduced in the intervention group compared to the placebo group (P = 0.002). It seems that GSE can be considered one of the appropriate strategies for controlling insulin resistance, hyperlipidemia, hypertension and hepatic steatosis in NAFLD patients. The clinical trial was registered in the Iranian Clinical Trial Registration Center (IRCT20190731044392N1). https://irct.behdasht.gov.ir/trial/61413 . (The registration date: 30/03/2022).

Beta-Hydroxybutyrate Levels and Risk of Diabetic Ketoacidosis in Adults with Type 1 Diabetes Treated with Sotagliflozin.

Introduction: Sodium glucose cotransporter inhibitors may increase beta-hydroxybutyrate (BHB) in insulin-requiring patients. We determined factors associated with BHB changes from baseline (ΔBHB) and diabetic ketoacidosis (DKA) in patients with type 1 diabetes (T1D) receiving sotagliflozin as an insulin adjunct. Research Design and Methods: This post hoc analysis compared ΔBHB levels in adults with T1D receiving sotagliflozin 400 mg or placebo for 6 months. We evaluated clinical and metabolic factors associated with ΔBHB and used logistic regression models to determine predictors associated with BHB values >0.6 and >1.5 mmol/L (inTandem3 population; N = 1402) or with DKA events in a pooled analysis (inTandem1-3; N = 2453). Results: From baseline (median, 0.13 mmol/L), median fasting BHB increased by 0.04 mmol/L (95% confidence interval, 0.03-0.05; P < 0.001) at 24 weeks with sotagliflozin versus placebo; 67% of patients had no or minimal changes in BHB over time. Factors associated with on-treatment BHB >0.6 or >1.5 mmol/L included baseline BHB and sotagliflozin use. Age, insulin pump use, sotagliflozin use, baseline BHB, and ΔBHB were significantly associated with DKA episodes. Independent of treatment, DKA risk increased by 18% with each 0.1-mmol/L increase in baseline BHB and by 8% with each 0.1-mmol/L increase from baseline. Conclusion: Incremental increases in baseline BHB and ΔBHB were associated with a higher DKA risk independent of treatment. Adding sotagliflozin to insulin increased median BHB over 24 weeks in patients with T1D and was associated with increased DKA events. These results highlight the importance of BHB testing and monitoring and individualizing patient education on DKA risk, mitigation, identification, and treatment.

'Emerging into the World' - the regulation and control of dormancy and sprouting in geophytes.

Geophytic plants synchronize growth and quiescence with the external environment to survive and thrive under changing seasons. Besides seasonal growth adaptation, dormancy and sprouting are critical factors determining crop yield and market supply as various geophytes also serve as major food, floriculture, and ornamental crops. Dormancy in such crops decides crop availability in the market, as most of such crops are consumed during the dormant stage. On the other hand, uniform/maximal sprouting is crucial for maximum yield. Thus, dormancy and sprouting regulation have great economic importance. Dormancy-sprouting cycles in geophytes are regulated by genetic, exogenous (environmental), and endogenous (genetic, metabolic and hormonal, etc.) factors. Comparatively, the temperature is more dominant in regulating dormancy and sprouting in geophytes, unlike aboveground tissues, where both photoperiod and temperature control are involved. Despite huge economic importance, studies concerning the regulation of dormancy and sprouting are scarce in the majority of geophytes. To date, only a few molecular factors involved in the process have been suggested. Recently, omics studies on molecular and metabolic factors involved in dormancy and growth regulations of underground vegetative tissues have provided more insight into the mechanism. Here, we discuss current knowledge of the environmental and molecular regulation and control of dormancy and sprouting in geophytes and discuss challenges/questions that need to be addressed in the future for crop improvement.

Holoprosencephaly: The Disease and Its Related Disabilities

AbstractHoloprosencephaly (HPE), the most prevalent developmental anomaly affecting the forebrain in humans, occurs in ∼1 in 16,000 liveborn neonates, with an incidence reaching 1 in 250 in conceptuses. This condition is distributed worldwide. HPE is etiologically heterogeneous, and its pathogenesis is variable. Environmental, teratogenic, genetic, or metabolic factors can contribute to the development of HPE. Notably, maternal insulin-dependent diabetes mellitus and maternal alcoholism are among the primary causative factors. HPE may be linked to various well-defined multiple malformation syndromes characterized by a normal karyotype, such as Smith–Lemli–Opitz's, Pallister–Hall's, or velocardiofacial syndrome. Alternatively, it can be associated with chromosomal abnormalities. (i.e., Patau's syndrome and, less frequently, Edwards' syndrome or Down's syndrome). The major genes implicated in HPE are SHH, ZIC2, SIX3, and TGIF. The range of HPE is extensive, covering diverse neuropathological phenotypes of varying severity. Three classical types of HPE can be distinguished in increasing order of severity: lobar HPE, characterized by separated right and left ventricles with some continuity across the frontal cortex; semilobar HPE, featuring a partial separation; and the most severe form, alobar HPE, where there is a single brain ventricle and the absence of an interhemispheric fissure. Additionally, there are other variations of HPE, ranging in severity, including the less severe interhemispheric median HPE (also known as middle interhemispheric variant). The phenotypic spectrum of HPE is highly extensive, encompassing severe cerebral malformations to microforms. Children with HPE often encounter numerous medical challenges; among them neurological disorders, craniofacial malformations, endocrine disorders, oral and motor dysfunction, and dysfunction of the autonomic nervous system. Neurologic problems, such as cerebral palsy and seizures, are common. The diagnosis of HPE is typically made prenatally, relying primarily on ultrasound and magnetic resonance imaging examinations. The prognosis for individuals with HPE is largely dependent on its underlying causes. Those with cytogenetic abnormalities, in particular, face a significantly poorer prognosis, with only 2% surviving beyond 1 year.

Determinants of bacterial survival and proliferation in blood.

Bloodstream infection is a major public health concern associated with high mortality and high healthcare costs worldwide. Bacteremia can trigger fatal sepsis whose prevention, diagnosis and management have been recognized as a global health priority by the World Health Organization. Additionally, infection control is increasingly threatened by antimicrobial resistance, which is the focus of global action plans in the framework of a One Health response. In-depth knowledge of the infection process is needed to develop efficient preventive and therapeutic measures. The pathogenesis of bloodstream infection is a dynamic process resulting from the invasion of the vascular system by bacteria, which finely regulate their metabolic pathways and virulence factors to overcome the blood immune defenses and proliferate. In this review, we highlight our current understanding of determinants of bacterial survival and proliferation in the bloodstream and discuss their interactions with the molecular and cellular components of blood.

Umami Altering Salivary Proteome: A Study across a Sensitivity Spectrum on Subjects.

This study delved into the relationship between umami taste sensitivity (UTS) and variations in the salivary proteome among 12 healthy nonsmokers utilizing 4D data-independent acquisition-based proteomics. By assessing UTS through monosodium l-glutamate (MSG) detection thresholds, we discovered notable differences: individuals with high UTS detected umami at significantly lower MSG concentrations (0.20 ± 0.12 mM) compared to their low UTS counterparts (2.51 ± 1.21 mM). Both groups showed an upregulation of the S100A1 protein under MSG stimulation, indicating a potent biochemical response to umami stimuli. The high UTS group exhibited enhanced metabolic pathways including those for amino acid, lipid, and organic acid biosynthesis, essential for maintaining taste receptor functionality and enhancing signal transduction. This group also demonstrated increased activity in cytochrome P450 enzymes and ribonucleoprotein complexes, suggesting a readiness to manage metabolic challenges and optimize umami perception. In contrast, the low UTS group showed adaptive mechanisms, possibly through modulation of receptor availability and function, with an upregulation of structural and ribosomal proteins that may support taste receptor production and turnover. These findings suggest that varying biological mechanisms underpin differences in umami perception, which could significantly influence dietary preferences and nutritional outcomes, highlighting the intricate interplay of genetic, physiological, and metabolic factors in taste sensitivity.

The potential association between metabolic disorders and pulmonary tuberculosis: a Mendelian randomization study

BackgroundMetabolic disorders (MetDs) have been demonstrated to be closely linked to numerous diseases. However, the precise association between MetDs and pulmonary tuberculosis (PTB) remains poorly understood.MethodSummary statistics for exposure and outcomes from genome-wide association studies (GWASs) for exposures and outcomes were obtained from the BioBank Japan Project (BBJ) Gene–exposure dataset. The 14 clinical factors were categorized into three groups: metabolic laboratory markers, blood pressure, and the MetS diagnostic factors. The causal relationship between metabolic factors and PTB were analyzed using two-sample Mendelian Randomization (MR). Additionally, the direct effects on the risk of PTB were investigated through multivariable MR. The primary method employed was the inverse variance-weighted (IVW) model. The sensitivity of this MR analysis was evaluated using MR-Egger regression and the MR-PRESSO global test.ResultsAccording to the two-sample MR, HDL-C, HbA1c, TP, and DM were positively correlated with the incidence of active TB. According to the multivariable MR, HDL-C (IVW: OR 2.798, 95% CI 1.484–5.274, P = 0.001), LDL (IVW: OR 4.027, 95% CI 1.140–14.219, P = 0.03) and TG (IVW: OR 2.548, 95% CI 1.269–5.115, P = 0.009) were positively correlated with the occurrence of PTB. TC (OR 0.131, 95% CI 0.028–0.607, P = 0.009) was negatively correlated with the occurrence of PTB. We selected BMI, DM, HDL-C, SBP, and TG as the diagnostic factors for metabolic syndrome. DM (IVW, OR 1.219, 95% CI 1.040–1.429 P = 0.014) and HDL-C (IVW, OR 1.380, 95% CI 1.035–1.841, P = 0.028) were directly correlated with the occurrence of PTB.ConclusionsThis MR study demonstrated that metabolic disorders, mainly hyperglycemia, and dyslipidemia, are associated with the incidence of active pulmonary tuberculosis.

Stress-impaired reward pathway promotes distinct feeding behavior patterns.

Although dietary behaviors are affected by neuropsychiatric disorders, various environmental conditions can have strong effects as well. We found that mice under multiple stresses, including social isolation, intermittent high-fat diet, and physical restraint, developed feeding behavior patterns characterized by a deviated bait approach (fixated feeding). All the tested stressors affected dopamine release at the nucleus accumbens (NAcc) shell and dopamine normalization reversed the feeding defects. Moreover, inhibition of dopaminergic activity in the ventral tegmental area that projects into the NAcc shell caused similar feeding pattern aberrations. Given that the deviations were not consistently accompanied by changes in the amount consumed or metabolic factors, the alterations in feeding behaviors likely reflect perturbations to a critical stress-associated pathway in the mesolimbic dopamine system. Thus, deviations in feeding behavior patterns that reflect reward system abnormalities can be sensitive biomarkers of psychosocial and physical stress.

Can weight-adjusted waist circumference index become a single anthropometric predictor of prostate-specific antigen concentration? A National Health and Nutrition Examination Survey analysis (2003-2010).

Recent studies have introduced the weight-adjusted waist circumference index (WWI) as a viable obesity indicator that may better reflect centripetal obesity and its associated risks. In examining the connection between WWI and prostate-specific antigen (PSA), this study leveraged data from the National Health and Nutrition Examination Survey 2003-2010, including 5732 participants. Our initial analysis indicated a significant positive association between WWI and PSA levels. However, subsequent models that adjusted for covariates such as age, race, and a range of metabolic and cardiovascular health-related factors revealed that the strength and significance of this relationship were attenuated. Model 1 showed a highly significant correlation (p < 0.0001). Yet, in Model 2, which accounted for age and race, the association softened (p = 0.0520). Moreover, when a full spectrum of health covariates was included in Model 3, the association was no longer significant (p = 0.9775). These findings suggest that while an unadjusted correlation exists, its potential use as a diagnostic predictor is limited without considering the broader health context. Therefore, it is crucial to review such data with multiple considerations in mind, and extensive attention should be paid to the evaluation of covariates.

The contribution of metabolic risk factors to cardiovascular mortality in Golestan cohort study: Population attributable fraction estimation

BackgroundCardiovascular diseases (CVDs) are the leading causes of global mortality and disability. Several studies demonstrated that metabolic risk factors increase cardiovascular mortality. The aim of this study is to examine CVDs deaths and population attributable fractions (PAFs) of their metabolic risk factors in Iran. MethodsThis is a study on 8621 participants aged 45–75 years and older, recruited in the repeated measurement phase of the Golestan cohort study (GCS) in northeast of Iran. The Cox proportional hazards model was used to determine the adjusted hazard ratios (HRs). PAFs were calculated to enumerate CVDs mortality avoidable in the population if metabolic risk factors were eliminated. ResultsThe mortality of CVDs was attributable to metabolic factors, including high waist circumference (PAF, 28 %, [95 % CI: 16%–38 %]), high fasting blood sugar (FBS) (20 %, [15%–24 %]), overweight and obesity (19 %, [8%–28 %]), high blood pressure (16 %, [11%–21 %]), high low-density lipoprotein cholesterol (LDL-C) (8 %, [1%–15 %]), and high triglyceride (TG) (7 %, [3%–11 %]). Collectively, these metabolic risk factors accounted for 50 % of CVDs deaths. Females (67 %, [50%–78 %]) had a higher joint PAF of metabolic risk factors compared to males (43 %, [27%–55 %]). ConclusionsThe pattern of CVDs mortality attributable to metabolic risk factors in this study is not the same as similar studies in other parts of the world and previous studies in Iran. It is imperative that CVDs risk factors be specifically evaluated and addressed in various populations due to variety in geographical and temporal patterns in contribution of metabolic risk factors to CVD mortality.

Gender Differences in Liver Steatosis and Fibrosis in Overweight and Obese Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease before and after 8 Weeks of Very Low-Calorie Ketogenic Diet.

Obesity and metabolic syndrome are linked to steatotic liver disease (SLD), the most common form of chronic liver disease. Lifestyle modifications and dieting are strategies that can prevent metabolic dysfunction-associated steatotic liver disease (MASLD). The very low-calorie ketogenic diet (VLCKD) is a helpful treatment for MASLD and has been recommended for people affected by obesity; we evaluated the effect of gender on steatosis and fibrosis in a cohort of 112 overweight or obese patients undergoing an eight-week treatment with a VLCKD. Differences between the genders in terms of anthropometric measures, body composition, and metabolic indicators were examined before, during, and after the nutritional intervention. At baseline, there were significant differences between men and women in terms of anthropometric parameters, blood pressure, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), fasting insulin, hepatic markers, and lipid profile. Men had considerably higher levels of liver steatosis (measured by CAP) and liver stiffness (measured by E) under basal conditions than women. After the VLCKD, there were reductions in both genders of controlled attenuation parameter (CAP), body weight, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, insulin resistance, fat mass (FM), free fat mass (FFM), and fasting blood glucose, insulin, glycated hemoglobin (HbA1c), triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, alanine transaminase (ALT), gamma-glutamyl transferase (γGT), and uric acid levels. Only in men, liver stiffness, aspartate aminotransferase (AST), creatinine, and C-reactive protein (CRP) levels significantly decreased. Moreover, men had significantly greater levels of liver steatosis: the male gender featured an increase of 23.96 points of the Fibroscan CAP. Men exhibited higher levels of steatosis and fibrosis than women, and these differences persist despite VLCKD. These gender-specific variations in steatosis and fibrosis levels could be caused by hormonal and metabolic factors, suggesting that different therapeutic strategies might be required depending on the gender.