Metabolic Factors Research Articles

Emerging into the world: 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. Together with 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 determines crop availability in the market, as most of them 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, hormonal, etc.) factors. Comparatively, the temperature is more dominant in regulating dormancy and sprouting in geophytes, unlike above-ground 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 regulation 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.

The predictive value of body mass index, waist circumference, and triglycerides/ high-density lipoprotein cholesterol ratio in assessing severity in patients with knee osteoarthritis and metabolic syndrome

BackgroundStudies have shown the importance of metabolic factors like BMI, waist circumference, and lipid profile in predicting knee osteoarthritis severity. However, their predictive ability in knee osteoarthritis patients with metabolic syndrome still needs to be explored. ObjectivesEvaluate the predictive ability of Body mass index (BMI), waist circumference, and triglyceride/ High-density lipoprotein cholesterol (HDL-c) ratio in determining the severity of knee osteoarthritis in patients with metabolic syndrome. Materials and methodsA cross-sectional study at Ho Chi Minh City Hospital for Rehabilitation and Professional Diseases from January 2023 to January 2024 included 697 patients meeting ACR 1991 and NCEP-ATP III criteria for knee osteoarthritis and metabolic syndrome, respectively. Logistic regression analyzed the predictive ability of BMI, waist circumference, and triglyceride/HDL-C ratios. Six hundred ninety-seven patients were divided into two groups: severe and non-severe knee osteoarthritis. The criteria for severity were defined as the presence of both: (1) Kellgren-Lawrence grade 3 or higher on knee radiographs and (2) moderate or higher knee pain. Two models were constructed to analyze the predictive ability of severe knee osteoarthritis. Model 1 included univariate factors, while Model 2 incorporated multivariate models. ResultsAmong the 697 patients who participated in the study, the average age was 58.7 ± 12.1 years, and females accounted for 71.3 %. The mean BMI and waist circumference were 24.8 ± 2.0 kg/m2 and 86.2 ± 6.0 cm, respectively. In model 1 (univariate), the discriminative ability of BMI, waist circumference, and triglycerides/HDL-c in predicting severity was excellent, with respective AUCs of 0.90 (95 % CI: 0.87–0.92, p < 0.001), 0.81 (95 % CI: 0.78–0.85, p < 0.001), and 0.85 (95 % CI: 0.82–0.88, p < 0.001). In model 2 (combined model), the combination of all three factors resulted in an AUC of 0.93 (95 % CI: 0.91–0.95, p < 0.001) with a specificity of up to 90.2 %. ConclusionBMI, waist circumference, and triglyceride/HDL-C ratio are individual and combined predictors of knee osteoarthritis severity in patients with metabolic syndrome.

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.

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.

Metabolic Factors Associated with Endoscopic Atrophy, Intestinal Metaplasia, and Gastric Neoplasms in Helicobacter pylori-Positive Patients.

Previous studies demonstrate an association between metabolic factors and Helicobacter pylori-related gastric cancer. However, the association of gastric atrophy or intestinal metaplasia (IM) with these factors remains unknown. Data on 1603 Helicobacter pylori-positive patients who underwent esophagogastroduodenoscopy between 2001 and 2021 were evaluated. The outcome measures were endoscopic atrophy, IM grade, and the incidence of endoscopically diagnosed and pathologically confirmed gastric neoplasms. Clinical factors associated with these findings were also determined. Advanced age; successful Helicobacter pylori eradication; and comorbidities including diabetes mellitus (DM), hypertension, dyslipidemia, and fib4 index were significantly associated with endoscopic gastric atrophy grade. Male sex; advanced age; and comorbidities including DM, hypertension, dyslipidemia, hyperuricemia, fatty liver, aortic calcification, and fib4 index were also significantly associated with endoscopic IM grade, whereas advanced age, successful Helicobacter pylori eradication, DM, fatty liver, and fib4 index were significantly associated with the incidence of gastric neoplasms. Several metabolic disorders, including DM, hypertension, dyslipidemia, hyperuricemia, and fatty liver disease, are risk factors for advanced-grade gastric atrophy, intestinal metaplasia, and gastric neoplasms. Risk stratification according to these factors, particularly those with metabolic disorders, would affect EGD surveillance for Helicobacter pylori-positive patients.

The Human Blood N-Glycome: Unraveling Disease Glycosylation Patterns.

Most of the proteins in the circulation are N-glycosylated, shaping together the total blood N-glycome (TBNG). Glycosylation is known to affect protein function, stability, and clearance. The TBNG is influenced by genetic, environmental, and metabolic factors, in part epigenetically imprinted, and responds to a variety of bioactive signals including cytokines and hormones. Accordingly, physiological and pathological events are reflected in distinct TBNG signatures. Here, we assess the specificity of the emerging disease-associated TBNG signatures with respect to a number of key glycosylation motifs including antennarity, linkage-specific sialylation, fucosylation, as well as expression of complex, hybrid-type and oligomannosidic N-glycans, and show perplexing complexity of the glycomic dimension of the studied diseases. Perspectives are given regarding the protein- and site-specific analysis of N-glycosylation, and the dissection of underlying regulatory layers and functional roles of blood protein N-glycosylation.

The effect and mechanism of combined exposure of MC-LR and NaNO2 on liver lipid metabolism

Microcystin-LR (MC-LR) and sodium nitrite (NaNO2) co-exist in the environment and are hepatotoxic. The liver has the function of lipid metabolism, but the impacts and mechanisms of MC-LR and NaNO2 on liver lipid metabolism are unclear. Therefore, we established a chronic exposure model of Balb/c mice and used LO2 cells for in vitro verification to investigate the effects and mechanisms of liver lipid metabolism caused by MC-LR and NaNO2. The results showed that after 6 months of exposure to MC-LR and NaNO2, the lipid droplets content was increased, and the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were raised in the liver (P < 0.05). Moreover, MC-LR and NaNO2 synergistically induced hepatic oxidative stress by decreasing total superoxide dismutase (T-SOD) activity and glutathione (GSH) levels and increasing malondialdehyde (MDA) content levels. In addition, the levels of Nrf2, HO-1, NQO1 and P-AMPK was decreased and Keap1 was increased in the Nrf2/HO-1 pathway. The key factors of lipid metabolism, SREBP-1c, FASN and ACC, were up-regulated in the liver. More importantly, there was a combined effect on lipid deposition of MC-LR and NaNO2 co-exposure. In vitro experiments, MC-LR and NaNO2-induced lipid deposition and changes in lipid metabolism-related changes were mitigated after activation of the Nrf2/HO-1 signaling pathway by the Nrf2 activator tertiary butylhydroquinone (TBHQ). Additionally, TBHQ alleviated the rise of reactive oxygen species (ROS) in LO2 cells induced by MC-LR and NaNO2. Overall, our findings indicated that MC-LR and NaNO2 can cause abnormal liver lipid metabolism, and the combined effects were observed after MC-LR and NaNO2 co-exposure. The Nrf2/HO-1 signal pathway may be a potential target for prevention and control of liver toxicity caused by MC-LR and NaNO2.

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.

Liver Steatosis is Prevalent in Lean People With HIV and Associated With Exposure to Antiretroviral Treatment-A Cross-sectional Study.

Steatotic liver disease is suggested to have a higher prevalence and severity in people with HIV (PHIV), including in those with a normal body mass index (BMI). In this study, we used data from the 2000HIV cohort to (1) assess the prevalence of liver steatosis and fibrosis in lean versus overweight/obese PHIV and (2) assess associations in these subgroups between steatosis and fibrosis with traditional risk factors and HIV-specific characteristics. The 2000HIV study cohort comprises 1895 virally suppressed PHIV that were included between 2019 and 2021 in 4 HIV treatment centers in the Netherlands. The majority (58.5%) underwent vibration-controlled transient elastography for the assessment of liver steatosis and fibrosis. The prevalence of steatosis (controlled attenuation parameter ≥263 dB/m) and fibrosis (liver stiffness measurement ≥7.0 kPa) was estimated. Multiple factors including HIV characteristics and antiretroviral drugs were tested in a logistic regression model for association with steatosis and fibrosis. Analyses were performed separately for lean (Asian descent: BMI < 23 kg/m2, other descent: BMI < 25 kg/m2) and overweight/obese (other BMI) participants. Of 1050 PHIV including 505 lean and 545 overweight/obese PHIV, liver steatosis was observed in 37.7% of the overall study population, 19.7% of lean, and 54% of overweight/obese PHIV, whereas fibrosis was observed in 9.0% of the overall study population, 5.9% of lean, and 12.0% of overweight/obese PHIV.All associations with fibrosis and most associations with steatosis concerned metabolic factors such as type 2 diabetes mellitus (overall population: adjusted odds ratio [aOR] for steatosis: 2.3 [1.21-4.4], P = .011; aOR for fibrosis: 3.7 [1.82-7.53], P < .001). Furthermore, in lean PLHIV, liver steatosis was associated with CD4 and CD8 counts at enrollment, dual therapy, and history of treatment with raltegravir (aOR: 3.6 [1.53-8.47], P = .003), stavudine (aOR: 3.73 [1.69-8.2], P = .001), and indinavir (aOR: 3.86 [1.59-9.37], P = .003). These associations were not observed in overweight/obese PHIV. Liver steatosis was highly prevalent, affecting approximately one-fifth of lean PHIV and half of overweight/obese PHIV. Fibrosis was observed in a minority. Both steatosis and fibrosis were associated with traditional metabolic risk factors. In addition, (prior) exposure to specific antiretroviral drugs was associated liver steatosis in lean, but not in overweight/obese PHIV. Implementing increased screening protocols could enhance the identification of steatotic liver disease in lean PHIV.

Molecular Responses of the Eukaryotic Cell Line INT407 on the Internalized Campylobacter jejuni-The Other Side of the Coin.

Campylobacter jejuni is a zoonotic bacterium with the capacity to invade the epithelial cells during the pathogenic process. Several bacterial factors have been identified to contribute to this process, but our knowledge is still very limited about the response of the host. To reveal the major routes of this response, a whole-transcriptome analysis (WTA) was performed where gene expressions were compared between the 1st and the 3rd hours of internalization in INT407 epithelial cells. From the 41,769 human genes tested, altogether, 19,060 genes were shown through WTA to be influenced to different extents. The genes and regulation factors of transcription (296/1052; 28%), signal transduction (215/1052; 21%), apoptosis (153/1052; 15%), immune responses (97/1052; 9%), transmembrane transport (64/1052; 6%), cell-cell signaling (32/1052; 3%), cell-cell adhesions (29/1052; 3%), and carbohydrate metabolism (28/1052; 3%) were the most affected biological functions. A striking feature of the gene expression of this stage of the internalization process is the activation of both immune functions and apoptosis, which convincingly outlines that the invaded cell faces a choice between death and survival. The seemingly balanced status quo between the invader and the host is the result of a complex process that also affects genes known to be associated with postinfectious pathological conditions. The upregulation of TLR3 (3.79×) and CD36 (2.73×), two general tumor markers, and SERPINEB9 (11.37×), FNDC1 (7.58×), and TACR2 (8.84×), three factors of tumorigenesis, confirms the wider pathological significance of this bacterium.

The Streptococcus pyogenes stand-alone regulator RofA exhibits characteristics of a PRD-containing virulence regulator.

Streptococcus pyogenes [group A streptococcus (GAS)] is a human pathogen capable of infecting diverse tissues. To successfully infect these sites, GAS must detect available nutrients and adapt accordingly. The phosphoenolpyruvate transferase system (PTS) mediates carbohydrate uptake and metabolic gene regulation to adapt to the nutritional environment. Regulation by the PTS can occur through phosphorylation of transcriptional regulators at conserved PTS-regulatory domains (PRDs). GAS has several PRD-containing stand-alone regulators with regulons encoding both metabolic genes and virulence factors [PRD-containing virulence regulators (PCVRs)]. One is RofA, which regulates the expression of virulence genes in multiple GAS serotypes. It was hypothesized that RofA is phosphorylated by the PTS in response to carbohydrate levels to coordinate virulence gene expression. In this study, the RofA regulon of M1T1 strain 5448 was determined using RNA sequencing. Two operons were consistently differentially expressed across growth in the absence of RofA; the pilus operon was downregulated, and the capsule operon was upregulated. This correlated with increased capsule production and decreased adherence to keratinocytes. Purified RofA-His was phosphorylated in vitro by PTS proteins EI and HPr, and phosphorylated RofA-FLAG was detected in vivo when GAS was grown in low-glucose C medium. Phosphorylated RofA was not observed when C medium was supplemented 10-fold with glucose. Mutations of select histidine residues within the putative PRDs contributed to the in vivo phosphorylation of RofA, although phosphorylation of RofA was still observed, suggesting other phosphorylation sites exist in the protein. Together, these findings support the hypothesis that RofA is a PCVR that may couple sugar metabolism with virulence regulation.

New regulatory role of Znf1 in transcriptional control of pentose phosphate pathway and ATP synthesis for enhanced isobutanol and acid tolerance.

To develop a cost-effective microbial cell factory for the production of biofuels and biochemicals, an understanding of tolerant mechanisms is vital for the construction of robust host strains. Here, we characterized a new function of a key metabolic transcription factor named Znf1 and its involvement in stress response in Saccharomyces cerevisiae to enhance tolerance to advanced biofuel, isobutanol. RNA-sequencing analysis of the wild-type versus the znf1Δ deletion strains in glucose revealed a new role for transcription factor Znf1 in the pentose phosphate pathway (PPP) and energy generation. The gene expression analysis confirmed that isobutanol induces an adaptive cell response, resulting in activation of ATP1-3 and COX6 expression. These genes were Znf1 targets that belong to the electron transport chain, important to produce ATPs. Znf1 also activated PPP genes, required for the generation of key amino acids, cellular metabolites, and maintenance of NADP/NADPH redox balance. In glucose, Znf1 also mediated the upregulation of valine biosynthetic genes of the Ehrlich pathway, namely ILV3, ILV5, and ARO10, associated with the generation of key intermediates for isobutanol production.Using S. cerevisiae knockout collection strains, cells with deleted transcriptional regulatory gene ZNF1 or its targets displayed hypersensitivity to isobutanol and acid inhibitors; in contrast, overexpression of ZNF1 enhanced cell survival. Thus, the transcription factor Znf1 functions in the maintenance of energy homeostasis and redox balance at various checkpoints of yeast metabolic pathways. It ensures the rapid unwiring of gene transcription in response to toxic products/by-products generated during biofuel production. Importantly, we provide a new approach to enhance strain tolerance during the conversion of glucose to biofuels.

Unravelling the Triad of Lung Cancer, Drug Resistance, and Metabolic Pathways.

Lung cancer, characterized by its heterogeneity, presents a significant challenge in therapeutic management, primarily due to the development of resistance to conventional drugs. This resistance is often compounded by the tumor's ability to reprogram its metabolic pathways, a survival strategy that enables cancer cells to thrive in adverse conditions. This review article explores the complex link between drug resistance and metabolic reprogramming in lung cancer, offering a detailed analysis of the molecular mechanisms and treatment strategies. It emphasizes the interplay between drug resistance and changes in metabolic pathways, crucial for developing effective lung cancer therapies. This review examines the impact of current treatments on metabolic pathways and the significance of considering metabolic factors to combat drug resistance. It highlights the different challenges and metabolic alterations in non-small-cell lung cancer and small-cell lung cancer, underlining the need for subtype-specific treatments. Key signaling pathways, including PI3K/AKT/mTOR, MAPK, and AMPK, have been discussed for their roles in promoting drug resistance and metabolic changes, alongside the complex regulatory networks involved. This review article evaluates emerging treatments targeting metabolism, such as metabolic inhibitors, dietary management, and combination therapies, assessing their potential and challenges. It concludes with insights into the role of precision medicine and metabolic biomarkers in crafting personalized lung cancer treatments, advocating for metabolic targeting as a promising approach to enhance treatment efficacy and overcome drug resistance. This review underscores ongoing advancements and hurdles in integrating metabolic considerations into lung cancer therapy strategies.

Piceatannol Upregulates SIRT1 Expression in Skeletal Muscle Cells and in Human Whole Blood: In Vitro Assay and a Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Trial.

Piceatannol (PIC), a polyphenol abundant in passion fruit seeds, is reported to promote fat metabolism. This study investigated whether PIC affects sirtuin 1 (SIRT1) expression and metabolic factors in C2C12 skeletal muscle cells. C2C12 myotubes were stimulated with PIC, and alterations in gene expression, protein levels, mitochondrial DNA content, and fatty acid levels were assessed using real-time PCR, Western blotting, and Nile red staining. Furthermore, we examined changes in SIRT1 expression following the consumption of a test food containing 100 mg PIC for 2 weeks among adults with varying age and body mass index ranges. Both PIC and passion fruit seed extract induced SIRT1 expression in C2C12 myotubes to a greater extent than resveratrol. PIC also increased the expression of genes associated with mitochondrial biogenesis and fatty acid utilization, increased mitochondrial DNA content, and suppressed oleic acid-induced fat accumulation. Moreover, participants who consumed PIC exhibited significantly higher SIRT1 mRNA expression in whole blood compared to those in the placebo group. These findings suggest that PIC induces SIRT1 expression both in vitro and in the human body, which may promote mitochondrial biosynthesis and fat metabolism.

239 Variation in muscle protein synthesis in growing gilts is partially associated with insulin resistance and sensitivity

Abstract Pigs with similar body weight (BW), same genetic background and sex vary in protein deposition (PD) overgrowth. We aimed to study metabolic factors influencing PD in 65 kg BW gilts. Gilts were fed ad libitum a diet balanced to maximize PD. Dual X-rays were conducted to estimate body protein mass on d 1 and 21, allowing calculation of PD by difference. On d 23, the gilts were categorized into Low (157 g/d) and High (219 ± 9.97 g/d) PD groups. In each group, eight pigs underwent jugular vein cannulation. After a 48-h recovery period, where they were fed at 90% of the measured feed intake, they were fasted for 8 h. All pigs were then given a 300 g meal at time 0, and blood samples were collected at 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150, 178, and 178 min, to study insulin and glucose responses. At 180 min post-meal, a solution of L-13C valine was administered i.v. (18 ape – flooding dose), and liver, duodenum, and longissimus dorsi muscle samples were collected within 5 minutes of slaughter. The fractional synthesis rate (FSR, %/d), absolute synthesis rate (ASR, g/d), ribosomal capacity for protein synthesis (Cs), and the efficiency of protein synthesis (KRNA) based on total RNA concentration in skeletal muscle were calculated. The insulin resistance index (HOMA-B) and insulin sensitivity index (QUICKI) were also determined. The difference between Low and High PD gilts was compared using a F-test. The longissimus dorsi muscle exhibited a 31% greater (P = 0.01) FSR in High compared with Low PD group. No significant differences were observed in the FSR of the jejunum and liver. High PD gilts showed a 55% greater ASR in whole-body muscles (P = 0.003) and 42% greater ASR in the liver (P = 0.04) compared with Low PD gilts, with no difference for the ASR in the jejunum. The KRNA in the longissimus dorsi was 48% greater in High PD gilts (P = 0.01), with no differences in KRNA for the jejunum or liver. Cs did not differ between Low and High PD gilts. The QUICKI index tended to be greater in High PD gilts (P = 0.10). Spearman’s correlation revealed that longissimus dorsi FSR was negatively correlated with the HOMA-B index (r = -0.53; P = 0.04). Increases in the HOMA-B index tended to be associated with greater KRNA (r = -0.49; P = 0.06). These correlations highlight the complex interplay of metabolic and hormonal factors involved in the observed differences in protein synthesis and efficiency in growing gilts. Insulin resistance and sensitivity may play a role in influencing skeletal muscle PD variations.