Metabolic Effects Research Articles

Polysaccharides: The Sweet and Bitter Impacts on Cardiovascular Risk

Cardiovascular risk is a clinical factor that represents the probability of developing cardiovascular diseases (CVDs). This risk is shaped by non-modifiable and modifiable factors, including dietary patterns, which are the main lifestyle factor influencing CVD. Dietary polysaccharides, integral to nutrition, have varying effects on cardiovascular health depending on their type and source. They include starches, non-starch polysaccharides, and prebiotic fibers, categorized further into soluble and insoluble fibers. Soluble fibers, found in oats, legumes, and fruits, dissolve in water, forming gels that help lower serum cholesterol and modulate blood glucose levels. Insoluble fibers, present in whole grains and vegetables, aid in bowel regularity. The cardiovascular benefits of polysaccharides are linked to their ability to bind bile acids, reducing cholesterol levels, and the production of short-chain fatty acids by gut microbiota, which have anti-inflammatory properties. However, not all polysaccharides are beneficial; refined starches can lead to adverse metabolic effects, and chitosan to mixed effects on gut microbiota. This review examines the dualistic nature of polysaccharides, highlighting their beneficial roles in reducing cardiovascular risk factors and the potential adverse effects of specific types.

Leptin receptor neurons in the dorsomedial hypothalamus require distinct neuronal subsets for thermogenesis and weight loss.

The dorsomedial hypothalamus (DMH) receives inputs from the preoptic area (POA), where ambient temperature mediates physiological adaptations of energy expenditure and food intake. Warm-activated POA neurons suppress energy expenditure via brown adipose tissue (BAT) projecting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (dDMH/DHA). Our earlier work identified leptin receptor (Lepr)-expressing, BAT-projecting dDMH/DHA neurons that mediate metabolic leptin effects. Yet, the neurotransmitter (glutamate or GABA) used by dDMH/DHALepr neurons remains unexplored and was investigated in this study using mice. We report that dDMH/DHALepr neurons represent equally glutamatergic and GABAergic neurons. Surprisingly, chemogenetic activation of glutamatergic and/or GABAergic dDMH/DHA neurons were capable to increase energy expenditure and locomotion, but neither reproduced the beneficial metabolic effects observed after chemogenetic activation of dDMH/DHALepr neurons. We clarify that BAT-projecting dDMH/DHA neurons that innervate the raphe pallidus (RPa) are exclusively glutamatergic Lepr neurons. In contrast, projections of GABAergic or dDMH/DHALepr neurons overlapped in the ventromedial arcuate nucleus (vmARC), suggesting distinct energy expenditure pathways. Brain slice patch clamp recordings further demonstrate a considerable proportion of leptin-inhibited dDMH/DHALepr neurons, while removal of pre-synaptic (indirect) effects with synaptic blocker increased the proportion of leptin-activated dDMH/DHALepr neurons, suggesting that pre-synaptic Lepr neurons inhibit dDMH/DHALepr neurons. We conclude that stimulation of BAT-related, GABA- and glutamatergic dDMH/DHALepr neurons in combination mediate the beneficial metabolic effects. Our data support the idea that dDMH/DHALepr neurons integrate upstream Lepr neurons (e.g., originating from POA and ARC). We speculate that these neurons manage dynamic adaptations to a variety of environmental changes including ambient temperature and energy state. SIGNIFICANCE STATEMENT: Our earlier work identified leptin receptor expressing neurons in the dDMH/DHA as an important thermoregulatory site. Dorsomedial hypothalamus (DMH) Lepr neurons participate in processing and integration of environmental exteroceptive signals like ambient temperature and circadian rhythm, as well as interoceptive signals including leptin and the gut hormone glucagon-like-peptide-1 (GLP1). The present work further characterizes dDMH/DHALepr neurons as a mixed glutamatergic and GABAergic population, but with distinct axonal projection sites. Surprisingly, select activation of glutamatergic and/or GABAergic populations are all able to increase energy expenditure, but are unable to replicate the beneficial metabolic effects observed by Lepr activation. These findings highlighting dDMH/DHA Lepr neurons as a distinct subgroup of glutamatergic and GABAergic neurons that are under indirect and direct influence of the interoceptive hormone leptin and if stimulated are uniquely capable to mediate beneficial metabolic effects. Our work significantly expands our knowledge of thermoregulatory circuits and puts a spotlight onto DMH-Lepr neurons for the integration into whole body energy and body weight homeostasis.

Lock-in effect of infrastructures metabolism in China's residential centralized heating: View from consumption and production end

Lock-in effect of infrastructures metabolism in China's residential centralized heating: View from consumption and production end

Konjac glucomannan and κ-carrageenan improve hepatic fatty acid metabolism and colonic microbiota in suckling piglet.

Konjac glucomannan (KGM) and κ-carrageenan are polysaccharides that have garnered attention for their potential health benefits. This study aimed to evaluate the maternal supplementation of KGM and κ-carrageenan (SF) during later gestation and lactation on the effect of hepatic lipid metabolism and colonic microflora in offspring. Regarding antioxidant and inflammatory factors in the suckling piglet liver, our results showed that nuclear factor erythroid 2-related factor 2 (Nrf2) and interleukin (IL)-10 levels were significantly increased in the SF group (P<0.05). In liver mitochondrial function, the mRNA levels of voltage-dependent anion channel 1 (VDAC1), fission 1 (Fis1), and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) were significantly up-regulated in the SF group compared to the control (Con) group (P<0.05). The mRNA level of peroxisome proliferator-activated receptor alpha (PPARα) was remarkably down-regulated in the SF group (P<0.05). In the colonic microflora of suckling piglets, we found that the SF group increased the abundance of Megasphaera and reduced the abundance of Erysipelotrichaceae_unclassified. The occludin level was significantly increased in the SF group than in the Con group (P<0.05). In summary, maternal supplementation with SF improves hepatic lipid metabolism and colonic microflora in suckling piglets.

Cuproptosis and copper as potential mechanisms and intervention targets in Alzheimer's disease.

Recently study has found a new form of copper-dependent death called cuproptosis, which differs from apoptosis, ferroptosis, and necrosis. The main process of cuproptosis is copper directly combined with lipid-acetylated proteins in the TCA cycle of mitochondrial response, leading to the aggregation of lipid-acetylated proteins and the loss of Fe-S cluster proteins, resulting in mitochondrial dysfunction, and eventually causing cell death. Previous studies demonstrated that an imbalance in copper homeostasis exacerbates the pathological progression of Alzheimer's disease (AD) through the induction of oxidative stress, inflammatory response, and the accumulation of Aβ deposition and tau protein hyperphosphorylation. However, the underlying mechanisms remains to be elucidated. More importantly, research identifies the role of cuproptosis and further elucidates the underlying molecular mechanisms in AD. This review summarized the effects of copper metabolism on AD pathology, the characteristics and mechanism of cuproptosis and we discuss the significance of cuproptosis in the pathogenesis of AD.

Maternal ingestion of cannabidiol (CBD) in mice leads to sex-dependent changes in memory, anxiety, and metabolism in the adult offspring, and causes a decrease in survival to weaning age

RationaleThe consequences of perinatal cannabidiol (CBD) exposure are severely understudied, but are important, given its widespread use and believed safety as a natural supplement. ObjectiveThe objective of this study was to test the health, metabolic, and behavioral consequences of perinatal CBD exposure on dams and their offspring raised to adult. MethodsPrimiparous female C57BL/6 J mice were orally administered 100 mg/kg CBD in strawberry jam to expose offspring during gestation, lactation, or both using a cross-fostering design. Adult offspring were metabolically profiled using indirect calorimetry and intraperitoneal glucose tolerance testing. Adults were behaviorally phenotyped, video recorded, and mouse position tracked using DeepLabCut. ResultsCBD was detected in maternal plasma using LC-MS 10-min post consumption (34.2 ± 1.7 ng/ul) and peaked within 30 min (371.0 ± 34.0 ng/ul). Fetal exposure to CBD significantly decreased survival of the pups, and decreased male postnatal development, but did not alter litter size, maternal body weight or pup birth weight. We observed many sex-dependent effects of perinatal CBD exposure. Exposure to CBD during gestation and lactation increased meal size, caloric intake, and respiratory exchange ratio for adult male offspring, while exposure during lactation decreased fasting glucose, but had no effect on clearance. Adult female offspring exposed to CBD during lactation showed increased drink size. Perinatal CBD exposure increased obsessive compulsive- and decreased anxiety-like behaviors (marble burying, light-dark box, elevated-plus maze) in female mice, decreased long-term object memory in male mice, and had no effect on attention tasks for either sex. ConclusionsWe conclude that orally-administered CBD during pregnancy affects behavior and metabolism in a sex-dependent manner, and mice are differentially sensitive to exposure during gestation vs. lactation, or both. Because long-term changes are observed following perinatal exposure to the drug, and exposure significantly decreases survival to weaning, more research during development is warranted.

Dawn-to-dusk intermittent fasting is associated with overexpression of autophagy genes: A prospective study on overweight and obese cohort

Aim and BackgroundA growing body of evidence supports the impact of intermittent fasting (IF) on longevity and healthy aging via the modulation of autophagy genes. The activation of the catabolic autophagic machinery (LAMP2, LC3B, ATG5, and ATG4D) has protective effects against degenerative aging and chronic diseases. This research examined the changes in the expression of the aforementioned genes upon the observance of dawn-to-dusk IF among metabolically healthy participants with overweight and obesity. MethodsFifty-one (51) participants (36 males and 15 females, 38.84 ± 11.73 years) with overweight and obesity (BMI = 29.75 ± 5.04 kg/m2) were recruited and monitored before and at the end of the commencement of the four-week IF. Six healthy subjects with normal BMI (21.4±2.20 kg/m2) were recruited only to standardize the reference for normal levels of gene expressions. At the two time points, anthropometric, biochemical, and dietary assessments were performed, and LAMP2, LC3B, ATG5, and ATG4D gene expressions were assessed using qRT-PCR on RNA extracted from whole blood samples. ResultsAt the end of IF, and compared to the pre-fasting levels, the relative gene expressions among participants with overweight/obesity were significantly increased for the three autophagy genes LAMP2, LC3B, and ATG5, with increments of about 4.2 folds, 1.9-fold, and 1.4-fold, respectively. In contrast, the increase in the ATG4D gene was not significant. Concomitantly, significant decreases were found in body weight, BMI, fat mass, body fat percent, hip and waist circumferences, LDL, IL-6, and TNF-a (P <0.05), While HDL, IL-10, and CD163 significantly increased (P <0.05). Binary logistic regression analysis for genetic expressions showed no significant association between high-energy intake, waist circumference, or obesity and the four gene expressions. ConclusionsFour consecutive weeks of dawn-to-dusk IF of Ramadan is associated with the upregulation of autophagy gene expressions in participants with overweight/obesity, and this may explain, at least in part, its favorable short-term temporal metabolic and health-improving effects on early aging-related markers. Hence, IF presumably may entail a protective impact against early markers of aging and metabolic diseases in participants with overweight/obesity.

Crystallization induced by fungi and bacteria.

Crystallization induced by lithobiont microbial communities (fungi, bacteria, lichens) has received great attention in science and beyond. The studies discussed here focus on the mechanisms and factors of microbial biomineralization. The multilevel modelling approach, which made it possible to solve this interdisciplinary problem, is highlighted. The effect of chemical composition of biofilms, including acidity of the medium and cation oxidation degree, on oxalate formation is discussed. The variants of interaction between biofilm components and growing oxalate crystals are addressed. Particular attention is paid to the effect of metabolism of fungi, bacteria and their associations on carbonate and oxalate crystallization under various trophic conditions and the transitions between them. The possibility of applying the identified patterns to reveal the role of fungi and bacteria in the oxalate-carbonate pathway and in biotechnologies is considered.

Abstract TMP113: Sex differences in the effects of social isolation on behavioral and metabolic parameters in a model of cerebral amyloid angiopathy

Introduction: The prevalence of social isolation (SI) increases with aging and contributes to poor health outcomes and increased risk of cognitive impairment, especially in Aβ-related diseases. Cerebral amyloid angiopathy (CAA) is characterized by amyloid β (Aβ) deposition in the cortical and leptomeningeal vessels, and is a leading cause of hemorrhagic stroke and age-related cognitive impairment. How social isolation affects vascular amyloid deposition, cognitive decline and social behavior in CAA is unknown. Methods: TgSwDI mice carrying Swedish, Dutch, and Iowa mutations of human amyloid precursor protein were used as a CAA model. Male and female C57BL/6 wildtype (WT) and CAA mice were randomly assigned to pair housing (PH) or SI at 3 months of age. Affective and social behaviors were assessed at baseline and every 3 months thereafter using the tail suspension test (TST) and three-chamber social interaction test. At 9 months post-SI, cognitive behaviors and general well-being were measured using fear conditioning (FC) and the nesting test, respectively. Body weights were recorded, and white adipocyte size was measured using immunostaining. Results: SI led to increased immobility in the TST at 3- and 6-months post-SI in both male and female WT and CAA mice, suggesting depressive-like behavior (n=5-8/grp, p&lt;0.05). Isolated CAA mice displayed greater cognitive deficits in FC, while only male WT SI mice showed impaired cognition (n=5-12/grp, p&lt;0.005). Sex differences in social behavior were observed in isolated CAA mice. Specifically, at 6 months post-SI, female CAA mice displayed deficits in sociability and social novelty (n=4-9/grp, p&lt;0.05), which was not seen in male CAA mice. SI negatively impacts the general well-being in both male WT and CAA SI animals (n=5-12/grp, p&lt;0.005). Preliminary findings showed increased white adipocyte size in male WT SI mice with a similar trend in male CAA SI animals, pointing to potential metabolic effects of isolation. Conclusion: SI induced cognitive decline in both male and female CAA mice. Behavioral differences between sexes were noted in CAA mice including nesting ability, sociability, and depressive-like behaviors. Further research is needed to determine the cellular and molecular mechanism underlying SI-induced metabolic changes in CAA.

The Role of Lifestyle in the Prevention and Treatment of Insulin Resistance: A Review of Clinical and Intervention Studies

Introduction Insulin resistance (IR) is a metabolic disorder characterized by reduced tissue sensitivity to insulin, resulting in impaired glucose homeostasis. IR plays a pivotal role in the development of type 2 diabetes, metabolic syndrome, and associated cardiovascular complications. Effective strategies for the prevention and treatment of IR focus on lifestyle modification, including physical activity and stress management. Aim of the Study The aim of this study is to evaluate the role of lifestyle factors in the prevention and treatment of insulin resistance (IR) based on the analysis of clinical and interventional studies, with a particular focus on dietary interventions, physical activity programs, stress reduction techniques, and sleep quality improvement recommendations. Materials and Methods A review of clinical and interventional studies was conducted using databases such as PubMed. The analysis included studies evaluating the impact of specific lifestyle interventions on markers of insulin resistance (IR), such as fasting insulin levels, HOMA-IR indices and glucose tolerance. Particular attention was paid to randomized controlled trials (RCTs) and meta-analyses published between 2020 and 2024. Summary Studies have shown that diets such as the Mediterranean and DASH, combined with regular aerobic and resistance exercises, significantly improve insulin sensitivity. Additionally, stress-reduction techniques like mindfulness and yoga, along with adequate sleep quality, enhance positive metabolic effects. These findings highlight the need for a multifaceted approach to treating insulin resistance, incorporating dietary and behavioral changes. The review also points out research gaps and emphasizes the necessity of long-term studies to refine lifestyle recommendations for diverse populations

IRS2 as a driver of brain metastasis in colorectal cancer: a potential target for novel therapeutic strategies.

Colorectal cancer (CRC) ranks as the fourth most common cause of brain metastasis (BM), with its incidence on the rise. However, the molecular mechanisms driving the formation of these lesions from CRC remain unclear. We analyzed the FoundationOne genomic database, which includes over 35,000 CRC samples from both local and metastatic sites. The role of insulin receptor substrate 2 (IRS2) in CRC brain tropism was investigated using various in vitro (co-culture systems and 3D sphere formation assays), in vivo (intracranial and subcutaneous mouse models), and ex vivo (CRC Patient-Derived Explants (PDE)) models. The molecular and metabolic effects of IRS2 were examined through RNA sequencing and Seahorse analysis. The therapeutic potential of a combined treatment with NT219, an IRS2 inhibitor, and 5-fluorouracil (5-FU) was assessed using our CRC BM mouse model. Our research reveals a distinctive genomic profile of CRC BM and highlights the role of IRS2 in promoting CRC BM. IRS2 mediates its effect by modulating the β-catenin and oxidative phosphorylation (OXPHOS) pathways. We developed a mouse model of BM from CRC and demonstrated that treatment with the IRS2 inhibitor NT219, in combination with 5-FU, significantly suppresses BM development and prolongs survival. Our work underscores the unique role of IRS2 in facilitating CRC brain adaptation and suggests a novel therapeutic strategy for CRC patients with BM.

MC16 promotes mitochondrial biogenesis and ameliorates acute and diabetic nephropathy.

Kidney disease (KD) is a leading cause of mortality worldwide, affecting 〉10% of the global population. Two of the most common causes of KD are diabetes and acute kidney injury (AKI), both of which induce mitochondrial dysfunction resulting in renal proximal tubular damage/necrosis. Thus, pharmacological induction of mitochondrial biogenesis (MB) may provide a therapeutic strategy to block the onset/progression of KD. Here, we evaluated the pharmacological and potential therapeutic effects of a novel MB-inducing oxindole agent, MC16. Primary cultures of rabbit renal proximal tubule cells (RPTCs) were used to evaluate the cellular signalling and MB-inducing effects of MC16. Mice were used to determine the MB-inducing effects of MC16 in vivo, and the metabolic effects of MC16 on the renal cortical metabolome. Mouse models of AKI and diabetic kidney disease (DKD) were used to demonstrate the therapeutic potential of MC16 to ameliorate acute and diabetic nephropathy. MC16 activated the PI3K-AKT-eNOS-FOXO1 axis and induced MB in RPTCs. MC16 induced MB and altered the renal cortical metabolome of mice. MC16 accelerated renal recovery, reduced vascular permeability, and diminished mitochondrial dysfunction following AKI. MC16 decreased diabetes-induced renal swelling, improved renal and mitochondrial function, and diminished interstitial fibrosis in DKD mouse models. MC16 is a novel compound that induces MB and ameliorates acute and diabetic nephropathy in mice. This study underscores that targeting MB following the onset of renal/metabolic insults may provide a therapeutic strategy to mitigate the onset and/or progression of KD.

The Effect of Flavonoids and Topiramate on Glucose Carbon Metabolism in a HepG2 Steatosis Cell Culture Model: A Stable Isotope Study

Background: Insufficient treatment options are available for metabolic dysfunction-associated steatotic liver disease (MASLD). Flavonoids and topiramate have been studied for weight loss but need investigation into their effects on liver metabolism. This study’s aim was to examine the effects of flavonoids or topiramate on glucose metabolic carbon flux in a cell culture model of steatosis. Methods: Steatosis was induced in HepG2 cells through exposure to oleic acid (OA, 0.5 mml/L) conjugated to bovine serum albumin (2:1). Additionally, 50% U13C-glucose was supplied in the medium as a stable isotope tracer. Cells were treated with DMSO, 10 μM of naringenin, morin, silibinin, or topiramate (44 μM) for 72 h. A non-steatotic, untreated HepG2 cell control was included. Cell extracts were analyzed by gas chromatography/mass spectrometry and mass isotopomer distribution analysis for glycogen synthesis, de novo fatty acid synthesis, tricarboxylic acid (TCA) cycle activity, and ribose synthesis. Groups were compared by ANOVA with Tukey’s pair-wise testing. Results: Compared to untreated HepG2 controls, OA-exposed steatotic cells exhibited increased lipid accumulation by ORO staining (1.6-fold), enhanced palmitate de novo synthesis, reduced pyruvate carboxylase/pyruvate dehydrogenase (PC/PDH) ratio, and reduced ribose synthesis. Treatment with topiramate or silibinin ameliorated the lipid accumulation (1.3-fold) and mitigated enhancement of de novo synthesis. Morin-treated cells exhibited enhanced de novo synthesis but suppressed ribose synthesis. Conclusions: Potential mechanisms of reduced lipid accumulation by topiramate and silibinin may include suppression of palmitate de novo synthesis and a relative decrease in carbon flux through the PDH pathway. Further studies are needed on potential utility in MASLD based on their specific metabolic effects.

Olaparib-induced hyperglycemia in ovarian cancer patients - a case series analysis of a three-month therapy with a consideration of BMI.

Olaparib is a relatively new poly(ADP-ribose) polymerase inhibitor (PARPi) administered to ovarian cancer (OC) patients with a complete or partial response to first-line chemotherapy. One of the metabolic side effects of olaparib is the disruption of glucose homeostasis, often resulting in hyperglycemia The study was a retrospective analysis of olaparib-induced hyperglycemia in OC patients with initial normoglycemia following the first, second, and third month of olaparib treatment METHODS: The study involved 32 OC patients, classified into three groups according to their Body Mass Index (BMI): normal BMI (BMI 18.5-24.9kg/m2; n = 13), overweight (BMI 25-29.9kg/m2; n = 13), and obese (BMI ≥ 30kg/m2; n = 6). The fasting glucose (FG) concentration was evaluated after the first, second, and third cycle of olaparib treatment (a cycle is the equivalent of 28 days of treatment). The severity of the observed hyperglycemia was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A significant increase in glycemia was observed after the first and second cycles of olaparib treatment in the group with normal BMI and after the third cycle in overweight and obese patients. There were no significant differences in glucose levels among the groups following the first, the second, and the third cycle. Grade 1 hyperglycemia with impaired fasting glucose levels (5.6-6.9mmol/l) was found in 15 patients (normal BMI: n = 4, overweight: n = 9, and obesity: n = 2), while glycemia typical of diabetes (≥ 7.0mmol/l) was observed in one obese patient. Regardless of the weight of OC patients, it is essential to control glycemia during olaparib treatment.

Metabolic effects of heterocyclic amines on insulin‑induced AKT phosphorylation and gluconeogenic gene expression are modified by N-acetyltransferase 2 genetic polymorphism.

Heterocyclic amines (HCAs) are mutagens and carcinogens primarily generated when cooking meat at high temperatures or until well-done, and their major metabolic pathway includes hepatic N-hydroxylation via CYP1A2 followed by O-acetylation via N-acetyltransferase 2 (NAT2). NAT2 expresses a well-defined genetic polymorphism in humans resulting in rapid and slow acetylators. Recent epidemiological studies reported significant associations between dietary HCA exposure and insulin resistance and type II diabetes. We assessed the effect of some of the most common HCAs found in cooked meat, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, on insulin signaling and gluconeogenic gene expression in cryopreserved human hepatocytes characterized by their NAT2 genotype and phenotype to investigate the role of NAT2 genetic polymorphism in HCA-induced metabolic dysregulation. HCA treatment significantly reduced insulin-induced protein kinase B phosphorylation and significantly increased expression of genes involved in gluconeogenesis (G6PC, PCK1, FOXO1, and PPARA) in cryopreserved human hepatocytes from rapid but not from slow acetylators. The findings suggest that NAT2 genetic polymorphism modifies HCA-induced insulin resistance and gluconeogenic gene expression, implying that individuals with rapid acetylator phenotype may be at greater risk of dysregulated glucose homeostasis following exposure to HCAs.

Impact of obesity when associated with gestational diabetes on fetus heart

Abstract Background Obesity increases the metabolic effect of diabetes, which has a teratogenic impact on the fetus, including the heart. The aim of this study was to investigate the impact of obesity, when associated with gestational diabetes mellitus (GDM), on fetus’s heart systolic function using conventional fetal echocardiography and speckle-tracking technique. Methods This was a prospective mono-centric study. Standard fetal echocardiography and speckle-tracking technique were performed in 43 fetuses of mothers with GDM. Two groups were later compared: fetuses of non-obese women with GDM(G1)(n=25) and those of obese women with GDM(G2)(n=18). Results There was no significant difference between the two groups regarding mitral and tricuspid annular plane systolic excursion MAPSE(p=0,757) and TAPSE(p=0,554) or left ventricular ejection fraction(p=0,138). On the other hand, fetuses of women with GDM had a lower left ventricle global longitudinal strain (LV-GLS) (p=0,014; G1:-20,03 ± 0,94%, G2: -19,42 ± 1,08% ) Conclusion Our study suggests that the association of obesity and GDM may increase fetus’s systolic function impairment demonstrated by using speckle-tracking technique.

Allosteric regulation of pyruvate kinase enables efficient and robust gluconeogenesis by preventing metabolic conflicts and carbon overflow.

Gluconeogenesis, the reciprocal pathway of glycolysis, is an energy-consuming process that generates glycolytic intermediates from non-carbohydrate sources. In this study, we demonstrate that robust and efficient gluconeogenesis in bacteria relies on the allosteric inactivation of pyruvate kinase, the enzyme responsible for the irreversible final step of glycolysis. Using the model bacterium Bacillus subtilis as an example, we discovered that pyruvate kinase activity is inhibited during gluconeogenesis via its extra C-terminal domain (ECTD), which is essential for autoinhibition and metabolic regulation. Physiologically, a B. subtilis mutant lacking the ECTD in pyruvate kinase displayed multiple defects under gluconeogenic conditions, including inefficient carbon utilization, slower growth, and decreased resistance to the herbicide glyphosate. These defects were not caused by the phosphoenolpyruvate-pyruvate-oxaloacetate futile cycle. Instead, we identified two major metabolic consequences of pyruvate kinase dysregulation during gluconeogenesis: failure to establish high phosphoenolpyruvate (PEP) concentrations necessary for robust gluconeogenesis and increased carbon overflow into the medium. In silico analysis revealed that, in wild-type cells, an expanded PEP pool enabled by pyruvate kinase inactivation is critical for maintaining the thermodynamic feasibility of gluconeogenesis. Additionally, we discovered that B. subtilis exhibits glyphosate resistance specifically under gluconeogenic conditions, and this resistance depends on the PEP pool expansion resulting from pyruvate kinase inactivation. Our findings underscore the importance of allosteric regulation during gluconeogenesis in coordinating metabolic flux, efficient carbon utilization, and antimicrobial resistance.IMPORTANCEPyruvate kinase catalyzes the final irreversible step in glycolysis and is commonly thought to play a critical role in regulating this pathway. In this study, we identified a constitutively active variant of pyruvate kinase, which did not impact glycolysis but instead led to multiple metabolic defects during gluconeogenesis. Contrary to conventional understanding, these defects were not due to the phosphoenolpyruvate-pyruvate-oxaloacetate futile cycle. Our findings suggest that the defects arose from an insufficient buildup of the phosphoenolpyruvate pool and an increase in carbon overflow metabolism. Overall, this study demonstrates the essential role of pyruvate kinase allosteric regulation during gluconeogenesis in maintaining adequate phosphoenolpyruvate levels, which helps prevent overflow metabolism and enhances the thermodynamic favorability of the pathway. This study also provides a novel link between glyphosate resistance and gluconeogenesis.

Estradiol metabolism by gut microbiota in women’s depression pathogenesis: inspiration from nature

The recurrence and treatment resistance of depression remain significant issues, primarily due to an inadequate understanding of its pathogenesis. Recent scientific evidence indicates that gut microbiota influence estradiol metabolism and are associated with the development of depression in nonpremenopausal women. Integrating existing studies on the regulation of estradiol metabolism by microorganisms in nature and the relevance of its degradation products to depression, recent scientific explorations have further elucidated the key mechanisms by which gut microbiota catabolize estradiol through specific metabolic pathways. These emerging scientific findings suggest that the unique metabolic effects of gut microbiota on estradiol may be one of the central drivers in the onset and course of depression in non-menopausal women.

Nanoparticles: a promising tool against environmental stress in plants

With a focus on plant tolerance to environmental challenges, nanotechnology has emerged as a potent instrument for assisting crops and boosting agricultural production in the face of a growing worldwide population. Nanoparticles (NPs) and plant systems may interact molecularly to change stress response, growth, and development. NPs may feed nutrients to plants, prevent plant diseases and pathogens, and detect and monitor trace components in soil by absorbing their signals. More excellent knowledge of the processes of NPs that help plants survive various stressors would aid in creating more long-term strategies to combat these challenges. Despite the many studies on NPs’ use in agriculture, we reviewed the various types of NPs and their anticipated molecular and metabolic effects upon entering plant cells. In addition, we discussed different applications of NPs against all environmental stresses. Lastly, we introduced agricultural NPs’ risks, difficulties, and prospects.

Advancements in Managing Schizophrenia through Classical Approaches, Mechanisms, and Deep Brain Stimulation.

Schizophrenia is a heterogeneous neuropsychological disorder characterized by three distinct sets of symptoms: positive, negative, and cognitive. It carries significant public health implications and is estimated to affect up to 1% of the population. Despite extensive research, the underlying mechanisms of schizophrenia are not entirely understood, and existing antipsychotic treatments have notable limitations. Firstly, these treatments are effective for only approximately half of the patients. Secondly, they primarily alleviate positive symptoms such as misperceptions and thought disorders, which are core to the illness, while neglecting the negative symptoms like flat affect and social withdrawal, as well as cognitive symptoms such as learning and attention difficulties. Thirdly, these treatments come with significant neurofunctional and metabolic side effects, and in some cases, they can lead to issues like sexual dysfunction or agranulocytosis (in the case of Clozapine (CLZ)). In this review, we delve into currently available treatments for schizophrenia, with the utilization of Deep brain stimulation techniques to overcome the limitations of antipsychotics. We also discuss the major clinical trials for schizophrenia along with deep brain stimulation intervention.