Metabolic Dysregulation Research Articles

Physiology of malate dehydrogenase and how dysregulation leads to disease.

Malate dehydrogenase (MDH) is pivotal in mammalian tissue metabolism, participating in various pathways beyond its classical roles and highlighting its adaptability to cellular demands. This enzyme is involved in maintaining redox balance, lipid synthesis, and glutamine metabolism and supports rapidly proliferating cells' energetic and biosynthetic needs. The involvement of MDH in glutamine metabolism underlines its significance in cell physiology. In contrast, its contribution to lipid metabolism highlights its role in essential biosynthetic processes necessary for cell maintenance and proliferation. The enzyme's regulatory mechanisms, such as post-translational modifications, underscore its complexity and importance in metabolic regulation, positioning MDH as a potential target in metabolic dysregulation. Furthermore, the association of MDH with various pathologies, including cancer and neurological disorders, suggests its involvement in disease progression. The overexpression of MDH isoforms MDH1 and MDH2 in cancers like breast, prostate, and pancreatic ductal adenocarcinoma, alongside structural modifications, implies their critical role in the metabolic adaptation of tumor cells. Additionally, mutations in MDH2 linked to pheochromocytomas, paragangliomas, and other metabolic diseases emphasize MDH's role in metabolic homeostasis. This review spotlights MDH's potential as a biomarker and therapeutic target, advocating for further research into its multifunctional roles and regulatory mechanisms in health and disease.

Hepatic retinol dehydrogenase 11 dampens stress associated with the maintenance of cellular cholesterol levels

ObjectiveDysregulation of hepatic cholesterol metabolism can contribute to elevated circulating cholesterol levels, which is a significant risk factor for cardiovascular disease. Cholesterol homeostasis in mammalian cells is tightly regulated by an integrated network of transcriptional and post-transcriptional signalling pathways. Whilst prior studies have identified many of the central regulators of these pathways, the extended supporting networks remain to be fully elucidated. MethodsHere, we leveraged an integrated discovery platform, combining multi-omics data from 107 strains of mice to investigate these supporting networks. We identified retinol dehydrogenase 11 (RDH11; also known as SCALD) as a novel protein associated with cholesterol metabolism. Prior studies have suggested that RDH11 may be regulated by alterations in cellular cholesterol status, but its specific roles in this pathway are mostly unknown. ResultsHere, we show that mice fed a Western diet (high fat, high cholesterol) exhibited a significant reduction in hepatic Rdh11 mRNA expression. Conversely, mice treated with a statin (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitor) exhibited a 2-fold increase in hepatic Rdh11 mRNA expression. Studies in human and mouse hepatocytes demonstrated that RDH11 expression was regulated by altered cellular cholesterol conditions in a manner consistent with SREBP2 target genes HMGCR and LDLR. Modulation of RDH11 in vitro and in vivo demonstrated modulation of pathways associated with cholesterol metabolism, inflammation and cellular stress. Finally, RDH11 silencing in mouse liver was associated with a reduction in hepatic cardiolipin abundance and a concomitant reduction in the abundance of proteins of the mitochondrial electron transport chain. ConclusionTaken together, these findings suggest that RDH11 likely plays a role in protecting cells against the cellular toxicity that can arise as a by-product of endogenous cellular cholesterol synthesis.

Oxylipin dynamics in dairy cows during clinical ketosis and after treatment with niacin and flunixin meglumine

Dairy cows with clinical ketosis (CK) exhibit metabolic changes, including intense adipose tissue (AT) lipolysis and systemic insulin resistance that increase plasma BHB and free fatty acids (FFA). Cows with CK also have systemic inflammation, predisposing them to inflammatory and infectious diseases. This inflammatory process is modulated in part by oxidized fatty acids (oxylipins) that regulate all aspects of inflammation. Oxylipin profiles have been characterized in healthy periparturient cows, but their dynamics during CK are unknown. CK is an acute metabolic disease requiring clinical therapy, commonly including propylene glycol (PG) as a gluconeogenic agent. Recently, we showed that including lipolysis inhibitors such as niacin (NIA) and flunixin meglumine (FM) improved CK recovery. These drugs may modulate oxylipin biosynthesis by regulating the release of PUFA (oxylipin substrates) and cyclooxygenase activity. However, their impact on oxylipin profiles in cows with CK is unknown. The objective of this study was to determine the dynamics of specific linoleic and arachidonic acid-derived oxylipins during CK and following therapy with PG, NIA, and FM. Multiparous Jersey cows (n = 72; 7.1 DIM) with CK from a commercial dairy were sampled. Inclusion criteria were CK symptoms (lethargy, depressed appetite, and reduced rumen fill) and blood BHB ≥ 1.2 mmol/L. CK cows (n = 24/treatment) were randomly assigned to one of the 3 treatments: 1) PG:310 g orally once daily for 5 d, 2) PG+NIA:24 g orally once daily for 3 d, 3) PG+NIA+FM:1.1 mg/kg IV once daily for 3 d. Healthy cows (HC; n = 24) matched by lactation and DIM (±2 d) were also included. Plasma oxylipins were quantified at enrollment and 7d (d7) later using HPLC-MS/MS. At enrollment, CK had higher concentrations of arachidonic acid (AA) derived 5- and 20-HETE, 8,9-, 11,12-, and 14–15-DHET, and lower concentrations of linoleic acid (LA) derived 12,13-EpOME, 13-oxoODE 9,10- and 12,13-DiHOME. Integrated analysis of biological pathways and oxylipin profiles using Ingenuity Pathway Analysis (IPA) revealed AA metabolism as the top pathway activated during CK. By d7, treatment with PGNIAFM restored plasma PUFAs and oxylipins to profiles similar to HC. IPA analysis showed that PGNIAFM activated the zinc transporter SLC30A7, associated with reduced activation of the AA pathway. Results indicate that higher FA availability during CK, driven in part by dysregulated lipolysis, increases the pool of substrates for oxylipin biosynthesis. These oxylipins may play a role in both metabolic dysregulation and restoring homeostasis during CK. Inhibiting lipolysis and cyclooxygenase activity with NIA and FM can alter AA and LA-derived oxylipins biosynthesis. These findings underscore the potential use of lipolysis inhibitors NIA and FM in CK therapeutics and highlight the importance of understanding oxylipin pathways in the pathogenesis of CK.

Quantifying acyl-chain diversity in isobaric compound lipids containing monomethyl branched-chain fatty acids

Compound lipids comprise a diverse group of metabolites present in living systems, and metabolic- and environmentally-driven structural distinctions across this family is increasingly linked to biological function. However, methods for deconvoluting these often isobaric lipid species are lacking or require specialized instrumentation. Notably, acyl-chain diversity within cells may be influenced by nutritional states, metabolic dysregulation, or genetic alterations. Therefore, a reliable, validated method of quantifying structurally similar even-, odd-, and branched-chain acyl groups within intact compound lipids will be invaluable for gaining molecular insights into their biological functions. Here we demonstrate the chromatographic resolution of isobaric lipids containing distinct combinations of straight-chain and branched-chain acyl groups via ultra-high-pressure liquid chromatography (UHPLC)-mass spectrometry (MS) using a C30 liquid chromatography column. Using metabolically-engineered adipocytes lacking branched-keto acid dehydrogenase A (Bckdha), we validate this approach through a combination of fatty acid supplementation and metabolic tracing using monomethyl branched-chain fatty acids and valine. We observe resolution of numerous isobaric triacylglycerols and other compound lipids, demonstrating the resolving utility of this method. This approach adds to the toolbox for laboratories to quantify and characterize acyl chain diversity across the lipidome.

Dietary Lysine Supplementation Causes Metabolic Dysregulation and Kidney Cyst Growth in Mice with Polycystic Kidney Disease

Dietary Lysine Supplementation Causes Metabolic Dysregulation and Kidney Cyst Growth in Mice with Polycystic Kidney Disease

Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism

Pulmonary fibrosis is a chronic interstitial lung disease involving systemic inflammation and abnormal collagen deposition. Dysregulations in lipid metabolism, such as macrophage-dependent lipid catabolism, have been recognized as critical factors for the development of pulmonary fibrosis. However, little is known about the signaling pathways involved and the key regulators. Here we found that triggering receptor expressed on myeloid cells 2 (TREM2) plays a pivotal role in regulating the lipid handling capacities of pulmonary macrophages and triggering fibrosis. By integrating analysis of single-cell and bulk RNA sequencing data from patients and mice with pulmonary fibrosis, we revealed that pulmonary macrophages consist of heterogeneous populations with distinct pro-fibrotic properties, and found that both sphingolipid metabolism and the expression of chemotaxis-related genes are elevated in fibrotic lungs. TREM2, a sensor recognizing multiple lipid species, is specifically upregulated in a subset of monocyte-derived macrophages. Blockade of TREM2 by conventional/conditional knock-out or soluble TREM2 administration can attenuate bleomycin-induced pulmonary fibrosis. By utilizing scRNA Seq and lipidomics, we found that Trem2 deficiency downregulates the synthesis of various sphingomyelins, and inhibits the expression of chemokines such as Ccl2. Together, our findings not only reveal the alterations in lipidomic profiles and the atlas of pulmonary macrophages during pulmonary fibrosis, but also suggest that targeting TREM2, the crucial regulator affecting both pulmonary sphingolipid metabolism and the chemokines secretion, can benefit pulmonary fibrosis patients in the future.

Untargeted metabolomics combined with pseudotargeted lipidomics revealed the metabolite profiles of blood-stasis syndrome in type 2 diabetes mellitus

ObjectiveBlood-stasis syndrome (BSS), an important syndrome in Type 2 diabetes mellitus(T2DM), is associated with the pathophysiological mechanisms underlying diabetic vascular complications. However, BSS has not been fully characterized as of yet. Due to the strong correlation between BSS and vasculopathy, we hypothesized that the metabolic characteristics of BSS in T2DM (T2DM BSS) are highly specific. By combining untargeted metabolomics and pseudotargeted lipidomics approaches, this study aimed to comprehensively elucidate the metabolic traits of T2DM BSS, thereby providing novel insights into the vascular complications of diabetes and establishing a foundation for precision medicine. MethodsThe survey was conducted in Haidian District of Beijing from October 2021 to November 2021, and data collection was completed in January 2022. Liquid chromatography-mass spectrometry (LC-MS) based untargeted metabolomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS) based pseudotargeted lipidomics were performed to detect metabolites and lipids. Multivariate, univariate, and pathway analyses were utilized to investigate metabolic changes. The unique metabolites of BSS were obtained by inter-group comparisons and screening. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic accuracy of metabolites. ResultsA total of 1189 participants completed the survey, of which 120 participants were recruited in this study and further divided into a discovery cohort (n = 90) and a validation cohort (n = 30). Among these, 21 participants were selected for psuedotargeted lipidomics analysis. 81 metabolites, mainly involving glycerophospholipids, were identified as unique metabolites of T2DM BSS, while fatty acyls (FAs) were identified as unique lipids. T2DM BSS was associated with significant dysregulation in glycerophospholipid metabolism and choline metabolism within cancer pathways as major metabolic disturbances. Furthermore, analyses of both the discovery and validation cohorts, indicated that LysoPC (20:5(5Z,8Z,11Z,14Z,17Z)/0:0) and LysoPC (15:0) had the greatest impact on distinguishing BSS. ConclusionAltered levels of glycerophospholipids and FAs have been associated with T2DM BSS. These results provide valuable mechanistic insights linked with the development of BSS in T2DM subjects.

Intergenerational neurotoxicity of polystyrene nanoplastics in offspring mice is mediated by dysfunctional microbe-gut-brain axis

Nanoplastics (NPs) are ubiquitous in daily life, posing potential risks to the environment and human. While their negative effects on parental organisms have been extensively studied, intergenerational effects are still in the early stages of investigation. Here, we aimed to investigate the impact of maternal exposure to an environmentally relevant level of polystyrene NPs (PSNPs, 100 nm) during gestation and lactation (∼32 days, 50 μg/mouse/day) on neurotoxicity mediated by the microbe-gut-brain axis in offspring mice. Maternal PSNPs exposure significantly increased brain TNF-α level and microglia by 1.43 and 1.48 folds respectively, compared to control, accompanied by nuclear pyknosis and cell vacuolization in cortex and hippocampus. Targeted neurotransmitter metabolomics analysis revealed dysregulation in dopamine and serotonin metabolism. Specifically, dopamine levels increased significantly from 0.007 ng/L to 0.015 ng/L, while N-acetylseroton and 3,4-dihydroxyphenylacetic acid decreased significantly from 0.002 and 0.929 ng/L to 0.001 and 0.680 ng/L, respectively. Through a combination of 16S rRNA sequencing and biochemical analysis, we discovered that maternal PSNPs exposure led to a depletion of anti-inflammatory bacteria and an enrichment of pro-inflammatory bacteria resulting in intestinal barrier damage, elevated levels of lipopolysaccharide in blood, and subsequent activation of neuroinflammation. Meanwhile, gut bacteria dysbiosis interfered with communication between gut and brain by dysregulating neurotransmitter synthesis, as evidenced by significant associations between neurotransmitter-related bacteria (Akkermansia, Family_XIII_AD3011_group, Lachnoclostridium) and dopamine/serotonin related metabolites. Furthermore, transcriptional alterations in dopamine and serotonin related pathways were observed in the enteric nervous system, suggesting abnormal signal transduction from gut to brain contributes to neurotoxicity. This study provides new insights into NPs-induced neurotoxicity within the context of microbe-gut-brain axis and highlights the risk of cerebral dysfunction in offspring with maternal NPs exposure.

ZBED3 exacerbates hyperglycemia by promoting hepatic gluconeogenesis through CREB signaling

BackgroundElevated hepatic glucose production (HGP) is a prominent manifestation of impaired hepatic glucose metabolism in individuals with diabetes. Increased hepatic gluconeogenesis plays a pivotal role in the dysregulation of hepatic glucose metabolism and contributes significantly to fasting hyperglycemia in diabetes. Previous studies have identified zinc-finger BED domain-containing 3 (ZBED3) as a risk gene for type 2 diabetes (T2DM), and its single nucleotide polymorphism (SNPs) is closely associated with the fasting blood glucose level, suggesting a potential correlation between ZBED3 and the onset of diabetes. This study primarily explores the effect of ZBED3 on hepatic gluconeogenesis and analyzes the relevant signaling pathways that regulate hepatic gluconeogenesis. MethodsThe expression level of ZBED3 was assessed in the liver of insulin-resistant (IR)-related disease. RNA-seq and bioinformatics analyses were employed to examine the ZBED3-related pathway that modulated HGP. To investigate the role of ZBED3 in hepatic gluconeogenesis, the expression of ZBED3 was manipulated by upregulation or silencing using adeno-associated virus (AAV) in mouse primary hepatocytes (MPHs) and HHL-5 cells. In vivo, hepatocyte-specific ZBED3 knockout mice were generated. Moreover, AAV8 was employed to achieve hepatocyte-specific overexpression and knockdown of ZBED3 in C57BL/6 and db/db mice. Immunoprecipitation and mass spectrometry (IP-MS) analyses were employed to identify proteins that interacted with ZBED3. Co-immunoprecipitation (co-IP), glutathione S-transferase (GST) - pulldown, and dual-luciferase reporter assays were conducted to further elucidate the underlying mechanism of ZBED3 in regulating hepatic gluconeogenesis. ResultsThe expression of ZBED3 in the liver of IR-related disease models was found to be increased. Under the stimulation of glucagon, ZBED3 promoted the expression of hepatic gluconeogenesis-related genes PGC1A, PCK1, G6PC, thereby increasing HGP. Consistently, the rate of hepatic gluconeogenesis was found to be elevated in mice with hepatocyte-specific overexpression of ZBED3 and decreased in those with ZBED3 knockout. Additionally, the knockdown of ZBED3 in the liver of db/db mice resulted in a reduction in hepatic gluconeogenesis. Moreover, the study revealed that ZBED3 facilitated the nuclear translocation of protein arginine methyltransferases 5 (PRMT5) to influence the regulation of PRMT5-mediated symmetrical dimethylation of arginine (s-DMA) of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), which in turn affects the phosphorylation of CREB and ultimately promotes HGP. ConclusionsThis study indicates that ZBED3 promotes hepatic gluconeogenesis and serves as a critical regulator of the progression of diabetes.

Uncovering lipid dynamics in Staphylococcus aureus osteomyelitis using multimodal imaging mass spectrometry

Osteomyelitis occurs when Staphylococcus aureus invades the bone microenvironment, resulting in a bone marrow abscess with a spatially defined architecture of cells and biomolecules. Imaging mass spectrometry and microscopy are tools that can be employed to interrogate the lipidome of S.aureus-infected murine femurs and reveal metabolic and signaling consequences of infection. Here, nearly 250 lipids were spatially mapped to healthy and infection-associated morphological features throughout the femur, establishing composition profiles for tissue types. Ether lipids and arachidonoyl lipids were altered between cells and tissue structures in abscesses, suggesting their roles in abscess formation and inflammatory signaling. Sterols, triglycerides, bis(monoacylglycero)phosphates, and gangliosides possessed ring-like distributions throughout the abscess, suggesting a hypothesized dysregulation of lipid metabolism in a population of cells that cannot be discerned with traditional microscopy. These data provide insight into the signaling function and metabolism of cells in the fibrotic border of abscesses, likely characteristic of lipid-laden macrophages.

Ferroptosis and myocardial ischemia-reperfusion: mechanistic insights and new therapeutic perspectives.

Myocardial ischemia-reperfusion injury (MIRI) is a significant factor in the development of cardiac dysfunction following a myocardial infarction. Ferroptosis, a type of regulated cell death driven by iron and marked by lipid peroxidation, has garnered growing interest for its crucial involvement in the pathogenesis of MIRI.This review comprehensively examines the mechanisms of ferroptosis, focusing on its regulation through iron metabolism, lipid peroxidation, VDAC signaling, and antioxidant system dysregulation. We also compare ferroptosis with other forms of cell death to highlight its distinct characteristics. Furthermore, the involvement of ferroptosis in MIRI is examined with a focus on recent discoveries concerning ROS generation, mitochondrial impairment, autophagic processes, ER stress, and non-coding RNA regulation. Lastly, emerging therapeutic strategies that inhibit ferroptosis to mitigate MIRI are reviewed, providing new insights into potential clinical applications.

The Relationship Between Age at Diabetes Onset and Clinical Outcomes in Newly Diagnosed Type 2 Diabetes: A Real-World Two-Center Study.

This study was developed with the goal of clarifying whether there is any relationship between type 2 diabetes mellitus (T2DM) age of onset and clinical outcomes for patients in National Metabolic Management Centers (MMC). From September 2017 - June 2022, 864 total T2DM patients were recruited in MMC and assigned to those with early-onset and late-onset diabetes (EOD and LOD) based on whether their age at disease onset was ≤ 40 or > 40 years. All patients received standardized management. Baseline and 1-year follow-up data from these two groups of patients were assessed. Associations between onset age and other factors were evaluated with a multivariate linear regression approach, adjusting for appropriate covariates. Outcomes in particular subgroups were also assessed in stratified analyses. Markers of dysregulated glucose metabolism and BMI values were significantly higher among EOD patients as compared to LOD patients. Subjects in both groups exhibited significant improvements in several disease-related parameters on 1-year follow-up after undergoing metabolic management. EOD patients exhibited significantly greater percentage reductions in HbA1c levels (-28.49 (-44.26, -6.45)% vs -13.70 (-30.15,-1.60)%, P =0.017) relative to LOD patients following adjustment for confounders. Significant differences were also detected between these groups when focused on subgroups of patients who were male, exhibited a BMI ≥ 25, an HbA1c ≥ 9, or had a follow-up frequency < 2. Data from a 1-year follow-up time point suggest that a standardized metabolic disease management model can promote effective metabolic control in newly diagnosed T2DM patients, particularly among individuals with EOD.

Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis

Background & AimExpression of P21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD. MethodsCDKN1A expression levels were evaluated in different patients‘ cohorts with SLD, fibrosis, and advanced chronic liver disease (ACLD). Cdkn1a-/- and Cdkn1a+/+ mice were fed with either a Western diet (WD), a Lieber-DeCarli (LdC) diet plus multiple EtOH binges, or a DuAL diet. Primary hepatocytes were isolated and functional assays performed. ResultsA significant increase in CDKN1A expression was observed in patients with steatohepatitis and fibrosis (with a positive correlation with both NAS and fibrosis staging scores), cirrhosis and ACLD. Cdkn1a+/+ mice, fed a DuAL diet exhibited liver injury and cell death increased reactive oxygen species (ROS), and markers of senescence (γH2AX, β-GAL, Cdkn1a/p53) contributing to steatosis and inflammation. In contrast, Cdkn1a-/- mutant mice showed a significant decrease in senescence-associated markers as well as in markers of liver injury, hepatic steatosis and an increase in – fatty acid oxidation (FAO) and reduction in free fatty acid (FFA) uptake as well as de novo lipogenesis. Mechanistically, activation of the AMPK-SIRT3 was observed in Cdkn1a-deleted animals. ConclusionsCdkn1a deletion protected against preclinical SLD by promoting FAO and preventing FFA uptake and de novo lipogenesis via the AMPK-SIRT3 axis. CDKN1A expression was found to be directly correlated with increased severity of NAS and fibrosis in SLD patients. CDKN1A could be a potential theragnostic target for the treatment of metabolic dysregulation in SLD patients, with and without alcohol consumption.

Role of gut microbiota and immune cells in metabolic-associated fatty liver disease: clinical impact.

In 2020, a revised definition of fatty liver disease associated with metabolic dysfunction (MAFLD) was proposed to replace non-alcoholic fatty liver (NAFLD). Liver steatosis and at least one of the three metabolic risk factors, including type 2 diabetes, obesity, or signs of metabolic dysregulation, are used to diagnose MAFLD. MAFLD, similarly to NAFLD, is characterized by a spectrum of disease ranging from simple steatosis to advanced metabolic steatohepatitis with or without fibrosis, and may progress to cirrhosis and liver cancer, including increased risk of other critical extrahepatic diseases. Even though the pathophysiology of MAFLD and potential therapeutic targets have been explored in great detail, there is yet no Food and Drug Administration approved treatment. Recently, gut microbiome-derived products (e.g., endotoxins and metabolites) involved in intestinal barrier disruption, systemic inflammation, and modification of intrahepatic immunity have been associated with MAFLD development and progression. Therefore, different strategies could be adopted to modify the gut microbiome to improve outcomes in early and progressive MAFLD. Here, we provide an overview of mechanisms that may link the gut microbiome and immune response during the onset of liver steatosis and progression to steatohepatitis and fibrosis in patients with MAFLD. Finally, gut microbiota-based approaches are discussed as potential personalized treatments against MAFLD.

Vocal communication in asocial BTBR mice is more malleable by a ketogenic diet in juveniles than adults

Deficits in social communication and language development are a hallmark of autism spectrum disorder currently with no effective approaches to reduce the negative impact. Interventional studies using animal models have been very limited in demonstrating improved vocal communication. Autism has been proposed to involve metabolic dysregulation. Ketogenic diet (KD) is a metabolism-based therapy for medically intractable epilepsy, and its applications in other neurological conditions have been increasingly tested. However, how KD would affect vocal communication has not been explored. The BTBR mouse strain is widely used to model asocial phenotypes. They display robust and pronounced deficits in vocalization during social interaction, and have metabolic changes implicated in autism.We investigated the effects of KD on ultrasonic vocalizations (USVs) in juvenile and adult BTBR mice during male–female social encounters.After a brief treatment with KD, the number, spectral bandwidth, and much of the temporal structure of USVs were robustly closer to control levels in both juvenile and adult BTBR mice. Composition of call categories and transitioning between individual call subtypes were more effectively altered to more closely align with the control group in juvenile BTBR mice.Together, our data provide further support to the hypothesis that metabolism-based dietary intervention could modify disease expression, including core symptoms, in autism. Future studies should tease apart the molecular mechanisms of KD’s effects on vocalization.

Endocrine disturbance and metabolic dysregulation related to hyperandrogenism in polycystic ovary syndrome female mice

Endocrine disturbance and metabolic dysregulation related to hyperandrogenism in polycystic ovary syndrome female mice

Investigating brain–gut microbiota dynamics and inflammatory processes in an autistic-like rat model using MRI biomarkers during childhood and adolescence

Autism spectrum disorder (ASD) is characterized by social interaction deficits and repetitive behaviors. Recent research has linked that gut dysbiosis may contribute to ASD-like behaviors. However, the exact developmental time point at which gut microbiota alterations affect brain function and behavior in patients with ASD remains unclear. We hypothesized that ASD-related brain microstructural changes and gut dysbiosis induce metabolic dysregulation and proinflammatory responses, which collectively contribute to the social behavioral deficits observed in early childhood. We used an autistic-like rat model that was generated via prenatal valproic acid exposure. We analyzed brain microstructural changes using diffusion tensor imaging (DTI) and examined microbiota, blood, and fecal samples for inflammation biomarkers. The ASD model rats exhibited significant brain microstructural changes in the anterior cingulate cortex, hippocampus, striatum, and thalamus; reduced microbiota diversity (Prevotellaceae and Peptostreptococcaceae); and altered metabolic signatures. The shift in microbiota diversity and density observed at postnatal day (PND) 35, which is a critical developmental period, underscored the importance of early ASD interventions. We identified a unique metabolic signature in the ASD model, with elevated formate and reduced acetate and butyrate levels, indicating a dysregulation in short-chain fatty acid (SCFA) metabolism. Furthermore, increased astrocytic and microglial activation and elevated proinflammatory cytokines—interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α)—were observed, indicating immune dysregulation. This study provided insights into the complex interplay between the brain and the gut, and indicated DTI metrics as potential imaging-based biomarkers in ASD, thus emphasizing the need for early childhood interventions.

A binuclear metallohydrolase model for RelA/SpoT-Homolog (RSH) hydrolases

When challenged by starvation, bacterial organisms synthesize guanosine penta- and tetraphosphate, collectively denoted as (p)ppGpp, as second messengers to reprogram metabolism towards slower growth and enhanced stress tolerance. When starvation is alleviated, the RelA-SpoT homolog (RSH) hydrolases down-regulate (p)ppGpp, cleaving the 3’-diphosphate to produce GTP or GDP. Metazoan RSH hydrolases (MESH) possess phosphatase activity responsible for converting cytoplasmic NADPH to NADH in mammalian cells. Inhibitor development for this family may therefore provide therapies to combat bacterial infection or metabolic dysregulation. Despite the availability of dozens of high-resolution structures, catalytic mechanisms of RSH hydrolases have remained poorly understood. All RSH hydrolases tightly bind a Mn2+ near its active center, which is believed sufficient for hydrolase activity. In contrast to this notion, we demonstrate, using the (p)ppGpp hydrolase SpoT from Acinetobacter baumannii, that a second divalent cation, presumably a Mg2+ under physiological conditions, is required for efficient catalysis. We also show that SpoT preferentially cleaves 3’-diphosphate over 3’-phosphate substrates, likely due to a key coordination between the β-phosphate and the second metal center. MESH replaces this β-phosphate with the side chain of an aspartate residue, thereby functioning as a phosphatase. We propose a binuclear metallohydrolase model where an invariant ED (Glu-Asp) diad, previously believed to activate the water nucleophile, instead coordinates to a Mg2+ center. The refined molecular and evolutionary blueprint of RSH hydrolases will provide a more reliable foundation for the development of small-molecule inhibitors of this important enzyme family.

Polycystic Ovary Syndrome Markers and Mechanism

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder characterized by hormonal imbalances, metabolic dysregulation, and reproductive abnormalities. This study aims to elucidate the significance of PCOS markers and their mechanisms while outlining the methodology employed. A comprehensive literature review was conducted from 2020 to 2023 using databases like PubMed, ScienceDirect, EMBASE, and Google Scholar. Key search terms included "pathophysiology," "pathogenesis," "PCOS," "marker," and "biomarker," aligned with the PICOT criteria. After removing duplicates, articles underwent a two-phase screening process based on predefined inclusion criteria. Additionally, a marker mechanism flowchart was created using the Biorender application. Results highlighted the pivotal role of various markers in understanding PCOS pathophysiology and guiding clinical management. Anthropometric, visual, metabolic, inflammatory, endocrine, and oxidative stress markers were analyzed for their diagnostic, prognostic, and therapeutic implications in PCOS. The study underscores the importance of marker interactions in personalized PCOS management. Limitations in marker interpretation warrant further research to refine diagnostic accuracy and optimize therapeutic interventions. Integrating marker mechanisms enhances understanding of PCOS heterogeneity and informs targeted treatment approaches tailored to individual phenotypic variations.

Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways

Loss of parvalbumin (PV) expressing neurons (PV neurons) is relevant to the underlying mechanisms of the pathogenesis of neurological and psychiatric diseases associated with the dysregulation of neuronal excitatory networks and brain metabolism. Although PV modulates mitochondrial morphology, volume and dynamics, it is largely unknown whether mitochondrial dynamics affect PV expression and what the molecular events are responsible for PV neuronal degeneration. In the present study, L-buthionine sulfoximine (BSO, an inhibitor of glutathione synthesis) did not degenerate PV neurons under physiological condition. However, BSO-induced oxidative stress decreased PV expression and facilitated cyclin-dependent kinase 5 (CDK5) tyrosine (Y) 15 phosphorylation, dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and glutathione peroxidase-1 (GPx1) downregulation in PV neurons. Co-treatment of roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission) attenuated BSO-induced PV downregulation. WY14643 (an inducer of mitochondrial fission) reduced PV expression without affecting CDK5 Y15 phosphorylation. Following status epilepticus (SE), CDK5 Y15 phosphorylation and mitochondrial fission were augmented in PV neurons. These were accompanied by reduced GPx1-mediated inhibition of NF-κB p65 serine (S) 536 phosphorylation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 ameliorated SE-induced PV neuronal degeneration by mitigating CDK5 Y15 hyperphosphorylation, aberrant mitochondrial fragmentation and reduced GPx1-mediated NF-κB inhibition. Furthermore, SN50 (a NF-κB inhibitor) alleviated SE-induced PV neuronal degeneration, independent of dysregulation of mitochondrial fission, CDK5 hyperactivation and GPx1 downregulation. These findings provide an evidence that oxidative stress may activate CDK5-DRP1- and GPx1-NF-κB-mediated signaling pathways, which would be possible therapeutic targets for preservation of PV neurons in various diseases.