Metabolic Alterations Research Articles

Okra seed polysaccharides mitigate neuroinflammation and cognitive impairment via modulation of Nrf2/HO-1, HMGB1/RAGE/TLR4/NF-κB, NLRP3/Caspase-1, JAK-2/STAT-3, AMPK/SIRT1/m-TOR, PI3K/AKT/CREB/BDNF/TrkB and PERK/CHOP/Bcl-2 axes.

Global healthcare systems are under tremendous strain due to the increasing prevalence of neurodegenerative disorders. Growing data suggested that overconsumption of high-fat/high-carbohydrates diet (HFHCD) is associated with enhanced incidence of metabolic alterations, neurodegeneration, and cognitive dysfunction. Functional foods have gained prominence in curbing metabolic and neurological deficits. Consequently, this study endeavored to explore effects of purified Okra seed polysaccharides (OP) (Abelmoschus esculentus (L.) Moench) against HFHCD-induced metabolic alterations and cognitive dysfunction, with elucidating underlying contributed mechanistic pathways. OP hydrolysate was analyzed using GC-MS analysis. The biological study encompassed two phases, the first phase I (model establishment phase), for 3months, involved a control group, fed standard diet, and HFHCD group. The second phase (phase II) where HFHCD fed rats were re-divided into 3 equal subgroups, 1st subgroup received HFHCD, whereas second and third subgroups received OP, 200 or 400mg/kg/day, respectively, for 28days. GC-MS characterized OP as an arabinogalactouranan and revealed the monosaccharide composition as galacturonic acid: arabinose: glucose: galactose: rhamnose: xylose in ratio of 28.2: 23.3: 11.5: 4.2: 3.5: 2.0. The findings demonstrated that OP dose-dependently mitigated HFHCD-induced rise in body weights, lipid profiles, levels of blood glucose and disruption in behavioral outcomes, neurotransmitters, together with histopathological alterations in brain. Moreover, OP dose-dependently improved redox, neuroinflammatory, endoplasmic reticulum (ER) stress, autophagic and apoptotic biomarkers. OP can be regarded as promising functional food candidate to hamper HFHCD-induced metabolic alterations and cognitive deficit, via enhancing Nrf2/HO-1, AMPK/SIRT1 and PI3K/AKT/CREB axes, long with dampening of HMGB1/RAGE/TLR4, NLRP3/Caspase-1, JAK-2/STAT-3 and PERK/CHOP axes.

Significance of birth in the maintenance of quiescent neural stem cells.

Birth is one of the most important life events for animals. However, its significance in the developmental process is not fully understood. Here, we found that birth-induced alteration of glutamine metabolism in radial glia (RG), the embryonic neural stem cells (NSCs), is required for the acquisition of quiescence and long-term maintenance of postnatal NSCs. Preterm birth impairs this cellular process, leading to transient hyperactivation of RG. Consequently, in the postnatal brain, the NSC pool is depleted and neurogenesis is decreased. We also found that the maintenance of quiescent RG after preterm birth improves postnatal neurogenesis. This study demonstrates the significance of birth in the maintenance of quiescent NSCs.

The brainstem reticular formation pivots abnormal neural transmission in the course of Anorexia Nervosa.

Anorexia nervosa (AN) represents an eating disorder, which features the highest rate of mortality among all psychiatric disorders. The disease prevalence is increasing steadily, and an effective cure is missing. The neurobiology of the disease is largely unknown, and only a few studies were designed to disclose specific brain areas, where altered neural transmission may occur. In AN behavioral alterations surpassing altered feeding are present, which often involve archaic behaviors finalized to the survival of the species. In fact, alterations of sleep and reward-driven behavior accompany the eating disorder, where a disruption of peripheral and central circadian rhythms occurs along with effortful behaviors, aberrant learning and mild cognitive impairment. Abnormal behavior often co-exists with a number of metabolic alterations in peripheral organs. The present article wishes to analyze the potential role of altered brain circuitry within the brainstem reticular formation during AN. In fact, this brain area contains neuronal nuclei and pathways, which are pivotal in connecting eating pattern with archaic behaviorsand autonomic activity within peripheral organs. A number of reticular nuclei releasing catecholamine and non-catecholamine neurotransmittersare evidenced in relationship with altered behavioral states and vegetative control to produce this psycho-metabolic disorder. The relevance of the reticular formation in sustaining the disorder is discussed in the light of developing effective therapeutic strategies.

Metabolic Reprogramming of Neutrophils in the Tumor Microenvironment: Emerging Therapeutic Targets.

Neutrophils are pivotal in the immune system and have been recognized as significant contributors to cancer development and progression. These cells undergo metabolic reprogramming in response to various stimulus, including infections, diseases, and the tumor microenvironment (TME). Under normal conditions, neutrophils primarily rely on aerobic glucose metabolism for energy production. However, within the TME featured by hypoxic and nutrient-deprived conditions, they shift to altered anaerobic glycolysis, lipid metabolism, mitochondrial metabolism and amino acid metabolism to perform their immunosuppressive functions and facilitate tumor progression. Targeting neutrophils within the TME is a promising therapeutic approach. Yet, focusing on their metabolic pathways presents a novel strategy to enhance cancer immunotherapy. This review synthesizes the current understanding of neutrophil metabolic reprogramming in the TME, with an emphasis on the underlying molecular mechanisms and signaling pathways. Studying neutrophil metabolism in the TME poses challenges, such as their short lifespan and the metabolic complexity of the environment, necessitating the development of advanced research methodologies. This review also discusses emerging solutions to these challenges. In conclusion, given their integral role in the TME, targeting the metabolic pathways of neutrophils could offer a promising avenue for cancer therapy.

The role of 1-Deoxysphingolipids and Polyamines in the pathogenesis of placental syndrome

BackgroundPlacental syndrome, mainly composed of preeclampsia and fetal growth restriction, has an impact on the health of mother and baby dyads. While impaired placentation is central to their pathophysiology, the underlying molecular mechanisms remain incompletely understood. This study investigates the association between placental syndrome and metabolic alterations in 1-deoxysphingolipids (1-deoxySLs) and polyamines, along with their regulatory enzymes.MethodsThis prospective case-control study involved 26 healthy pregnant women and 17 with placental syndrome. Blood samples were collected from maternal, uterine venous, and umbilical cord veins. Levels of 1-deoxySL, spermine, and spermidine, as well as related enzymes of polyamine metabolism such as ornithine decarboxylase (ODC), spermidine/spermine N1-acetyltransferase (SSAT), polyamine oxidase (PAO), and spermine oxidase (SMO), were measured using the techniques of LC-MS and ELISA, respectively.ResultsWomen with placental syndrome had significantly higher levels of 1-deoxySL, spermine, and spermidine in all blood samples compared to the healthy pregnancy group. Additionally, ODC and SSAT levels were reduced significantly in the placental syndrome group, while PAO and SMO levels showed no significant differences. Strong positive correlations were found between the studied enzymes and biomolecules in healthy pregnancies, which were notably weaker in the placental syndrome group.ConclusionThis study demonstrates significantly altered levels of 1-deoxySL and polyamines, with corresponding enzyme activity changes, in placental syndrome compared to healthy pregnancies. The disrupted correlations between these biomolecules suggest alterations in their metabolic pathways and potential utility as biomarkers. Further mechanistic studies are warranted to elucidate their role in placental syndrome pathophysiology.

Boswellic acid exerts anti-tumor effect in oral squamous cell carcinoma by inhibiting PI3K/AKT1 mediated signaling pathway.

Boswellic acid (BA) is a bioactive compound derived from Boswellia trees. This study aims to investigate the anti-cancer properties of BA against KB oral squamous cancer cells and elucidate the underlying mechanisms. Escalating doses of BA were administered to KB cells, and various analyses were conducted using bioinformatic tools such as GEO, GEO2R, and STITCH database. MTT and trypan blue assays has been validated to measure the cytotoxicity by treating BA in KB Cells. Flow cytometry assessed cell cycle progression, apoptosis induction, and metabolic alterations. Network analysis identified relevant signaling pathways, while RT-PCR validated mRNA expression changes. Docking studies by Autodock evaluated beta-BA's binding affinity with mTOR-mediated pathways. BA effectively hindered KB cell progression, inducing G0/G1 phase cell cycle arrest and apoptosis. It also inhibited aerobic glycolysis, a hallmark of oral cancer cells. Network analysis revealed involvement in apoptosis and mTOR targets. RT-PCR confirmed downregulation of genes associated with aerobic glycolysis and apoptosis. Docking studies indicated strong binding between BA and mTOR pathways. BA shows promise in inhibiting KB oral squamous cancer cell growth. These findings underscore its potential as a treatment for oral cancer. Further research and clinical studies are needed to unlock its full therapeutic potential.

Metabolic shifts in glioblastoma: unraveling altered pathways and exploring novel therapeutic avenues.

Metabolic reprogramming stands out as a defining characteristic of cancer, including glioblastoma (GB), enabling tumor cells to overcome growth and survival challenges in adverse conditions. The dysregulation of metabolic processes in GB is crucial to its pathogenesis, influencing both tumorigenesis and the disease's invasive tendencies. This altered metabolism supplies essential energy substrates for uncontrolled cell proliferation and also creates an immunosuppressive microenvironment, complicating conventional therapies. A comprehensive understanding of the complexities of metabolic dysregulation in carbohydrate, amino acid, lipid and nucleotide pathways in GB holds promise for effective therapeutic interventions. Key metabolic enzymes, transporters, and signaling pathways and mitochondrial metabolism have been examined for their roles in GB pathology and their possible therapeutic potential. Addressing these metabolic targets has shown efficacy in preclinical models and is currently being evaluated in clinical trials. Combination therapies that exploit metabolic vulnerabilities alongside conventional treatments hold the promise of improving patient outcomes. This review explores the dynamic interplay between glioblastoma's aggressiveness and altered metabolism, offering insights into potential therapeutic strategies. Moreover, this review discusses the recent advancements in drug development aimed at targeting these dysregulated metabolic pathways.

Class IIa histone deacetylase (HDAC) inhibitor TMP269 suppresses lumpy skin disease virus replication by regulating host lysophosphatidic acid metabolism.

Lumpy skin disease virus (LSDV) infection poses a significant threat to global cattle farming. Currently, effective therapeutic agents are lacking. TMP269, a small molecule inhibitor of class IIa histone deacetylase inhibitor, plays a vital role in cancer therapy. In this study, we demonstrated that TMP269 treatment inhibits the early-stage replication of LSDV in a dose-dependent manner. RNA sequencing data revealed that metabolism-related signaling pathways were significantly enriched after LSDV infection. Furthermore, untargeted metabolomics analysis revealed that lysophosphatidic acid (LPA), a key metabolite of the glycerophospholipid pathway, was upregulated following LSDV infection and downregulated after TMP269 treatment. In addition, exogenous LPA promotes LSDV replication by activating the mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) signaling pathway and suppressing the host's innate immune response. Furthermore, treatment with the LPA receptor inhibitor Ki16425 suppressed LSDV replication and promoted the host's innate immune response. These findings suggest that LSDV infection can induce LPA expression and aid viral activation of the MEK/ERK signaling pathway and escape of the host's innate immune response, whereas TMP269 treatment can inhibit LPA production and limit its promotion of LSDV replication. These data identified the antiviral mechanism of TMP269 and a novel mechanism by which LSDV inhibits host innate immune responses, providing insights into the development of new preventive or therapeutic strategies targeting altered metabolic pathways.IMPORTANCELumpy skin disease virus (LSDV) poses a significant threat to global cattle farming. Owing to insufficient research on LSDV infection, pathogenesis, and immune escape mechanisms, prevention and control methods against LSDV infection are lacking. Here, we found that TMP269, a class IIa histone deacetylase inhibitor, significantly inhibited LSDV replication. We further demonstrated that TMP269 altered LSDV infection-induced host glycerophospholipid metabolism. In addition, TMP269 decreased the accumulation of lysophosphatidic acid (LPA), a key metabolite in glycerophospholipid metabolism, induced by LSDV infection, and exogenous LPA-promoted LSDV replication by activating the mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) signaling pathway and suppressing the host innate immune response. Our findings identified the antiviral mechanism of TMP269 and a novel mechanism by which LSDV manipulates host signaling pathways to promote its replication, offering insights into the development of novel antiviral agents against LSDV infection.

PSC and colitis: A complex relationship.

Primary sclerosing cholangitis is one of the most challenging conditions in hepatology, and due to our limited understanding of its pathogenesis, no causal therapies are currently available. While it was long assumed that a minority of people with IBD also develop PSC, which is sometimes labeled an extraintestinal manifestation of IBD, the clinical phenotype, genetic and intestinal microbiota associations strongly argue for PSC-IBD being a distinct form of IBD, existing alongside ulcerative colitis and Crohn's disease. In fact, the liver itself could contribute to intestinal pathology, clinically overt in 60 - 80 % of patients. Recent studies suggested that on a molecular level, almost all people with PSC have underlying colitis. The extent to which the liver and gut influence each other clinically and in terms of disease progression has not yet been conclusively revealed. However, while it seemed intuitive that the two diseases have a negative influence on each other, evidence suggests that sclerosing cholangitis can also be protective for the gut and that colitis can in certain settings ameliorate liver pathology. This underscores the complex pathophysiological relationships, where factors such as genetic predisposition, changes in the intestinal microbiota, altered bile acid metabolism, and immune cell migration are among the suspected contributors. PSC is an emerging disease with a significant impact on health-related quality of life of affected people. With this review, we aim to summarize the current knowledge on the gut-liver axis in PSC-IBD, provide new perspectives on risk stratification and treatment and identify gaps in our current knowledge. Our understanding of this complex relationship will therefore help to design clinical trials and shape the future therapy of PSC-IBD.

Multifunctional Near Infrared Polymer Dots for Enhanced Synergistic Photodynamic/Photothermal Effect In Vitro.

Synergistic photodynamic/photothermal therapy (PDT/PTT) can be used to target cancer cells by locally generating singlet oxygen species or increasing temperature under laser irradiation. This approach offers higher tumor ablation efficiency, lower therapeutic dose requirements, and reduced side effects compared to single treatment approaches. However, the therapeutic efficiency of PDT/PTT is still limited by the low oxygen levels within the solid tumors caused by abnormal vasculature and altered cancer cell metabolism. To address these challenges, we developed multifunctional nanoparticles with high catalytic activity for converting tumor hydrogen peroxide (H2O2) into oxygen (O2). Using poly(styrene-co-maleic anhydride) (PSMA) as a cross-linker, we generated compact, highly fluorescent Pdots, used poly[2,6-(4,4-bis(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']dithiophene)-alt-4,7-(2,1,3-benzothiadiazole)] (PCPDTBT) as a near-infrared photosensitizer for both photodynamic and photothermal applications, and incorporated manganese (Mn) ions to catalyze the H2O2-to-O2 conversion. These Mn-doped Pdots significantly enhance O2 production, achieving an enhanced 1O2 quantum yield from 0.46 to 0.64 with the addition of H2O2, achieving the goal of improving PDT efficiency. With this rational design, we produced Pdots with enhanced H2O2-to-1O2 converting ability for potential use in PDT. For photothermal applications, our Pdots generate a photothermal conversion efficiency of 53%. In vitro studies using human MCF7 adenocarcinoma cells confirmed the biocompatibility of these Pdots in the absence of laser exposure with a pronounced cell killing effect under laser irradiation for synergistic PDT/PTT. These results highlight the promise of Pdots in overcoming oxygen limitations, balancing the performance of PDT/PTT, and enhancing the therapeutic efficacy of PDT/PTT in cancer cells in vitro.

The paradoxical GH response at OGTT does not predict Pasireotide efficacy but matters for glucose metabolism.

A paradoxical increase in GH after oral glucose load (GH-Par) characterizes about one-third of acromegaly patients and is associated with a better response to first-generation somatostatin receptor ligands (fg-SRLs). Pasireotide is typically considered as a second-/third-line treatment. Here, we investigated the predictive role of GH-Par in pasireotide response and adverse event development. we collected a multicenter Italian retrospective cohort of 59 patients treated with pasireotide for at least 3months, all having GH profile from OGTT. IGF-1 normalization or at least 30% reduction at the last follow-up visit defined a responder patient. Considering the entire cohort, median IGF-1 levels before pasireotide (available in 57 patients) were 1.38 times the upper limit of normal (ULN) in patients with large (median size 18mm) and invasive (82%) adenomas after failure of fg-SRL treatment. After a 40-month median treatment, pasireotide effectively reduced IGF-1 ULN levels in 41 patients, 37 of whom achieving normalization, and 4 with a ≥ 30% reduction. Thirteen patients were classified as GH-Par. The median pasireotide duration, dosage, and efficacy (9/12 responder in the GH-Par group and 32/45 in the GH-NPar) were similar between groups. However, the occurrence of new-onset or worsening glucose metabolism alterations (GMAs) after pasireotide was more frequent in GH-NPar (from 37 to 80%; p < 0.001) compared to GH-Par patients (from 69 to 76%), likely due to the higher prevalence of pre-existing GMAs in the GH-Par group before starting pasireotide (p = 0.038). The GH-Par does not predict the response to pasireotide in acromegaly but can predict a worse metabolic profile.

Glutamine-glutamate centered metabolism as the potential therapeutic target against Japanese encephalitis virus-induced encephalitis

BackgroundJapanese encephalitis (JE) induced by Japanese encephalitis virus (JEV) infection is the most prevalent diagnosed epidemic viral encephalitis globally. The underlying pathological mechanisms remain largely unknown. Given that viruses are obligate intracellular parasites, cellular metabolic reprogramming triggered by viral infection is intricately related to the establishment of infection and progression of disease. Therefore, uncovering and manipulating the metabolic reprogramming that underlies viral infection will help elucidate the pathogenic mechanisms and develop novel therapeutic strategies.MethodsMetabolomics analysis was performed to comprehensively delineate the metabolic profiles in JEV-infected mice brains and neurons. Metabolic flux analysis, quantitative real-time PCR, western blotting and fluorescence immunohistochemistry were utilized to describe detailed glutamine-glutamate metabolic profiles during JEV infection. Exogenous addition of metabolites and associated compounds and RNA interference were employed to manipulate glutamine-glutamate metabolism to clarify its effects on viral replication. The survival rate, severity of neuroinflammation, and levels of viral replication were assessed to determine the efficacy of glutamine supplementation in JEV-challenged mice.ResultsHere, we have delineated a novel perspective on the pathogenesis of JE by identifying an aberrant low flux in glutamine-glutamate metabolism both in vivo and in vitro, which was critical in the establishment of JEV infection and progression of JE. The perturbed glutamine-glutamate metabolism induced neurotransmitter imbalance and created an immune-inhibitory state with increased gamma-aminobutyric acid/glutamate ratio, thus facilitating efficient viral replication both in JEV-infected neurons and the brain of JEV-infected mice. In addition, viral infection restrained the utilization of glutamine via the glutamate-α-ketoglutaric acid axis in neurons, thus avoiding the adverse effects of glutamine oxidation on viral propagation. As the conversion of glutamine to glutamate was inhibited after JEV infection, the metabolism of glutathione (GSH) was simultaneously impaired, exacerbating oxidative stress in JEV-infected neurons and mice brains and promoting the progression of JE. Importantly, the supplementation of glutamine in vivo alleviated the intracranial inflammation and enhanced the survival of JEV-challenged mice.ConclusionAltogether, our study highlights an aberrant glutamine-glutamate metabolism during JEV infection and unveils how this facilitates viral replication and promotes JE progression. Manipulation of these metabolic alterations may potentially be exploited to develop therapeutic approaches for JEV infection.Graphical

SLC1A5 is a key regulator of glutamine metabolism and a prognostic marker for aggressive luminal breast cancer

Cancer cells exhibit altered metabolism, often relying on glutamine (Gln) for growth. Breast cancer (BC) is a heterogeneous disease with varying clinical outcomes. We investigated the role of the amino acid transporter SLC1A5 (ASCT2) and its association with BC subtypes and patient outcomes. In large BC cohorts, SLC1A5 mRNA (n = 9488) and SLC1A5 protein (n = 1274) levels were assessed and correlated their expression with clinicopathological features, molecular subtypes, and patient outcomes. In vitro SLC1A5 knockdown and inhibition studies in luminal BC cell lines (ZR-75-1 and HCC1500) were used to further explore the role of SLC1A5 in Gln metabolism. Statistical analysis was performed using chi-squared tests, ANOVA, Spearman’s correlation, Kaplan–Meier analysis, and Cox regression. SLC1A5 mRNA and SLC1A5 protein expression were strongly correlated in luminal B, HER2 + and triple-negative BC (TNBC). Both high SLC1A5 mRNA and SLC1A5 protein expression were associated with larger tumour size, higher grade, and positive axillary lymph node metastases (P < 0.01). Importantly, high SLC1A5 expression correlated with poor BC-specific survival specifically in the highly proliferative luminal subtype (P < 0.001). Furthermore, SLC1A5 knockdown by siRNA or GPNA inhibition significantly reduced cell proliferation and glutamine uptake in ZR-75-1 cells. Our findings suggest SLC1A5 plays a key role in the aggressive luminal BC subtype and represents a potential therapeutic target. Further research is needed to explore SLC1A5 function in luminal BC and its association with Gln metabolism pathways.

Early maternal undernutrition induces sex-related metabolic changes in adult offspring.

Nutritional status during the developmental periods leads to predisposition to several diseases and comorbidities, highlighting metabolic and reproductive changes throughout adult life, and in the next generations. One of the experimental models used to induce undernutrition is litter size expansion, which decreases the availability of breast milk to pups and delays development. This work evaluated the effects of maternal undernutrition induced by litter size expansion, a maternal undernutrition preconception model, on the metabolic and reproductive alterations of the offspring. For this, metabolic and reproductive parameters were evaluated in male and female offspring of female rats reared in normal (NL - 10 pups: 5 males and 5 females) and large (LL - 16 pups: 8 males and 8 females) litters. Male and female offspring of LL mothers presented higher food intake than the offspring of NL mothers. Male offspring from undernourished females showed reduced body weight from lactation to adulthood, nasoanal distance in childhood, increased nasoanal distance, and decreased Lee index in adult life, while female offspring showed decreased nasoanal distance in childhood. The male offspring from LL mothers showed increased insulin plasma levels and glucose tolerance, and reduced triglycerides plasma levels, without changes in the female offspring. These results indicate that neonatal undernutrition in females predisposes their male and female offspring to develop metabolic alterations, without reproductive repercussions, and male offspring seems to be more susceptible to present these metabolic changes than females. Thus, there are sexual differences in the metabolic responses of the offspring elicited by maternal preconceptional undernutrition.

SERT-Deficient Mice Fed Western Diet Reveal Altered Metabolic and Pro-Inflammatory Responses of the Liver: A Link to Abnormal Behaviors.

The inheritance of the short SLC6A4 allele, encoding the serotonin transporter (SERT) in humans, increases susceptibility to neuropsychiatric and metabolic disorders, with aging and female sex further exacerbating these conditions. Both central and peripheral mechanisms of the compromised serotonin (5-HT) system play crucial roles in this context. Previous studies on SERT-deficient (Sert-/-) mice, which model human SERT deficiency, have demonstrated emotional and metabolic disturbances, exacerbated by exposure to a high-fat Western diet (WD). Growing evidence suggests the significance of hepatic regulatory mechanisms in the neurobiology of central nervous system disorders, supporting the 'liver-brain' concept. However, the relationship between aberrant behavior and hepatic alterations under conditions of SERT deficiency remains poorly investigated. One-year-old female Sert-/- mice and their wild-type (WT) littermates were subjected to a control diet (CD) or the WD for a duration of three weeks. The WD had a higher caloric content and was characterized by an elevated saturated fat content (21%) compared to the CD (4.5%) and contained 0.2% cholesterol. Mice were evaluated for anxiety-like behavior, exploration and locomotor activity in the open field test, as well as glucose tolerance and histological indicators of hepatic steatosis. Hepatic pro-inflammatory and metabolism-related gene expression and markers of nitrosative stress, were analyzed utilizing real-time polymerase chain reaction (RT-PCR) and correlated with behavioral and histological outcomes. In comparison to unchallenged mice, Sert-/-/WD mutants, but not the WT/WD group, had increased locomotion and anxiety-like behavior, increased hepatic steatosis, and elevated expression of insulin receptor B and pro-inflammatory cytokines interleukin-1β (Il-1β) and Tnf, as well as decreased expression of leptin receptor B. The two genotypes displayed distinct gene expression patterns of nitric oxide (NO)-related molecules inducible NO synthase (iNos) and arginase (Arg2), insulin receptor-related signaling factors: cluster of differentiation 36 (Cd36), ecto-nucleotide pyrophosphatase/phosphodiesterase (Enpp), protein tyrosine phosphatase N1 (Ptpn1), cytochrome P450 omega-hydroxylase 4A14 (Cyp4a14), acyl-CoA synthetase 1 (Acsl1) and phosphatase and tensin homolog (Pten). Furthermore, there were profound differences in correlations between molecular, histological, and behavioral measurements across the two genotypes. Our findings suggest that the genetic deficiency of SERT results in abnormal hepatic pro-inflammatory and metabolic adaptations in response to WD. The significant correlations observed between behavioral measures and pro-inflammatory and metabolic alterations in WD-fed mice suggest the importance of liver-brain interactions and their role in the aberrant behaviors exhibited by Sert-/- mutants. This study presents the first evidence that altered liver functions are associated with pathological behaviors arising from genetic SERT deficiency.

Impact of single nucleotide polymorphisms (SNPs) in antioxidant-enzyme genes on the concentrations of folate, homocysteine and glutathione in plasma from healthy subjects after folic acid supplementation – a randomized controlled crossover trial

BackgroundOne-carbon metabolism links folate and methionine metabolism and this is essential for nucleotide synthesis in the cells. Alterations in one-carbon metabolism are associated with cardiovascular disease (CVD), type 2 diabetes and cancer. Our aim was to investigate whether SNPs in antioxidant-enzyme genes impact the concentrations of folate in serum (s-folate), plasma total homocysteine (p-tHcy) and total glutathione in plasma (p-tGSH) in healthy subjects after supplementation with folic acid.MethodsIn a randomized, double blind, crossover study, healthy subjects received 0.8 mg folic acid per day or a placebo for two weeks. Twenty-four male, and sixty-seven female subjects participated in this study. Participants were aged 36.4 ± 14.8 years (mean ± SD). We studied SNPs in six genes by PCR methods. The concentrations of s-folate, p-tHcy and p-tGSH were measured in fasting samples with Cobas and an HPLC-fluorescence method. Student T-tests and ANOVA were used for the statistical calculations.Main findingsThe subjects with SNP (rs4880) in superoxide dismutase (SOD2) gene (CC) allele had higher concentrations of s-folate and lower concentrations of p-tHcy than subjects with (CT + TT) alleles, (p = 0.014 and p = 0.012). Contrary to SOD2 (CC) allele, the subjects with SNP (rs1001179) catalase (CAT) CC allele had lower concentrations of s-folate (p = 0.029), higher concentrations of p-tGSH (0.017) and higher concentrations of p-tHcy before and after folic acid supplementations (p = 0.015, p = 0.017) than the subjects with (CT + TT) allele. Glutathione transferase (theta)1 (GST-T1) genotype was associated with higher concentrations of s-folate than GST-T0 before (p = 0.025) and after folic acid supplementation (p = 0.047). SNP (rs1050450) in glutathione peroxidase (GPX1) had also impact on the concentrations of p-tGSH (p = 0.011) in healthy subjects.ConclusionSNPs in SOD2 (rs4880), CAT (rs1001179), and GST1 impact the concentrations of s-folate, and p-tHcy in healthy subjects before and after folic acid supplementation. Our findings suggest that SNPs in antioxidant-genes have a role in health and disease by impacting the concentrations of s-folate, p-tHcy and p-tGSH.

Skeletal muscle disorders as risk factors for type 2 diabetes.

The incidence and prevalence of muscular disorders and of type 2 diabetes (T2D) is increasing and both represent highly significant healthcare problems, both economically and compromising quality of life. Interestingly, skeletal muscle dysfunction and T2D share some commonalities including dysregulated glucose homeostasis, increased oxidative stress, dyslipidemia, and cytokine alterations. Several lines of evidence have hinted to a relationship between skeletal muscle dysfunction and T2D. For instance, T2D affects skeletal muscle morphology, functionality, and overall health through altered protein metabolism, impaired mitochondrial function, and ultimately cell viability. Conversely, humans suffering from myopathies and their experimental models demonstrated increased incidence of T2D through altered muscle glucose disposal function due to abnormal calcium homeostasis, compromised mitochondrial function, dyslipidemia, increased inflammatory cytokines and fiber size alterations and disproportions. Lifestyle modifications are essential for improving and maintaining mobility and metabolic health in individuals suffering from myopathies along with T2D. In this review, we updated current literature evidence on clinical incidence of T2D in inflammatory, mitochondrial, metabolic myopathies, and muscular dystrophies and further discussed the molecular basis of these skeletal muscle disorders leading to T2D.

Effects of patent foramen ovale in migraine: a metabolomics-based study.

Patent foramen ovale (PFO), a cardiac anatomical anomaly inducing abnormal haemodynamics, leads to a paradoxical bypass of the pulmonary circulation. PFO closure might alleviate migraines; however, clinical evidence and basic experiments for the relationship are lacking. To explore the effect of PFO on migraine, 371 migraineurs finishing blood tests and contrast transthoracic echocardiography for the detection of PFO were prospectively included. Multivariate regression analysis revealed that PFO was independently associated with aura, and lower cystatin-C (cys-C) and calcium levels. Among them, patients with PFO who underwent percutaneous PFO closure were continuously followed up 1year after the operation. The intensity of migraine was significantly relieved and the levels of cys-C and calcium increased after PFO closure. Untargeted and targeted metabolomics of plasma from migraineurs before and after PFO closure revealed that 5-HT and glutathione (GSH) metabolites were differentially expressed after PFO closure. The differential metabolites were then validated in the plasma and brain tissues of PFO mouse models by LC-MS/MS analysis. Desorption electrospray ionization mass imaging demonstrated that these metabolic alterations occurred mainly in the posterior cerebral cortex. Collectively, aura, cys-C and calcium could be biomarkers of migraineurs with PFO. PFO might have an impact on the posterior head associated with the regulation of 5-HT and GSH. PFO closure might relieve migraine by improving 5-HT clearance metabolism and ameliorating redox reactions. Our results may provide evidence for an indication of PFO closure in migraine and support the related potential mechanism. KEY POINTS: Aura, and levels of cystatin-C and calcium are biomarkers of migraineurs with a patent foramen ovale (PFO). The clearance of pulmonary metabolism of 5-HT and deoxygenated blood might be the reason for the improvement of migraine symptoms in patients with PFO. The posterior region of the brain is the main area responsible for PFO-induced migraine.

Network topology and metabolic alterations in early- and mid-stage Parkinson's disease: insights from fluorodeoxyglucose PET imaging.

Parkinson's disease (PD) is a neurodegenerative disorder with distinct metabolic alterations in the brain, which are detectable via 18F-FDG PET. This study aims to delineate glucose metabolism patterns and network topology changes across early- and mid-stage PD patients. A total of 80 PD patients (Hoehn-Yahr stages 1-3) were retrospectively analyzed, including 40 early-stage and 40 mid-stage cases, along with 40 age-matched healthy controls. All participants underwent 18F-FDG PET imaging. The brain metabolic activity was quantified, and network topology was assessed using graph theory metrics. Statistical comparisons between PD stages and control groups were performed to identify significant differences in metabolic patterns and network alterations. Early-stage PD patients exhibited hypermetabolism in regions such as the pons and thalamus, with significant differences in metabolic activity compared with controls. Mid-stage PD patients showed more extensive hypermetabolism in the pons, right cerebellum, and putamen, alongside hypometabolism in the cuneus and calcarine regions. Hub node connectivity analysis revealed decreased connectivity in temporal and occipital lobes for both stages, while the limbic and frontal lobes showed enhanced connectivity. Compared with early-stage PD, mid-stage PD had reduced connectivity in the limbic system but increased in the frontal and occipital lobes. 18F-FDG PET imaging reveals progressive metabolic disruptions and network changes in PD, offering potential biomarkers for disease staging and therapeutic targeting, while also aiding in the understanding of disease progression and guiding therapeutic interventions.

Cardiovascular Risk Factor and Atherosclerosis in Rheumatoid Arthritis (RA).

To highlight advancements in managing traditional and rheumatoid arthritis (RA) specific risk factors and the impact of RA treatments on cardiovascular outcomes. Advancements in rheumatoid arthritis management have paralleled declining trends in cardiovascular disease risks. Biomarkers like CRP, Lipoprotein(a), Apolipoprotein B 100, and imaging tools such as coronary artery calcium scoring enhance cardiovascular risk stratification, particularly in intermediate-risk RA patients. While effective RA treatments, have demonstrated substantial cardiovascular benefits, subclass differences were noted in high-risk patients. Increased risk of cardiovascular disease is driven by chronic inflammation, altered lipid metabolism, and traditional risk factors. Effective RA treatment significantly lowers cardiovascular events. Standard treatment of hypertension, diabetes and hypercholesterolemia are effective and lowers RA disease activity and inflammatory markers. While RA is considered a risk enhancing state in calculating CV risk scores, currently there exists no RA disease -specific blood pressure, blood sugar or lipid targets.