N-acetylaspartate from fat cells regulates postprandial body temperature.

N-acetylaspartate (NAA), the brain's second most abundant metabolite, provides essential substrates for myelination through its hydrolysis. However, activities and physiological roles of NAA in other tissues remain unknown. Here, we show aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs systemic NAA levels for postprandial body temperature regulation. Proteomics and mass spectrometry revealed NAA accumulation in WAT of Aspa knockout mice stimulated the pentose phosphate pathway and pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA positively correlates with the pyrimidine intermediate orotidine and this relationship predicted lower body mass index in humans. Using whole-body and tissue-specific knockout mouse models, we demonstrate that fat cells provided plasma NAA and suppressed postprandial body temperature elevation. Furthermore, exogenous NAA supplementation reduced body temperature. Our study unveils WAT-derived NAA as an endocrine regulator of postprandial body temperature and physiological homeostasis.

The role of TMPRSS6 gene polymorphism in iron resistance iron deficiency anaemia (IRIDA): a systematic review.

Iron resistance iron deficiency anaemia is a rare autosomal recessive disorder characterized by hypochromic microcytic anaemia, low transferrin saturation and inappropriately high hepcidin levels. The aetiology of this condition is rooted in genetic variations within the transmembrane serine protease 6 (TMPRSS6) genes, responsible for encoding matriptase-2, a pivotal negative regulator of hepcidin. We conducted a systematic search across four electronic databases, yielding 538 articles in total out of which 25 were finally included and were preceded further, aiming to prognosticate prevalent single nucleotide polymorphisms (SNPs) and detrimental genetic alterations. This review aims to elucidate the effects of various SNPs and pathogenic mutations on both haematological and biochemical parameters, as well as their potential interethnic correlation. Employing bioinformatics tools, we subjected over 100 SNPs to scrutiny, discerning their potential functional ramifications. We found rs1373272804, rs1430692214 and rs855791 variants to be most frequent and were having a significant impact on haematological and biochemical profile. We found that individuals of European ancestry were more prone to have these variants compared to other ethnic groups. In conclusion, this review not only sheds light on the association of TMPRSS6 polymorphism in iron resistance iron deficiency anaemia (IRIDA), but also highlights the critical need for further investigations involving larger sample size and more diverse ethnic groups around the globe. These future studies will be vital for gaining a stronger and more reliable understanding of how these genetic differences are linked to the development of IRIDA.

A rare case of infection and spontaneous rupture in ovarian mucinous cystadenoma.

Ovarian cysts exhibit variable clinical presentations depending on their size, type and resulting sequelae. Rupture of ovarian cysts is infrequent, and cyst infections are even rarer. Here, we report an unusual case involving a young, non-pregnant woman who presented acutely with features of peritonitis and sepsis and was found to have a complex adnexal mass. Following a rigorous diagnostic evaluation, which included an urgent exploratory laparotomy and salpingo-oophorectomy, common diagnoses including tubo-ovarian abscess, endometriotic cyst and pelvic tuberculosis were ruled out. Instead, she was diagnosed with an ovarian mucinous cystadenoma that had become infected, possibly due to pelvic inflammatory disease, leading to spontaneous rupture. Such a presentation has rarely been reported, especially in a non-pregnant setting. Therefore, we emphasise the importance of considering this rare complication as a potential differential diagnosis in similar clinical presentations and discuss the management implications, including the importance of adequately treating pelvic inflammatory disease.

Mind-body practice as a primer to maintain psychological health among pregnant women-YOGESTA-a randomized controlled trial.

Objective: The objective of this study was to investigate the impact of Gestational Yoga-YOGESTA (Gestational Yoga), on the neuropsychology, quality of life, and personality of pregnant women. Design: Open label, randomized controlled trial, used allocation concealment to allocate the treatment. Setting: Department of Obstetrics and Gynecology and Neuroscience Research Lab, Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Participants: We recruited a total of 100 pregnant women visiting the Outpatient Department of Obstetrics and Gynecology. Participants were aged between 18 and 35 with uncomplicated pregnancies and they were randomly assigned to either the Yoga group (YG) or the usual care group (UCG). A total of 77 pregnant women completed both the pre- and post-survey, with 34 participants in the Yoga group and 43 in the Usual care group. Intervention: Pregnant women in their second and third trimesters were provided with a 16-week online Prenatal Yoga intervention. The intervention began after enrollment in the 2nd trimester, specifically between the 16th and 20th week, and was conducted 5 days a week until delivery, with an average intervention period of 47.18 ± 2.031 (mean ± SEM) days. Chief outcome measures: We measured Perceived stress, Depression, Anxiety, Stress, and quality of life by using standard questionnaires. Results: A total of 77 participants were included in the analysis, with 34 assigned to the Yoga group and 43 assigned to the control group. Most of the measured parameters demonstrated significant changes. The Yoga group exhibited a noteworthy decrease in perceived stress, depression, anxiety, and psychological stress, as well as an improvement in the psychological and environmental domains of QOL-BREF. Conversely, the control group demonstrated a significant increase in perceived stress, depression, anxiety, and psychological stress, along with a reduction in the physical, psychological, and social domains of QOL-BREF at the follow-up stage. Although the two groups were similar at baseline, the Yoga group showed substantial enhancements in perceived stress, depression, anxiety, physiological stress, and overall quality of life when compared to the control group at follow-up. Conclusion: The study's findings indicate that stress, anxiety, and depression are more likely to occur as gestational age progresses during pregnancy. Nevertheless, practicing Prenatal Yoga can effectively manage these changes and enhance the quality of life for expectant mothers.Clinical trial registration: Clinical Trials Registry-India, Identifier CTRI/2021/01/030827.

The transcription factor ChREBP links mitochondrial lipidomes to mitochondrial morphology and progression of diabetic kidney disease.

A substantial body of evidence has established the contributions of both mitochondrial dynamics and lipid metabolism to the pathogenesis of diabetic kidney disease (DKD). However, the precise interplay between these two key metabolic regulators of DKD is not fully understood. Here, we uncover a link between mitochondrial dynamics and lipid metabolism by investigating the role of carbohydrate-response element-binding protein (ChREBP), a glucose-responsive transcription factor and a master regulator of lipogenesis, in kidney podocytes. We find that inducible podocyte-specific knockdown of ChREBP in diabetic db/db mice improves key biochemical and histological features of DKD in addition to significantly reducing mitochondrial fragmentation. Because of the critical role of ChREBP in lipid metabolism, we interrogated whether and how mitochondrial lipidomes play a role in ChREBP-mediated mitochondrial fission. Our findings suggest a key role for a family of ether phospholipids in ChREBP-induced mitochondrial remodeling. We find that overexpression of glyceronephosphate O-acyltransferase, a critical enzyme in the biosynthesis of plasmalogens, reverses the protective phenotype of ChREBP deficiency on mitochondrial fragmentation. Finally, our data also points to Gnpat as a direct transcriptional target of ChREBP. Taken together, our results uncover a distinct mitochondrial lipid signature as the link between ChREBP-induced mitochondrial dynamics and progression of DKD.

Vitamin B2 enables regulation of fasting glucose availability.

Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARα, including those required for gluconeogenesis. We also found PPARα knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPARα agonist fenofibrate activated the integrated stress response and refilled amino acid substrates to rescue fasting glucose availability and overcome B2D phenotypes. These findings identify metabolic responses to FAD availability and nominate strategies for the management of organic acidemias and other rare IEMs.

The abiotic removal of organic micropollutants with iron and manganese oxides in rapid sand filters for groundwater treatment.

Rapid sand filters (RSFs) have shown potential for removing organic micropollutants (OMPs) from groundwater. However, the abiotic removal mechanisms are not well understood. In this study, we collect sand from two field RSFs that are operated in series. The sand from the primary filter abiotically removes 87.5% of salicylic acid, 81.4% of paracetamol, and 80.2% of benzotriazole, while the sand from the secondary filter only removes paracetamol (84.6%). The field collected sand is coated by a blend of iron oxides (FeOx) and manganese oxides (MnOx) combined with organic matter, phosphate, and calcium. FeOx adsorbs salicylic acid via bonding of carboxyl group with FeOx. The desorption of salicylic acid from field sand indicates that salicylic acid is not oxidized by FeOx. MnOx adsorbs paracetamol through electrostatic interactions, and further transforms it into p-benzoquinone imine through hydrolysis-oxidation. FeOx significantly adsorbs organic matter, calcium, and phosphate, which in turn influences OMP removal. Organic matter on field sand surfaces limits OMP removal by blocking sorption sites on the oxides. However, calcium and phosphate on field sand support benzotriazole removal via surface complexation and hydrogen bonding. This paper provides further insight into the abiotic removal mechanisms of OMPs in field RSFs.

Circadian clock control of MRTF/SRF pathway suppresses beige adipocyte thermogenic recruitment.

The morphological transformation of adipogenic progenitors into mature adipocytes requires dissolution of actin cytoskeleton with loss of myocardin-related transcription factor (MRTF)/serum response factor (SRF) activity. Circadian clock confers temporal control in adipogenic differentiation, while the actin cytoskeleton-MRTF/SRF signaling transduces extracellular physical niche cues. Here, we define a novel circadian transcriptional control involved in actin cytoskeleton-MRTF/SRF signaling cascade that modulates beige fat thermogenic function. Key components of actin dynamic-MRTF/SRF pathway display circadian regulation in beige fat depot. The core clock regulator, brain and muscle arnt-like 1 (Bmal1), exerts direct transcriptional control of genes within the actin dynamic-MRTF/SRF cascade that impacts actin cytoskeleton organization and SRF activity. Employing beige fat-selective gene-targeting models together with pharmacological rescues, we further demonstrate that Bmal1 inhibits beige adipogenesis and thermogenic capacity in vivo via the MRTF/SRF pathway. Selective ablation of Bmal1 induces beigeing with improved glucose homeostasis, whereas its targeted overexpression attenuates thermogenic induction resulting in obesity. Collectively, our findings identify the clock-MRTF/SRF regulatory axis as an inhibitory mechanism of beige fat thermogenic recruitment with significant contribution to systemic metabolic homeostasis.

A novel model of gestational diabetes: Acute high fat high sugar diet results in insulin resistance and beta cell dysfunction during pregnancy in mice.

Gestational diabetes mellitus (GDM) affects 7-18% of all pregnancies. Despite its high prevalence, there is no widely accepted animal model. To address this, we recently developed a mouse model of GDM. The goal of this work was to further characterize this animal model by assessing insulin resistance and beta cell function. Mice were randomly assigned to either control (CD) or high fat, high sugar (HFHS) diet and mated 1 week later. At day 0 (day of mating) mice were fasted and intraperitoneal insulin tolerance tests (ipITT) were performed. Mice were then euthanized and pancreata were collected for histological analysis. Euglycemic hyperinsulinemic clamp experiments were performed on day 13.5 of pregnancy to assess insulin resistance. Beta cell function was assessed by glucose stimulated insulin secretion (GSIS) assay performed on day 0, 13.5 and 17.5 of pregnancy. At day 0, insulin tolerance and beta cell numbers were not different. At day 13.5, glucose infusion and disposal rates were significantly decreased (p<0.05) in Pregnant (P) HFHS animals (p<0.05) suggesting development of insulin resistance in P HFHS dams. Placental and fetal glucose uptake was significantly increased (p<0.01) in P HFHS dams at day 13.5 of pregnancy and by day 17.5 of pregnancy fetal weights were increased (p<0.05) in P HFHS dams compared to P CD dams. Basal and secreted insulin levels were increased in HFHS fed females at day 0, however at day 13.5 and 17.5 GSIS was decreased (p<0.05) in P HFHS dams. In conclusion, this animal model results in insulin resistance and beta cell dysfunction by mid-pregnancy further validating its relevance in studying the pathophysiology GDM.

The rheumatoid arthritis drug auranofin lowers leptin levels and exerts antidiabetic effects in obese mice.

Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological targeting of inflammation lacks durable therapeutic effects in insulin-resistant conditions. Through a computational screen, we discovered that the FDA-approved rheumatoid arthritis drug auranofin improved insulin sensitivity and normalized obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia in mouse models of T2DM. We also discovered that auranofin accumulation in WAT depleted inflammatory responses to a high-fat diet without altering body composition in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the antidiabetic effects of auranofin. These experiments also revealed that the metabolic benefits of leptin reduction were superior to immune impacts of auranofin in WAT. Our studies uncover important metabolic properties of anti-inflammatory treatments and contribute to the notion that leptin reduction in the periphery can be accomplished to treat obesity and T2DM.

Role of genomic DNA methylation in PCOS pathogenesis: a systematic review and meta-analysis involving case-controlled clinical studies.

Polycystic ovary syndrome (PCOS) is often associated with aberrant DNA methylation. Despite the advances in diagnostics and treatment of PCOS, the pathophysiological mechanism remains unknown. Several genes are epigenetically dysregulated in PCOS and associated with pathological consequences of PCOS and metabolic comorbidities; however, the methylation status of specific genes and to what extent the genes are deregulated in terms of methylation pattern are unknown. This review aimed to analyse the existing data for specific genes and find conclusive evidence of their involvement in PCOS and associated risks. A comprehensive literature search was conducted in five electronic databases. The case-controlled clinical studies using both PCOS and healthy women and evaluating the methylation pattern without any treatment or intervention were included in the study. A random-effect model was used to extract the data for meta-analysis, and outcomes were expressed as standardized mean difference with a 95% CI. From 541 screened records, 41 studies were included in the review and 21 of them were used for meta-analysis of 20 genes. Meta-analysis revealed a significant global DNA hypomethylation in different tissues and peripheral blood of patients with PCOS compared to healthy controls. Specific gene methylation assessment revealed that genes associated with several functions were significantly hypomethylated and hypermethylated in patients with PCOS. This review provides conclusive evidence of epigenetic deregulation of specific genes in PCOS. These genes can potentially be used to develop diagnostic biomarkers or as targets for personalized therapy.

Calcium/calmodulin-dependent protein kinase kinase 2 regulates hepatic fuel metabolism.

OBJECTIVE: The liver is the primary internal metabolic organ that coordinates whole body energy homeostasis in response to feeding and fasting. Genetic ablation or pharmacological inhibition of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) has been shown to significantly improve hepatic health and peripheral insulin sensitivity upon overnutrition with high fat diet. However, the precise molecular underpinnings that explain this metabolic protection have remained largely undefined. METHODS: To characterize the role of CaMKK2 in hepatic metabolism, we developed and challenged liver-specific CaMKK2 knockout (CaMKK2LKO) mice with high fat diet and performed glucose and insulin tolerance tests to evaluate peripheral insulin sensitivity. We used a combination of RNA-Sequencing, glucose and fatty acid istotopic tracer studies, a newly developed Seahorse assay for measuring the oxidative capacity of purified peroxisomes, and a degenerate peptide libarary to identify putative CaMKK2 substrates that mechanistically explain the protective effects of hepatic CaMKK2 ablation. RESULTS: Consistent with previous findings, we show that hepatic CaMKK2 ablation significantly improves indices of peripheral insulin sensitivity. Mechanistically, we found that CaMKK2 phosphorylates and regulates GAPDH to promote glucose metabolism and PEX3 to blunt peroxisomal fatty acid catabolism in the liver. CONCLUSION: CaMKK2 is a central metabolic fuel sensor in the liver that significantly contributes to whole body systems metabolism.

Effect of electrolyte composition on electrochemical oxidation: Active sulfate formation, benzotriazole degradation, and chlorinated by-products distribution.

Electrochemical oxidation is an effective technique for treating persistent organic pollutants, which are hardly removed in conventional wastewater treatment plants. Sulfate and chloride salts commonly used and present in natural wastewater influence the electrochemical degradation process. In this study, the effect of electrolyte composition on the active sulfate species (SO4●⁻ and S2O82⁻) formation, benzotriazole degradation-a model organic compound, and chlorinated by-products distribution have been investigated while using a boron-doped diamond (BDD) anode. Different Na2SO4:NaNO3 and Na2SO4:NaCl ratios with constant conductivity of 10 mS/cm were used in the experiments and applied anode potential was kept constant at 4.3 V vs. Ag/AgCl. The electrogenerated SO4●⁻ and S2O82⁻ formation were faster in 10:1 and 2:1 Na2SO4:NaNO3 ratios than in the 1:0 ratio. The ●OH-mediated SO4●⁻ production has prevailed in 10:1 and 2:1 ratios. However, ●OH-mediated SO4●⁻ production has hindered the 1:0 ratio due to excess chemisorption of SO42⁻ on the BDD anode. Similarly, the faster benzotriazole degradation, mineralization, and lowest energy consumption were achieved in the 10:1 Na2SO4:NaNO3 and Na2SO4:NaCl ratio. Besides, chlorinated organic by-product concentration (AOX) was lower in the 10:1 Na2SO4:NaCl ratio but increased with the increasing chloride ratio in the electrolyte. LC-MS analysis shows that several chlorinated organic transformation products were produced in 0:1 to 2:1 ratio, which was not found in the 10:1 Na2SO4:NaCl ratio. A comparatively higher amount of ClO4⁻ was formed in the 10:1 ratio than in 2:1 to 0:1 ratio. This ClO4⁻ formation train evidence the effective ●OH generation in a sulfate-enriched condition because the ClO4⁻ formation is positively correlated to ●OH concentration. Overall results show that sulfate-enriched electrolyte compositions are beneficial for electrochemical oxidation of biorecalcitrant organic pollutants.

Sclerosing Perivascular Epithelioid Cell Tumor of the Uterus: A Rare Entity Posing Diagnostic Challenge.

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal uterine tumor and the histological variant, sclerosing PEComa is exceedingly rare. Sclerosing PEComas preferentially occur in the retroperitoneum and occurrence in the uterine corpus is seldom seen. These tumors pose a diagnostic challenge and need distinction from morphological mimickers such as epithelioid smooth muscle tumors, endometrial stromal sarcoma, and metastatic carcinoma. Accurate diagnosis can be established coupling histomorphology with immunostaining. The distinction from other entities is of prime importance considering the therapeutic and prognostic implications. Herein, we describe a case of uterine sclerosing variant of PEComa with diagnostic difficulties and key to diagnose this entity.

Cytodiagnosis of bilateral abdominopelvic masses in a postmenopausal woman.

Cytologic diagnosis of ovarian low-grade serous carcinoma.

Identification of At-risk Pregnant Population for Over-the-Counter Drug Usage in Low-Resource Settings.

OBJECTIVE: Nearly 1.5 billion people of an Asian country are living their lives without a country-specific over-the-counter (OTC) drug list. A study was planned to assess the understanding and practice of OTC medication consumption in the pregnant population. METHODS: A questionnaire-based cross-sectional study evaluating different perspectives on OTC drug consumption was planned in around 500 pregnant women attending tertiary care outpatient antenatal clinics. The association of knowledge, attitude and practice versus indications, knowledge regarding harmful effects possible, reasons for choosing OTC medication, the practice of consulting nonmedical persons and drug interactions with the disease or prescription medications was determined. Regression analysis was performed in statistical software R. RESULTS: Seven percent (36/516) of pregnant women were found to consume oral antimicrobials without prescription. Local chemist consultation was the most common channel (72.48%) to procure the OTC medicines. Participants with good knowledge score showed an odds ratio (OR) of 1.87 (95% C.I.; 1.28-2.73), 1.6 (95% C.I.; 0.99-2.63), 1.66 (95% C.I.; 1.14-2.42) and 2.66 (95% C.I.; 1.49-4.89) for self-medication encouragement tendency possible, restricting sale of OTC medications, the habit of reading drug leaflets and understanding the potentially harmful effects, with OTC drugs, respectively. Right-attitude participants showed an OR of 1.89 (95% C.I.; 1.29-2.80) and 1.8 (95% C.I.; 1.19-2.76) for identifying knowledge of acetaminophen overdose and liver damage link as well as the disease symptom masking possibility with OTC, respectively. Participants with insufficient knowledge and attitude scores showed an association with more OTC antacid-antiemetics and analgesic use, respectively. CONCLUSION: Antenatal pregnant women need to be guided on avoiding OTC antimicrobial usage. Both obstetricians and regulators have to play an active role in educating pregnant women and contributing to developing country-specific OTC drug lists with the guidelines. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13224-021-01481-2.

PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes.

Cardiac metabolism is a high-oxygen-consuming process, showing a preference for long-chain fatty acid (LCFA) as the fuel source under physiological conditions. However, a metabolic switch (favoring glucose instead of LCFA) is commonly reported in ischemic or late-stage failing hearts. The mechanism regulating this metabolic switch remains poorly understood. Here, we report that loss of PHD2/3, the cellular oxygen sensors, blocks LCFA mitochondria uptake and ß-oxidation in cardiomyocytes. In high-fat-fed mice, PHD2/3 deficiency improves glucose metabolism but exacerbates the cardiac defects. Mechanistically, we find that PHD2/3 bind to CPT1B, a key enzyme of mitochondrial LCFA uptake, promoting CPT1B-P295 hydroxylation. Further, we show that CPT1B-P295 hydroxylation is indispensable for its interaction with VDAC1 and LCFA ß-oxidation. Finally, we demonstrate that a CPT1B-P295A mutant constitutively binds to VDAC1 and rescues LCFA metabolism in PHD2/3-deficient cardiomyocytes. Together, our data identify an oxygen-sensitive regulatory axis involved in cardiac metabolism.

Endothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin.

The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. Here we show osteocalcin, recognized as a bone-secreted metabolic hormone, is expressed in mouse primary endothelial cells isolated from heart, lung and liver. In human osteocalcin promoter-driven green fluorescent protein transgenic mice, green fluorescent protein signals are enriched in endothelial cells lining aorta, small vessels and capillaries and abundant in aorta, skeletal muscle and eye of adult mice. The depletion of lipoprotein receptor-related protein 1 induces osteocalcin through a Forkhead box O -dependent pathway in endothelial cells. Whereas depletion of osteocalcin abolishes the glucose-lowering effect of low-density lipoprotein receptor-related protein 1 depletion, osteocalcin treatment normalizes hyperglycemia in multiple mouse models. Mechanistically, osteocalcin receptor-G protein-coupled receptor family C group 6 member A and insulin-like-growth-factor-1 receptor are in the same complex with osteocalcin and required for osteocalcin-promoted insulin signaling pathway. Therefore, our results reveal an endocrine/paracrine role of endothelial cells in regulating insulin sensitivity, which may have therapeutic implications in treating diabetes and insulin resistance through manipulating vascular endothelium.