Disorders Of Homeostasis Research Articles

Multiple effects of kisspeptin on neuroendocrine, reproduction, and metabolism in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a highly prevalent and heterogeneous disease characterized by a combination of reproductive and endocrine abnormalities, often associated with metabolic and mental health disorders. The etiology and pathogenesis of PCOS remain unclear, but recent research has increasingly focused on the upstream mechanisms underlying its development. Among these, kisspeptin (KISS) signaling has emerged as a pivotal component in the regulation of the hypothalamic-pituitary-gonadal axis, with significant roles in reproductive function, energy regulation, and metabolism. Women with PCOS commonly exhibit disruptions in gonadotropin secretion, including elevated luteinizing hormone (LH) levels, imbalanced LH/follicle-stimulating hormone (FSH) ratios, and increased androgen levels, all of which are usually parallel with abnormal KISS signaling. Furthermore, alterations in the KISS/KISS1R system within the central and circulatory systems, as well as peripheral tissues, have been implicated in the development of PCOS. These changes affect multiple pathophysiological domains, including reproductive function, energy regulation, metabolic homeostasis, inflammatory response, and emotional disorders, and are further influenced by lifestyle and environmental factors. This review aims to comprehensively summarize the existing experimental and clinical evidence supporting these roles of KISS in PCOS, with the goal of establishing a foundation for future research and potential clinical applications.

Phenylmercury stress induces root tip swelling through auxin homeostasis disruption

We previously reported that in Arabidopsis, the phytochelatin-mediated metal-detoxification machinery is also essential for organomercurial phenylmercury (PheHg) tolerance. PheHg treatment causes severe root growth inhibition in cad1-3, an Arabidopsis phytochelatin-deficient mutant, frequently accompanied by abnormal root tip swelling. Here, we examine morphological and physiological characteristics of PheHg-induced abnormal root tip swelling in comparison to Hg(II) stress and demonstrate that auxin homeostasis disorder in the root is associated with the PheHg-induced root tip swelling. Both Hg(II) and PheHg treatments severely inhibited root growth in cad1-3 and simultaneously induced the disappearance of starch-containing plastid amyloplasts in columella cells. However, further confocal imaging of the root tip revealed distinct effects of Hg(II) and PheHg toxicity on root cell morphology. PheHg treatment suppressed most major genes involved in auxin homeostasis, whereas these expression levels were up-regulated after 24 h of Hg(II) treatment. PheHg-triggered suppression of auxin transporters PIN1, PIN2, and PIN3 as GFP-fusion proteins was observed in the root tip, accompanied by an auxin reporter DR5rev::GFP signal reduction. Supplementation of indole-3-acetic acid (IAA) drastically canceled the PheHg-induced root swelling, however, Hg(II) toxicity was not mitigated by IAA. The presented results show that the collapse of auxin homeostasis especially in root tips is a cause for the abnormal root tip swelling under PheHg stress conditions.

Диагностическая эффективность и прогностическая значимость антропометрических параметров как маркеров гиперлептинемии у подростков

Leptin is an energy homeostasis marker synthesized by cells of adipose tissue (adipocytes) and gastric mucosa. The search for clinical and anthropometric parameters associated with energy homeostasis disorders in excess body weight (BW) and obesity is necessary for stratification of patients at risk for early implementation of energy homeostasis disorders. The purpose of this re-search was to evaluate the relationship between serum leptin concentration and anthropometric parameters reflecting the topography of subcutaneous fat in adolescents of different ethnicities with excess BW and obesity in order to identify the most informative anthropometric parameters of energy homeosta-sis disorders. Materials and methods used: a single-center cross-sectional study of 362 adolescents aged 11 to 17 y/o residing in the Republic of Buryatia and the Irkutsk Oblast of Russia was conducted in 2015-2016 that included the participants as follows: 186 Caucasians (46 boys/140 girls) and 176 Mongoloids (96 boys/80 girls); 136 adolescents in the control group (38%) and 226 adolescents with excess BW and obesity (62%). All par-ticipants had their linear height, BW, waist (WC) and hip (HC) circumference, skinfold thickness measured as well as the body mass index (BMI, in kg per m2) calculated. The concentrations of glucose, total cholesterol, high-density, low-density and very low-density lipoprotein cholesterol, triglycerides and in-sulin were determined. The HOMA index was calculated. Serum leptin was de-termined by enzyme immunoassay using DBC Leptin ELISA kit (Diagnostics Biochem Canada Inc., Canada) with detection using BioTek Elx808 Microplate Spectrophotometer (Agilent Technologies, Inc., USA). Results: a strong posi-tive correlation was found between serum leptin levels and SDS BMI and trip-onderal BMI in adolescents of both ethnic groups: in Caucasian boys r=0.747 (p<0.001), r=0.767 (p<0.001), in Caucasian girls r=0.687 (p<0.001) and r=0.695 (p<0.001); in Mongoloid boys r=0.765 (p<0.001), r=0.852 (p<0.001), in Mongoloid girls r=0.612 (p<0.001), r=0.667 (p<0.001), respectively. Ac-cording to the results of ROC analysis, AUC WC/height showed good diagnos-tic significance for detecting hyperleptinemia (AUC=0.8-0.9) in adolescents from all the studied groups. Conclusion: the triponderal index and the WC/height ratio are informative anthropometric indicators for energy metabo-lism disorders and hyperleptinemia in Caucasian and Mongoloid adolescents of both genders with excess BW and obesity.

Ferroptosis as a Therapeutic Target in Neurodegenerative Diseases: Exploring the Mechanisms and Potential of Treating Alzheimer's Disease and Parkinson's Disease.

Amidst the rising global burden of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, there is an urgent need for novel therapeutic strategies to combat these debilitating conditions. These diseases are characterized by progressive neural dysfunction leading to cognitive impairments, for which current therapeutic strategies remain palliative at best. Recently, the discovery of ferroptosis, a novel cell death mode that is different from apoptosis and autophagy, has opened new avenues in the field of cognitive research. With in-depth research on ferroptosis, the clinical significance of iron homeostasis disorders and lipid peroxidation in the occurrence, development, and treatment of neurodegenerative diseases are gradually becoming apparent. This study aims to elucidate the roles of ferroptosis in the context of neurodegeneration and to explore its potential as a therapeutic target. By unraveling the intricate relationship between iron homeostasis disorders, oxidative damage, and lipid metabolism disturbances in these diseases, new intervention targets are revealed. It offers a new dimension to the management of neurocognitive impairments in Alzheimer's and Parkinson's diseases. The implications of these findings extend beyond just Alzheimer's and Parkinson's diseases. They also have relevance with other neurological conditions characterized by oxidative stress and iron dysregulation. This review contributes to increased knowledge of ferroptosis and provides a foundational understanding that could lead to the development of innovative therapeutic strategies. Ultimately, it may alleviate the development of neurodegenerative diseases and improve cognitive function by preventing ferroptosis, which has not only academic significance but also potential clinical significance.

Res@ZIF-90 suppress gastric cancer progression by disturbing mitochondrial homeostasis

BackgroundGastric cancer (GC) is still a serious threat to human health worldwide. As a natural compound, resveratrol has been proven to have anti-tumor activity, and the nano-delivery carrier has shown its excellent ability to retain and control drug release. MethodsRes@ZIF-90 underwent synthesis via a one-pot method and subsequent characterization encompassing Dynamic Light Scattering, Scanning Electron Microscope, Transmission Electron Microscope, and UV–vis absorption spectroscope. The release of resveratrol from Res@ZIF-90 across varied pH environments were delineated employing High Performance Liquid Chromatography. The mitochondrial targeting of Res@ZIF-90 was scrutinized utilizing Fluorescent Inverted Microscopy. The cytotoxic impact of Res@ZIF-90 on HGC-27 cells was evaluated through CCK-8 assay, Live/Dead staining, scratch test, and JC-1 assay. Furthermore, the HGC-27 tumor-bearing mice model was established to explore the anti-tumor effect of Res@ZIF-90. ResultsZIF-90 can effectively release resveratrol under acidic (pH = 5.5) conditions. In addition, Res@ZIF-90 could be taken up by cells and localized into mitochondria. ZIF-90 has no obvious cytotoxicity at the experimental concentration, while Res@ZIF-90 was more cytotoxic to HGC-27 cells than free resveratrol at the same concentration. Res@ZIF-90 significantly reduced the expressions of PGCS 1α, TFAM, PINK1, and COX IV, which together induced mitochondrial homeostasis disorders and inhibited the tumor growth of HGC-27 tumor-bearing mice in vivo. ConclusionsRes@ZIF-90 can inhibit the progression of gastric cancer by targeting the mitochondria of gastric cancer cells and disrupting mitochondrial homeostasis to produce cytotoxic effects. Res@ZIF-90 may be a promising antitumor drug with potential application value.

Increased Rab1a accelerates osteoarthritis by inhibiting autophagy via activation of the mTORC1-S6K pathway

IntroductionCartilage degradation is a critical alteration in the progression of osteoarthritis (OA) due to the disorder of chondrocyte metabolic homeostasis. Autophagy plays an important role in maintaining intracellular homeostasis. Recent investigations have increasingly underscored the importance of autophagy in modulating the pathological mechanisms underlying OA. Ras-related protein Rab-1a (Rab1a) has been illustrated to regulate autophagy in many diseases but not in OA. ObjectivesThis study aims to elucidate whether Rab1a could regulate the development of OA through modulation of chondrocyte autophagy and apoptosis. MethodsProteomic sequencing, Western blotting, and immunohistochemistry were applied to detect the expression level of Rab1a in vitro and in vivo. Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were rigorously identified. The effects of Rab1a and the interaction between Rab1a, mTORC1, autophagy and apoptosis were explored by qPCR, Western blotting, and immunofluorescence. An experimental mouse OA model was also performed to confirm the role of Rab1a in OA pathogenesis in vivo. Histological analysis was employed to demonstrate cartilage damage. ResultsRab1a expression was significantly upregulated in inflamed chondrocytes and knee OA cartilage. Inhibition of Rab1a partially attenuated the degradation of the extracellular matrix and cell apoptosis both in vitro and in vivo, whereas overexpression of Rab1a intensified cartilage matrix degradation and cellular apoptosis. Additionally, elevated Rab1a levels were observed to suppress autophagy and activate the mTORC1-S6K signaling pathway, thereby aggravating OA pathogenesis. ConclusionThe augmentation of Rab1a expression impairs autophagy and promotes apoptosis through the activation of the mTORC1-S6K signaling pathway, further exacerbating OA pathogenesis. This finding suggests that Rab1a serves as a promising and innovative therapeutic target for the prevention and treatment of OA.

International expert consensus statement on the diagnosis and management of congenital nephrogenic diabetes insipidus (arginine vasopressin resistance).

Congenital nephrogenic diabetes insipidus (NDI; also known as arginine vasopressin resistance) is a rare inherited disorder of water homeostasis, caused by insensitivity of the distal nephron to arginine vasopressin. Consequently, the kidney loses its ability to concentrate urine, which leads to polyuria, polydipsia and the risk of hypertonic dehydration. The diagnosis and management of NDI are very challenging and require an integrated, multidisciplinary approach. Here, we present 36 recommendations for diagnosis, treatment and follow-up in both children and adults, as well as emergency management, genetic counselling and family planning, for patients with NDI. These recommendations were formulated and graded by an international group of experts in NDI from paediatric and adult nephrology, urology and clinical genetics from the European Rare Kidney Disease Reference Network and the European Society of Paediatric Nephrology, as well as patient advocates, and were validated by a voting panel in a Delphi process. The goal of these recommendations is to provide guidance to health care professionals who care for patients with NDI and to patients and their families. In addition, we emphasize the need for further research on different aspects of this potentially life-threatening disorder to support the development of evidence-based guidelines in the future.

Cytokine Status Disorders and Their Role in the Pathogenesis of Chronic Abacterial Prostatitis of Non-Inflammatory Nature

Relevance. Chronic abacterial prostatitis (CAP) of a non-inflammatory nature remains a complex disease in terms of proven etiological factors and pathogenetic mechanisms. Recent studies define it as a nosology based on homeostasis disorders with damaging effects directed towards the prostate. Pathogenetically, this is cytokine aseptic inflammation and lipid peroxidation, which occurs under conditions of compromised antioxidant protection. Objective — to study the cytokine status in the experimental reproduction of non-inflammatory CAP models.Materials and methods. 100 male white rats were studied, 25 formed a control group, and the remaining ones were divided into 3 equal groups for experiments on creating various models of CAP and systemic chronic stress. At the end of the experiment, blood was taken and the prostate was removed to obtain a homogenate. The substrates were used to determine pro- and anti-inflammatory cytokines.Results. In the isolated CAP model of category IIIB, cytokine disorders were detected in prostate tissue (to a greater extent), and at the systemic level (to a lesser extent). The model of systemic immobilization stress proved the possibility of triggering cytokine disorders in prostate tissue characteristic of CAP IIIB. Severe homeostasis disorders at the systemic and local levels were observed in experiments where both systemic stress and the local CAP model were modeled.Conclusion. Cytokine imbalance plays a key role in the pathogenesis of СAP IIIB. At the same time, systemic and organ cytokine disorders interact with each other and, under certain circumstances, aggravate the damaging effect of each other.

Heterogenous Origins of Calcium Homeostasis Disorders Arising from Five Heterozygous Calcium-Sensing Receptor Variants.

The human calcium-sensing receptor (CaSR) plays a key role in calcium homeostasis, and most identified CASR variants are associated with hypercalcemic and hypocalcemic disorders. Here we characterized the pharmacological implications of five heterozygous CASR variants from individuals with familial hypocalciuric hypercalcemia 1 [FHH1: Y63C, I81T, Q459R, W818stop] or autosomal dominant hypocalcemia 1 [ADH1: R955stop]. Total and cell surface expression levels of wild-type (WT) and variant CaSRs expressed in human embryonic kidney 293T (HEK293T) cells were determined using ELISA, and the pharmacological properties of the receptors were delineated in two functional assays. The Y63C and I81T variations in the extracellular domain (ECD) of CaSR yielded markedly reduced cell surface expression and Ca2+ responsiveness, while Q459R displayed WT-like expression and functional properties. Truncation of the 7-transmembrane domain (7TMD) in W818stop eliminated cell surface expression, whereas R955stop in the intracellular carboxy-terminal yielded modestly increased surface expression and Ca2+ potency compared with WT CaSR. Interestingly, the effectiveness of positive allosteric modulators (PAMs) at the variants varied. Ca2+-mediated signaling through Y63C and I81T was significantly augmented by 7TMD-binding PAMs (NPS R-568 and Evocalcet) but not by ECD-binding PAMs (Etelcalcetide and Nb4), whereas signaling through Q459R and R955stop were robustly potentiated by all four PAMs. While the molecular phenotypes exhibited by the five CaSR variants concord with the clinical phenotypes in individuals harboring them, CASR variant-induced calcium homeostasis disorders clearly arise from diverse molecular origins, and the effectiveness of calcimimetics in these disorders could differ depending on the specific variants.

Monitoring Calcium-Sensing Receptor (CaSR)-Induced Intracellular Calcium Flux Using an Indo-1 Flow Cytometry Assay.

The calcium-sensing receptor (CaSR) has a critical role in maintaining serum calcium concentrations within the normal physiological range, and mutations in the receptor, or components of its signaling and trafficking pathway, cause disorders of calcium homeostasis. Inactivating mutations cause neonatal severe hyperparathyroidism or familial hypocalciuric hypercalcemia (FHH), while gain-of-function mutations cause autosomal dominant hypocalcemia (ADH). Characterizing the functional impact of mutations of the CaSR, and components of the CaSR-signaling pathway, is clinically important to enable correct diagnoses of FHH and ADH, optimize management, and prevent inappropriate parathyroidectomy or vitamin D supplementation. CaSR signals predominantly by activating the G-alpha subunit-11 to mobilize calcium release from intracellular stores. Thus, measurement of CaSR-induced intracellular calcium (Ca2+i) signaling is the gold standard method to investigate the pathogenicity of CaSR genetic variants. This protocol describes a method to assess CaSR-induced Ca2+I signaling using the Indo-1 calcium indicator dye and flow cytometry. This method has been used to assess multiple genetic variants in CaSR and components of its signaling and trafficking pathway in HEK293 cells.

The Effect of Selenium, Zinc, and their Combined Supplementation on Cardiometabolic Biomarkers-comparing their Effects in the Energy Restriction and High-fat Diet Methods in Obese Rats.

The fat distribution in the body determines the risk of cardiometabolic problems such as heart disease and diabetes. Some dietary supplements, such as selenium and zinc, possess lipolytic and anti-angiogenic functions, which may be a useful strategy in reducing the risk of cardiometabolic complications. This study evaluated the effect of zinc (Zn), selenium (Se), and their combined supplementation on cardiometabolic risk factors in male Wistar rats in two nutritional models, including caloric restriction (CR) and high-fat diet (HFD). The 48 male Wistar rats were divided into three diet groups (HFD and CR and normal diet (ND)). The HFD group was subdivided into four groups (N=8 rats in each group) that received (HFD+Se), (HFD+Zn), (HFD+Zn+Se), and HFD alone as the control group, respectively. After 8 weeks of intervention, biochemical tests were performed on serum levels, including measurement of lipid profile (triglyceride, Cholesterol, LDL and HDL) and glycemic indices (fasting blood sugar, insulin and insulin sensitivity markers). The results showed that supplementation significantly improved the lipid profile (P <0.001). A comparison of glucose homeostasis indices in the study groups also showed a significant difference. The serum level of glucose was higher in the HFD group than in the intervention groups (P <0.001). Also, the rate of improvement of lipid profile and glycemic indexes in the group receiving the combination of two supplements showed a better trend than those receiving zinc and selenium alone. However, the values were statistically significant only for glucose homeostasis indices (P <0.001). Although obesity is a multifactorial condition, controlling other risk factors, zinc and selenium and their combined supplementation can lead to promising solutions for the treatment of obesity-induced glucose and lipid homeostasis disorders.

Sirtuin Expression in Insulin-Sensitive Tissues of Rats with Impaired Glucose Tolerance is not Affected by Resistance Training or Zinc Supplementation.

While physical activity and zinc supplementation have shown benefits in diabetes management, little is known about their effect on less severe glucose homeostasis disorders, such as impaired glucose tolerance. On the other hand, sirtuins have an important role in glucose metabolism and insulin sensitivity, but to date, there is no information about the impact of zinc supplementation or physical activity on their regulation in individuals with impaired glucose homeostasis. The aim of this study was to assess the effect of supplemental zinc, muscle-resistance training, and their combination on the expression of selected sirtuins in insulin-sensitive tissues of rats with impaired glucose tolerance. Thirty male Wistar rats with impaired glucose tolerance were fed a high-fat diet for 12 weeks while subjected to zinc supplementation, resistance training, both, or none. Morphometric and metabolic evaluations were performed at the end of the experimental period, and gene expression of sirtuins 1, 2, 4, and 7 was assessed in liver, gastrocnemius muscle, and white adipose tissue. Results showed that zinc supplementation and/or resistance training did not improve metabolic parameters of rats with impaired glucose tolerance, nor did they affect the expression of selected sirtuins in any of the tissues evaluated. However, the expression of some sirtuins was associated with metabolic parameters in a tissue-specific manner. Additional studies are needed to evaluate whether zinc supplementation and/or resistance training can improve metabolic status or modulate sirtuins expression in advanced stages of impaired glucose homeostasis.

Metabolic and genetic basis of liver damage in mechanical jaundice of non-tumor genesis in obstractive cholangitis or biliary pancreatitis

Aim. Establishment of versatile mechanisms behind liver damage in mechanical jaundice of non-tumor genesis combined with acute obstructive cholangitis or acute biliary pancreatitis.Materials and methods. In total, 64 cases of mechanical jaundice developed against the background of cholelithiasis were studied. Group 1 included 30 patients with mechanical jaundice combined with cholangitis; group 2 included 34 patients with acute biliary pancreatitis. Bile duct reconstruction was performed by an open method followed by standardized treatment. The intensity of membrane lipid peroxidation was determined by the level of diene conjugates, malonic dialdehyde, superoxide dismutase activity, and the activity of phospholipase A2. The severity of endotoxemia was estimated; a molecular-genetic test of the polymorphism of antioxidant system genes was performed.Results. The significance of the gene polymorphism of antioxidant enzymes in the formation of systemic alterative phenomena and severity of liver damage in mechanical jaundice complicated by cholangitis or acute pancreatitis was determined by allocation of patient subgroups depending on the presence of mutant allele T in the gene of superoxide dismutase SOD2 (C1147T). The groups of patients with the presence of such polymorphism, regardless of the combined diseases, demonstrated more pronounced and prolonged liver functional disorders and homeostasis disorders after restoration of biliary tract patency.Conclusion. The presence of mutant alleles of the SOD2 gene (C47T) in patients with non-tumor mechanical jaundice combined with acute cholangitis or pancreatitis is associated with an increase in the intensity of damage mechanisms at the systemic level, primarily with membrane lipid peroxidation, which correlates with the severity of liver damage (r = 0.834–0.967; p &lt; 0.05).

Construction of an adverse outcome pathway for the cardiac toxicity of bisphenol a by using bioinformatics analysis

Bisphenol A (BPA), a common endocrine disruptor, has shown cardiovascular toxicity in several epidemiological studies, as well as in vivo and in vitro experimental studies. However, the related adverse outcome pathway (AOP) of BPA toxicity remains unraveled. This study aimed to develop an AOP for the cardiac toxicity of BPA through bioinformatics analysis. The interactions among BPA, genes, phenotypes, and cardiac toxicity were retrieved from several databases, including the Comparative Toxicogenomics Database, Computational Toxicology, DisGeNet, and MalaCards. The target genes and part of target phenotypes were obtained by Venn analysis and literature screening. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed for target genes by using the DAVID online analysis tool to obtain other target phenotypes. AOP hypotheses from BPA exposure to heart disease were established and evaluated comprehensively by a quantitative weight of evidence (QWOE) method. The target genes included ESR2, MAPK1, TGFB1, and ESR1, and the target phenotypes included heart contraction, cardiac muscle contraction, cellular Ca2+ homeostasis, cellular metabolic process, heart development, etc. Overall, the AOP of BPA cardiac toxicity was deduced to be as follows. Initially, BPA bound with ERα/β and then activated the MAPK, AKT, and IL-17 signaling pathways, leading to Ca2+ homeostasis disorder and increased inflammatory response. Subsequently, cardiac function was impaired, causing coronary heart disease, arrhythmia, cardiac dysplasia, and other heart diseases. According to the Bradford–Hill causal considerations, the score of AOP by QWOE was 69, demonstrating a moderate confidence and providing clues on cardiotoxicity-assessment procedure and further studies on BPA.

Disorders of potassium homeostasis after kidney transplantation.

Disturbances of potassium balance are often encountered when managing kidney transplant recipients (KTR). Both hyperkalemia and hypokalemia may present either as medical emergencies or chronic outpatient abnormalities. Despite the high incidence of hyperkalemia and its potential life-threatening implications, consensus on its management in KTR is lacking. Hypokalemia in KTR is also well-described, although it is given less attention by clinicians compared to hyperkalemia. This article discusses the etiology, pathophysiology and management of both types of potassium disorders in KTR. Once any emergent situation has been corrected, treatment approaches include correcting insulin deficiency if present, adjusting non-immunosuppressive and immunosuppressive medications, eliminating or supplementing potassium as needed, and dietary counselling. Although commonly of multifactorial etiology, ascertaining the specific cause in a particular patient will help guide successful management. Monitoring KTR through regular laboratory testing is essential to detect serious disturbances in potassium balance since patients are often asymptomatic.

Pathogenesis of Post-Covid Syndrome. The Key Role of the Immune System

When considering the pathogenesis of COVID-19 and post-Covid syndrome, disorders associated with the immune system come to the fore. Complexes of immune dysregulation, dissonant reactions of the patient’s innate and adaptive immune systems, should be considered the main causes of the complex pattern of lesions. These processes include cellular inflammation, disorder of hemovascular homeostasis, and organ damages. Consistent analysis of these processes serves as the basis for choosing therapeutic strategy schemes, taking into account clinical indicators and personal characteristics of patients.

Resveratrol stimulates brown of white adipose via regulating ERK/DRP1-mediated mitochondrial fission and improves systemic glucose homeostasis.

Diabetes mellitus and metabolic homeostasis disorders may benefit from white adipose tissue (WAT) browning, which is associated with mitochondrial fission. Resveratrol, a dietary polyphenol, exhibits beneficial effects against abnormalities related to metabolic diseases. However, it remains unknown whether resveratrol contributes to WAT browning by regulating mitochondrial fission. We administered resveratrol (0.4% mixed with control) to db/db mice for 12 weeks, measuring body weight, oral glucose tolerance, insulin tolerance, and histological changes. The uncoupling protein 1 (UCP1) and dynamin-related protein 1 (DRP1) expressions in the epididymal WAT were assessed via immunoblotting. We found that resveratrol improved systemic glucose homeostasis and insulin resistance in db/db mice, which was associated with increased UCP1 in epididymal WAT. Resveratrol-treated mice exhibited more fragmented mitochondria and increased phosphorylation of DRP1 in the epididymal WAT of the db/db mice. These results were further confirmed in vitro, where resveratrol induced extracellular signal-regulated kinase (ERK) signaling activation, leading to phosphorylation of DRP1 at the S616 site (p-DRP1S616) and mitochondrial fission, which was reversed by an ERK inhibitor in 3T3-L1 adipocytes. Resveratrol plays a role in regulating the phosphorylation of ERK and DRP1, resulting in the promotion of beige cells with epididymal WAT and the improvement of glucose homeostasis. Our present study provides novel insights into the potential mechanism of resveratrol-mediated effects on WAT browning, suggesting that it is, at least in part, mediated through ERK/DRP1-mediated mitochondrial fission.

Prognostic algorithm for early diagnosis of subcritical conditions as predictors of sudden cardiac death

Aim. To develop a method for early diagnosis of subcritical homeostasis disorders leading to sudden cardiac death (SCD). The basis is to improve the efficiency of predictive algorithms.Material and methods. This pilot, controlled, open-label, randomized, prospective clinical trial included 220 patients at risk of SCD and 150 patients without risk of SCD. Main and control groups was formed according to the global cardiovascular risk score. Based on the informative features proposed by specialized experts using multivariate statistics methods (discriminant analysis), two condition classes were formed. The conducted exploratory analysis confirmed the significance of diagnostic criteria in relation to SCD manifestation (manifestation of cardiac arrest — MCA), which is an integral assessment of a fatal complication. The development of decision rules was carried out on the basis of soft computing technology.Results. Taking into account the priority of clinical research, namely, the identification of subcritical stages of MCA, a classifier is proposed according to basic severity of patients — the severity of critical condition risk (SCCR). The discriminant function and intersection areas between MCA subclasses in the conditions of early SCD diagnosis determine the transition to soft computing technology. Membership functions for severe MCA are formed, followed by their iteration according to E. Shortliffe. The final decision rule, using a fuzzy classifier, differentiates the MCA into stages with different SCCR. In parallel with standard protocols for the management of severe somatic patients (chronic obstructive pulmonary disease, chronic kidney disease, hepatocellular failure), based on the proposed algorithm with an integral assessment of critical conditions, using the MCA decision rule in the main group in 30,5% of cases, subcritical stage was revealed, followed by targeted treatment and preventive support. In the first group, a subcritical condition was detected in 67 patients (30,5%); a critical condition without SCD — in 3 patients (1,4%). In all noted cases, early prevention of SCD was successfully carried out (these patients were transferred to a class with a lower SCD degree). Using conventional prognostic scores in this group, 46 patients (20,9%) were identified with a subcritical condition and 1 (0,4%) with a critical condition. In the control group, subcritical condition was determined in 35 patients (23,3%), of which 17 patients (11,3%) had a moderate risk of SCD. Using conventional prognostic scores, 23 patients (15,3%) with subcritical condition were identified.Conclusion. In the conditions of intensive care unit, general medicine departments, hemodialysis department, cardiac surgery, and organ transplantation department, an algorithm for early diagnosis and risk stratification of SCD with an integral assessment (MCA) should be used. The fuzzy classifier MCA according to SCCR makes it possible to carry out timely correction of treatment measures in addition to standard protocols.

The Role of Deubiquitinating Enzymes in Primary Bone Cancer.

Bone is a living, intricate, and dynamic tissue providing locomotion and protection of the body. It also performs hematopoiesis and mineral homeostasis. Osteosarcoma (OS), Ewing sarcoma (ES), and chondrosarcoma (CS) are primary bone cancers. OS and ES mostly develop in younger individuals, and CS generally develops in adults. Ubiquitination regulates numerous cellular processes. The deubiquitinating enzymes (DUBs) detach the ubiquitin molecules from the ubiquitin labeled substrate, altering ubiquitinated protein functions and regulating protein stability via various signaling pathways. Protein homeostasis and bone remodeling are both crucially influenced by the UPS. Recently, there have been several reports on DUBs involved in bone homeostasis and various bone disorders through the regulation of osteoblasts and osteoclasts via NF-κB, Wnt/β-catenin, TRAF6, TGFβ, ERK1/2, and PI3K/Akt pathways. However, DUBs regulating function in bone homeostasis is still in its infancy. Here, we summarized several recent identifications on DUBs, with a focus on their role in bone cancer progression. Therefore, the study attempts to summarize association with the expression level of DUBs as key factors driving bone cancers and alsoprovide new insights on DUBs as key pharmacologic targets for bone cancer therapeutics.

Mammalian copper homeostasis: physiological roles and molecular mechanisms.

In the past decade, evidence for the numerous roles of copper (Cu) in mammalian physiology has grown exponentially. The discoveries of Cu involvement in cell signaling, autophagy, cell motility, differentiation, and regulated cell death (cuproptosis) have markedly extended the list of already known functions of Cu, such as a cofactor of essential metabolic enzymes, a protein structural component, and a regulator of protein trafficking. Novel and unexpected functions of Cu transporting proteins and enzymes have been identified, and new disorders of Cu homeostasis have been described. Significant progress has been made in the mechanistic studies of two classic disorders of Cu metabolism, Menkes disease and Wilson's disease, which paved the way for novel approaches to their treatment. The discovery of cuproptosis and the role of Cu in cell metastatic growth have markedly increased interest in targeting Cu homeostatic pathways to treat cancer. In this review, we summarize the established concepts in the field of mammalian Cu physiology and discuss how new discoveries of the past decade expand and modify these concepts. The roles of Cu in brain metabolism and in cell functional speciation and a recently discovered regulated cell death have attracted significant attention and are highlighted in this review.