Pathogenesis Of Disorders Research Articles

Loss of tissue-type plasminogen activator causes multiple developmental anomalies

Abstract Hydrocephalus and Dandy-Walker malformation are among the most common congenital brain anomalies. We identified three consanguineous families with both obstructive hydrocephalus and Dandy-Walker malformation. To understand the molecular basis of these anomalies, we conducted genome-wide sequencing in these families. We identified three homozygous truncating variants in the PLAT gene in the four affected family members. All of them showed tetraventricular hydrocephalus. In two individuals, a membrane at the inferior aspect of the fourth ventricle was likely the cause of their hydrocephalus. Three cases exhibited Dandy-Walker malformation whereas the two oldest individuals displayed intellectual disability. PLAT encodes the tissue-type plasminogen activator, a serine protease whose main function is to cleave the proenzyme plasminogen to produce active plasmin. Interestingly, plasminogen deficiency has also been shown to cause obstructive hydrocephalus and Dandy-Walker malformation, suggesting that loss of PLAT causes these defects by disrupting plasmin production. In summary, we describe a recessive disorder characterized by obstructive hydrocephalus, Dandy-Walker malformation and intellectual disability in individuals with loss-of-function variants in PLAT. This discovery further strengthens the involvement of the plasminogen pathway in the pathogenesis of these developmental disorders.

Gut microbiota-derived 3-indoleacetic acid confers a protection against sepsis-associated encephalopathy through microglial aryl hydrocarbon receptors.

The gut microbiota significantly contributes to the pathogenesis of central nervous system disorders. Among the bioactive molecules produced by the gut microbiota, 3-indoleacetic acid (IAA) has been shown to attenuate oxidative stress and inflammatory responses. This experiment aimed to determine the impacts of IAA on sepsis-associated encephalopathy (SAE) and the underlying mechanisms. A total of 34 septic patients and 24 healthy controls were included in the analysis of the clinical correlation between fecal IAA and septic encephalopathy. Fecal microbiota transplantation was used to verify the role of the gut microbiota and its metabolites in SAE. Male C57BL/6 mice aged six to eight weeks, pre-treated with IAA via oral gavage, were subjected to the cecal ligation and puncture (CLP) procedures. This treatment was administered either in combination with an aryl hydrocarbon receptor (AhR) antagonist, CH223191, or a CSF1R inhibitor, PLX3397, to eliminate microglia. Both immunofluorescence staining and enzyme-linked immunosorbent assays were used to evaluate microglia activation and inflammatory cytokine secretion. Behavioral assessments were conducted to quantify neurological deficits. A decreased fecal level of IAA was observed in the patients with sepsis-associated delirium (SAD), a manifestation of SAE. A reduced IAA level was significantly associated with worsen clinical outcomes. Fecal microbiota transplantation from the SAD patients induced an SAE-like phenotype in mice, but supplementing exogenous IAA improved the SAE-like phenotype, mediated by microglia. IAA effectively binded with the aryl hydrocarbon receptor (AhR). Furthermore, IAA increased the nuclear activity of AhR in the lipopolysaccharide (LPS)-treated microglial cells, leading to reduced secretion of inflammatory cytokines. The AhR inhibitor CH223191 counteracted the protective effect of IAA against SAE in mice. Gut microbiota-derived IAA confers a protection against SAE by activating AhR in microglia, improving neuronal and cognitive impairments. Thus, IAA holds the promise as a potential therapeutic agent for managing SAE.

Copper homeostasis and neurodegenerative diseases

Copper, one of the most prolific transition metals in the body, required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine (DPA), and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline (PBT2), along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.

Unveiling the Biological Activities, Pharmacological Potential, and Health Benefits of Sorbifolin: A Comprehensive Review.

Bioactive phytochemicals act as important factors with preventive and therapeutic potential in the pathogenesis of several disorders, often related to oxidative stress. Many dietary plant secondary metabolites could lower these conditions. Sorbifolin is one of these metabolites. This work is the first review of sorbifolin, a flavone detected in various plant matrices as a major compound. The present study discussed the natural sources, extraction, purification, quantification, and assessment of the biological activities of sorbifolin. Several databases including Google Scholar, Web of Sciences, and Science-Direct were consulted for relevant English articles related to sorbifolin, the phytochemical profiles of several medicinal plants containing this compound, and its biological activities, such as antioxidant, anticancer, antimicrobial, anti-inflammatory, and antidiabetic. The positive in vitro and in silico outcomes reported in the literature should be followed by additional in vivo and clinical investigations to further research the mechanisms of action, pharmacokinetic/pharmacodynamic activities, toxicological effects, pharmacological properties, and therapeutic potential of sorbifolin.

Abstract 4122301: The Role of Hepatic CDS2 in Phosphatidylinositol Homeostasis and Lipid Metabolism

Background: Recent studies in both human genetics and mouse models have highlighted the significance of phosphatidylinositol (PI) in the progression of fatty liver disease (FLD). Despite this, the precise mechanisms underlying PI's role remain elusive. Aims: This study aimed to elucidate the involvement of PI in FLD by disrupting hepatic PI biosynthesis through modulation of CDP-diacylglycerol synthase 2 (CDS2) expression, the primary enzyme in PI biosynthesis (A). Methods: We generated liver-specific knockouts of CDS2 and SCAP (SREBP cleavage-activating protein) using adeno-associated virus (AAV) expressing sgRNA against each gene. Phospholipid species were analyzed and quantified by LC/MS. Results: CDS2 liver-specific knockout mice (B, C) exhibited a pronounced development of fatty liver, characterized by elevated triglyceride and cholesterol levels (C). Notably, liver PI levels were significantly reduced in CDS2 knockout mice (E), accompanied by dysregulated activation of sterol regulatory element-binding protein (SREBP) even during fasting conditions (F), leading to increased de novo lipogenesis. Intraperitoneal administration of exogenous PI effectively normalized SREBP cleavage (G), highlighting PI's critical role in SREBP regulation. Furthermore, simultaneous knockout of SCAP with CDS2 restored the normal liver phenotype, implicating SREBP activation as a central mechanism underlying fatty liver development in CDS2 knockout mice (H, I). Conclusion: Deletion of CDS2 in the liver reduced PI levels, subsequently inducing significant fatty liver due to dysregulated SREBP activation. This study underscores the importance of CDS2 in maintaining PI homeostasis, which in turn regulates SREBP activity and lipid metabolism. Our findings provide valuable insights into the pathogenesis of metabolic disorders and offer potential therapeutic strategies for targeting FLD.

Functional Food Nutrients, Redox Resilience Signaling and Neurosteroids for Brain Health

The interplay between functional food nutrients and neurosteroids has garnered significant attention for its potential to enhance stress resilience in health and/or disease. Several bioactive nutrients, including medicinal herbs, flavonoids, and bioavailable polyphenol-combined nanoparticles, as well as probiotics, vitamin D and omega-3 fatty acids, have been shown to improve blood–brain barrier (BBB) dysfunction, endogenous neurosteroid homeostasis and brain function. These nutrients can inhibit oxidative stress and neuroinflammation, which are linked to the pathogenesis of various neurological disorders. Interestingly, flavonoids exhibit dose-dependent effects, activating the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway at the physiological/low dose (neurohormesis). This leads to the upregulation of antioxidant phase II genes and proteins such as heme oxygenase-1 (HO-1) and sirtuin-1 (Sirt1), which are activated by curcumin and resveratrol, respectively. These adaptive neuronal response mechanisms help protect against reactive oxygen species (ROS) and neurotoxicity. Impaired Nrf2 and neurosteroid hormone signaling in the brain can exacerbate selective vulnerability to neuroinflammatory conditions, contributing to the onset and progression of neurodegenerative and psychiatric disorders, including Alzheimer’s disease, anxiety and depression and other neurological disorders, due to the vulnerability of neurons to stress. This review focuses on functional food nutrients targeting Nrf2 antioxidant pathway and redox resilience genes to regulate the neurosteroid homeostasis and BBB damage associated with altered GABAergic neurotransmission. By exploring the underlying molecular mechanisms using innovative technologies, we aim to develop promising neuroprotective strategies and personalized nutritional and neuroregenerative therapies to prevent or attenuate oxidative stress and neuroinflammation, ultimately promoting brain health.

Insights into the pathogenesis of gestational and hepatic diseases: the impact of ferroptosis

Ferroptosis, a distinct form of non-apoptotic cell death characterized by iron dependency and lipid peroxidation, is increasingly linked to various pathological conditions in pregnancy and liver diseases. It plays a critical role throughout pregnancy, influencing processes such as embryogenesis, implantation, and the maintenance of gestation. A growing body of evidence indicates that disruptions in these processes can precipitate pregnancy-related disorders, including pre-eclampsia (PE), gestational diabetes mellitus (GDM), and intrahepatic cholestasis of pregnancy (ICP). Notably, while ICP is primarily associated with elevated maternal serum bile acid levels, its precise etiology remains elusive. Oxidative stress induced by bile acid accumulation is believed to be a significant factor in ICP pathogenesis. Similarly, the liver’s susceptibility to oxidative damage underscores the importance of lipid metabolism dysregulation and impaired iron homeostasis in the progression of liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cholestatic liver injury, autoimmune hepatitis (AIH), acute liver injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). This review discusses the shared signaling mechanisms of ferroptosis in gestational and hepatic diseases, and explores recent advances in understanding the mechanisms of ferroptosis and its potential role in the pathogenesis of gestational and hepatic disorders, with the aim of identifying viable therapeutic targets.

Abstract 4138745: Blockade of Mineralocorticoid Receptor by Esaxerenone Improves Insulin Sensitivity in Obese Mice

Background: Aldosterone regulates blood pressure and electrolyte balance. However, overactivation of the mineralocorticoid receptor (MR) and elevated aldosterone levels are implicated in the pathogenesis of cardiometabolic disorders, though the underlying mechanisms are not fully understood. In this study, we investigated whether a novel, non-steroidal selective MR blocker, esaxerenone, ameliorates the development of metabolic disorders in obese mice models and examined the underlying mechanism. Methods: Esaxerenone (3 mg/kg/day) was orally administered to high-fat diet (HFD)-fed C57BL/6J or normal chow-fed db/db mice. Metabolic parameters, tissue morphology, and effects of esaxerenone on insulin sensitivity were assessed. Gene expression and insulin signaling, determined by Akt phosphorylation, were examined using quantitative RT-PCR and western blotting, respectively. In in-vitro experiments, insulin targets cell lines such as 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes were used. Insulin-responsive cells were treated with 10 nM or 100 nM esaxerenone or eplerenone for 30 minutes before 4-hour 1000 nM aldosterone stimulation. Insulin signaling was assessed 15 minutes after stimulation with 17 nM insulin. Results: Esaxerenone improved insulin sensitivity (P<0.05) without altering metabolic parameters in HFD-induced obese and db/db mice. Esaxerenone suppressed fat accumulation, adipocyte size, and liver lipid droplets compared with the vehicle-treated group (P<0.01). In adipose tissue, esaxerenone reduced macrophage infiltration (P<0.01) and the expression of inflammatory molecules (P<0.05). In in-vitro experiments, aldosterone significantly decreased the expression levels of PPARγ and adiponectin in 3T3-L1 adipocytes. Moreover, aldosterone attenuated insulin-induced Akt phosphorylation in 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes in a dose-dependent manner (P<0.01). Pretreatment with esaxerenone reversed the effect of aldosterone, whereas eplerenone, an MR antagonist, did not show a similar effect at the same dose. Conclusion: Inhibition of MR by esaxerenone improved insulin sensitivity in HFD-induced obese and genetically diabetic mice. The reduction of inflammation and fat accumulation and enhancement of insulin signaling were suggested to be underlying mechanisms. Esaxerenone might be a beneficial therapeutic approach for managing metabolic disorders.

Research progress on epigenetic mechanism of reproductive disorders

The "Developmental Origins of Health and Disease, DOHaD" theory suggests that adverse factors in early life can lead to the occurrence of chronic diseases in adulthood. In recent years, it has been discovered that maternal factors, intrauterine development environment and environmental exposure during pregnancy can mediate the changes of early egg/embryo development, promote the occurrence of reproductive disorders such as polycystic ovary syndrome, diminished ovarian reserve, and endometriosis, and induce intergenerational genetic effects. This article has reviewed the progress of research on maternal factors which may affect the pathogenesis of reproductive disorders, and expounds its mechanism from the perspectives of epigenetic mechanisms such as DNA methylation, histone modification and non-coding small RNA (miRNA) modification, with an aim to provide insights for studying the occurrence of adult reproductive disorders in early life and before pregnancy.

Social isolation induces addictive behavior and increases release of dopamine in the <i>nucleus accumbens</i> in response to stimulation of the positive reinforcing zone

The study of the role of social isolation in the pathogenesis of addictive behavior disorders is an important medical and biological problem. Of particular importance are the limitations of social experience in ontogenesis. This work makes an attempt to find a connection between social isolation in ontogenesis and impulsive-compulsive behavior, as an indicator of the premorbid background for gaming and other forms of behavioral addictions. The mechanisms of addictive behavior in rats reared in isolation (IS) were investigated by analyzing the extracellular release of dopamine in response to stimulation of the positive reinforcing zone. Before the experiments, male rats were kept in individual cages from the 21st day of birth to the 90th day. To study elements of addictive behavior, a variant of the Iowa Gambling Task in a 3-arm maze and a method of developing compulsive overeating using intermittent consumption of high-calorie foods were used. To study compulsive behavior, a marble test was used against the background of withdrawal from a high-calorie diet. Surgeries were performed to implant electrodes into the ventral tegmental area (VTA) and the nucleus accumbens in rats exhibiting elements of addictive behavior in the 3-arm maze. These animals were then trained to respond to VTA self-stimulation. Dopamine release was recorded telemetrically in freely moving rats in response to electrical stimulation of the VTA self-stimulation zone. Fast scan cyclic voltammetry was used to determine changes in dopamine levels in the extracellular environment of the nucleus accumbens. IS entered less into the arm with a high degree of probability but with a low reward, and entered more in the arm with a low degree of probability, but with a high reward, which is associated with the appearance of impulsivity in behavior. In the model of compulsive overeating, the number of approaches to the feeder in IS increased, and against the background of withdrawal of high-calorie food, IS were more active in the marble test. In IS exhibiting elements of addictive behavior in the 3-arm maze, the content of extracellular dopamine in response to electrical stimulation of the VTA self-stimulation zones did not reveal any differences compared to the control group of rats with addictive behavior in the maze. At the same time, IS exhibiting elements of addictive behavior in the maze showed a more pronounced dopamine response to a complex stimulus: a conditioned signal used during maze learning light + VTA stimulation. Thus, rearing in the IS causes an increase in dopamine release in the nucleus accumbens in response to stimulation of the positive reinforcement area associated with addictive behaviors: impulsivity and compulsivity. A conclusion is drawn about the prospects of studying the extracellular release of dopamine and assesses addictive behavior disorders caused by limited social contacts in ontogenesis.

Structural and Functional Biology of Mammalian ALOX Isoforms with Particular Emphasis on Enzyme Dimerization and Their Allosteric Properties

The human genome involves six functional arachidonic acid (AA) lipoxygenase (ALOX) genes, and the corresponding enzymes (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOXE3, ALOX5) have been implicated in cell differentiations and in the pathogenesis of inflammatory, hyperproliferative, metabolic, and neurological disorders. Humans express two different AA 15-lipoxygenating ALOX isoforms, and these enzymes are called ALOX15 (15-LOX1) and ALOX15B (15-LOX2). Chromosomal localization, sequence alignments, and comparison of the enzyme properties suggest that pig and mouse ALOX15 orthologs (leukocyte-type 12-LOX) on the one hand and rabbit and human ALOX15 orthologs on the other (reticulocyte-type 15-LOX1) belong to the same enzyme family despite their different reaction specificities with AA as a substrate. In contrast, human ALOX12 (platelet-type 12-LOX), as well as pig and mouse ALOX15 (leukocyte-type 12-LOX), belong to different enzyme families, although they exhibit a similar reaction specificity with AA as a substrate. The complex multiplicity of mammalian ALOX isoforms and the controversial enzyme nomenclatures are highly confusing and prompted us to summarize the current knowledge on the biological functions, enzymatic properties, and allosteric regulation mechanisms of mammalian ALOX15, ALOX15B, and ALOX12 orthologs that belong to three different enzyme sub-families.

Intestinal stem cell niche: An upcoming area of immense importance in gastrointestinal disorders.

The intestinal stem cell (ISC) niche is vital for maintaining the integrity and function of the intestinal epithelium. ISC populations, characterized by their high proliferation and multipotency, reside within a specialized microenvironment at the base of crypts. Crypt base columnar (CBC) cells at the deepest part of crypts serve as replicating ISCs, while position 4 label-retaining cells (LRCs) located higher up in the crypts are also important for ISC maintenance during experiments. The interplay between CBCs, position 4 LRCs, transient amplifying (TA) cells and other niche components, including the pericrypt stromal cells, ensures a continuous supply of differentiated epithelial cells. Recent advancements in ISC biomarker studies have provided valuable insights into their molecular signatures, regulatory pathways and roles in the pathogenesis of intestinal disorders. Understanding the ISC niche has significant therapeutic implications, as manipulating ISC behaviors and regenerating damaged or diseased intestinal tissue show promise for novel therapeutic approaches. ISC organoids have also provided a platform for studying intestinal diseases and testing personalized therapies. This comprehensive review covers the anatomical composition, physiological regulation, ISC biomarker studies, contribution to intestinal disorder pathogenesis and potential therapeutic implications of the ISC niche.

MicroRNAs as Regulators, Biomarkers, and Therapeutic Targets in Autism Spectrum Disorder.

The pathogenesis of autism spectrum disorder (ASD) is complex and is mainly influenced by genetic and environmental factors. Some research has indicated that environmental aspects may interplay with genetic aspects to enhance the risk, and microRNAs (miRNAs) are probably factors in explaining this link between heredity and the environment. MiRNAs are single-stranded noncoding RNAs that can regulate gene expression at the posttranscriptional level. Some research has indicated that miRNAs are closely linked to neurological diseases. Many aberrantly expressed miRNAs have been observed in autism, and these dysregulated miRNAs are expected to be potential biomarkers and provide new strategies for the treatment of this disease. This article reviews the research progress of miRNAs in autism, including their biosynthesis and function. It is found that some miRNAs show aberrant expression patterns in brain tissue and peripheral blood of autistic patients, which may serve as biomarkers of the disease. In addition, the article explores the novel role of exosomes as carriers of miRNAs with the ability to cross the blood-brain barrier and unique expression profiles, offering new possibilities for diagnostic and therapeutic interventions in ASD. The potential of miRNAs in exosomes as diagnostic markers for ASD is specifically highlighted, as well as the prospect of using engineered exosome-encapsulated miRNAs for targeted therapies.

Strategies for applying noninvasive brain stimulation techniques to treat psychiatric disorders

With the continuous development of science and technology, medical science, and bioengineering technology, various neuromodulation techniques, such as electrical, magnetic, acoustic, and optical modalities, are rapidly emerging in the therapeutic regime of psychiatric disorders. How to choose the appropriate noninvasive brain stimulation techniques for different psychiatric disorders and their clinical features is becoming a practical dilemma in clinical setting. In this paper, by describing the complex pathogenesis of psychiatric disorders and the limitations of existing therapeutic approaches on psychiatric disorders, combining with the characteristics of different neuromodulation techniques, we propose a new strategy of combined noninvasive brain stimulation to intervene in psychiatric disorders: high-intensity stimulation modulating the whole brain without inducing epilepsy should be as the basic treatment of psychiatric disorders, applying low-intensity stimulation with the advantage of specific targets/brain regions to modulate the residual symptoms or/and single symptom, and for refractory and acute psychiatric disorders, ECT/MECT is preferred for rapid symptom control; different noninvasive brain stimulation techniques can be combined with pharmacological and psychotherapeutic treatments, which will provide a new idea for the future development of this field.

Non-linear connection between the triglyceride–glucose index and prediabetes risk among Chinese adults: a secondary retrospective cohort study

BackgroundThe triglyceride–glucose (TyG) index has garnered recognition as a surrogate marker for insulin resistance, a pivotal factor in the pathogenesis of various metabolic disorders. Despite its emerging role, the empirical evidence delineating its association with prediabetes mellitus (Pre-DM) remains scant. This research aims to clarify the link between the TyG index and the likelihood of Pre-DM development within a Chinese demographic.MethodsThis investigation was structured as a retrospective cohort analysis, encompassing a sample of 179,177 Chinese adults. These individuals underwent medical examinations at the Rich Healthcare Group over a period spanning from 2010 to 2016. To ascertain the relationship between the TyG index and the incidence of Pre-DM, this study employed Cox regression analysis complemented by sensitivity and subgroup assessments. Furthermore, Cox proportional hazards regression with cubic spline functions and smooth curve fitting was incorporated to explore the existence of any non-linear connection within this association.ResultsUpon adjusting for a comprehensive array of confounding variables, a statistically significant positive correlation between the TyG index and the risk of Pre-DM was identified (HR: 1.60, 95%CI 1.56–1.65, P < 0.001). The analysis illuminated a non-linear relationship, with an inflection point at a TyG index value of 8.78. For TyG index values below and above this inflection point, the HR was calculated to be 1.94 (95%CI 1.86–2.03) and 1.26 (95%CI 1.20–1.33), respectively. Sensitivity analyses further fortified the reliability of these findings.ConclusionsThis comprehensive examination delineated a significantly positive, non-linear correlation between the TyG index and the risk of Pre-DM within a Chinese population. Individuals with TyG index values below 8.78 have a significantly increased risk of developing prediabetes. These findings underscore the TyG index’s potential efficacy as a predictive tool for assessing Pre-DM risk in clinical practice.

The role of leptin in endometrium disorders: literature review

Leptin is not only the main regulator of energy balance, but also it affects the reproductive and immune systems. Leptin and its receptors are expressed in the endometrium and are actively involved in the embryo implantation. According to numerous studies, expression and level changes of leptin are associated with the inflammatory and autoimmune diseases, including endometriosis and chronic endometritis. Hyperplastic and inflammatory diseases of the uterus are accompanied by a violation of the receptivity of the endometrium due to the dysregulation of many factors involved in proliferation, vascularization and decidualization of cells. Activity of most of these factors is due to the leptin action, however, there are no studies of the direct effect of leptin in the pathogenesis of disorders of the endometrium in hyperplastic and inflammatory diseases.Thus, the purpose of this literature review was to describe the putative molecular mechanisms of the effect of leptin on the development of endometrial pathology.Literature search was carried out from 03/20/2023 to 05/11/2023 using scientific literature databases: NCBI PubMed, Google Scholar (foreign sources), Cyberleninka, Elibrary (domestic sources): references for the period 1995-2023 were analyzed. The following keywords were used for the search: leptin, endometrial dysfunction, endometrial receptivity, inflammation, pelvic inflammatory disease.

Unraveling the Role of Wnt Signaling Pathway in the Pathogenesis of Autism Spectrum Disorder (ASD): A Systematic Review.

Autism spectrum disorder (ASD), or simply autism, is a neurodevelopmental disorder characterized by social communication deficit, restricted interests, and repetitive behavior. Several studies suggested a link between autism and the dysregulation of the Wnt signaling pathway which is mainly involved in cell fate determination, cell migration, cell polarity, neural patterning, and organogenesis. Despite the absence of effective therapy, significant progress has been made in understanding the pathogenesis of ASD. Neuropharmacological studies showed that drugs acting on the Wnt pathway like Canagliflozin can alleviate autistic-like behavior in animal models. Hence, this pathway could potentially be a futuristic therapeutic target to mitigate autism's symptoms. This systematic review aims to collect and analyze evidence that elucidates how alterations in the Wnt pathway may contribute to the pathogenesis of autism in animal models at the molecular, cellular, and physiological levels. Comprehensive searches were conducted across multiple databases, including PubMed, Web of Science, Embase, and Scopus to identify relevant studies up to March 2024. The inclusion criteria encompassed experimental studies that focused on the link between autism and this pathway, and the quality assessment was ensured by SYRCLE's risk of bias tools. Collectively, the included articles highlighted the possible implication of this pathway in the abnormalities found in autism, which impacted processes such as energy metabolism, oxidative stress, and neurogenesis. These alterations could underlie autistic behavior by affecting synaptic transmission and mitochondrial function.

Double negative T cells promote surgery-induced neuroinflammation, microglial engulfment and cognitive dysfunction via the IL-17/CEBPβ/C3 pathway in adult mice

CD3(+) CD4(−) CD8(−) double negative T cells (DNTs) manifest themselves in autoimmune diseases and associated inflammation. In the central nervous system, the increased presence of DNTs is associated with the progression of neurological conditions and brain injury. Active DNTs that produce IL-17 have been regarded as a pro-inflammatory phenotype. The IL-17 signaling pathway mediates neuroinflammatory responses by inducing glial activation and producing inflammatory factors. Neuroinflammation is considered integral to the pathogenesis of perioperative neurocognitive disorders (PNDs), commonly developed after surgery in susceptible patients. We and others have demonstrated a significant role for complement C3 in surgery-induced neuroinflammation and cognitive impairment but the regulatory mechanisms for this remain unexplored. We hypothesized that surgery induces DNT infiltration into the CNS that in turn upregulate complement C3 expression and this causes changes that contribute to cognitive impairment. Using an adult murine abdominal surgery model, we investigated perioperative changes in cognitive performance, quantifying the presence of T cell subsets and phenotype, IL-17 signaling pathway activation, glial cell activation and C3 expression in the brain. Postoperative IL-17 specific inhibitor GSK2981278 administration or preoperatively conditional CEBPβ knock-down by AAV9 viral vector were then applied to evaluate the effect of inhibiting IL-17 signaling pathway on postoperative C3 expression and cognitive performance. The results showed an increased hippocampus infiltration of DNTs with augmented IL-17 production, along with C3 upregulation and cognitive impairment. Both inhibition of IL-17 or knock-down of CEBPβ significantly suppressed C3 expression, synaptic engulfment by microglia and attenuated cognitive impairment. These findings indicate that DNTs promote postoperative neuroinflammation and cognitive impairment via the IL-17/CEBPβ/C3 pathway and targeting this IL-17 axis could be a potential therapeutic strategy to ameliorate postoperative neuroinflammation and cognitive impairment.

Role of Thrombosis in Neurodegenerative Diseases: An Intricate Mechanism of Neurovascular Complications.

Thrombosis, the formation of blood clots in arteries or veins, poses a significant health risk by disrupting the blood flow. It can potentially lead to major cardiovascular complications such as acute myocardial infarction or ischemic stroke (arterial thrombosis) and deep vein thrombosis or pulmonary embolism (venous thrombosis). Nevertheless, over the course of several decades, researchers have observed an association between different cardiovascular events and neurodegenerative diseases, which progressively harm and impair parts of the nervous system, particularly the brain. Furthermore, thrombotic complications have been identified in numerous clinical instances of neurodegenerative diseases, particularly Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. Substantial research indicates that endothelial dysfunction, vascular inflammation, coagulation abnormalities, and platelet hyperactivation are commonly observed in these conditions, collectively contributing to an increased risk of thrombosis. Thrombosis can, in turn, contribute to the onset, pathogenesis, and severity of these neurological disorders. Hence, this concise review comprehensively explores the correlation between cardiovascular diseases and neurodegenerative diseases, elucidating the cellular and molecular mechanisms of thrombosis in these neurodegenerative diseases. Additionally, a detailed discussion is provided on the commonly employed antithrombotic medications in the context of these neuronal diseases.

Myc functions downstream of InR and their concurrent upregulation additively restricts pathogenesis of human poly(Q) disorders in Drosophila disease models

Human polyglutamine [poly(Q)] disorders are caused by abnormal expansion of CAG repeats in one gene (disease specific), yet a plethora of cellular pathways are found to be involved in their pathogenesis and progression. Despite the tremendous effort, all pursuits for the development of intervention therapy against these disorders seem futile. Recent reports suggest combination therapy as a potential strategy to combat the complex pathogenesis of such neurodegenerative disorders. The present study attempted to identify a combinatorial intervention strategy against human poly(Q) disorders in Drosophila disease models. Due to its immense potential to be stimulated by drugs, the evolutionarily conserved insulin signalling cascade which is well-established modifier of human poly(Q) pathogenesis was selected for the selected for the study. Genetic screening studies identified Drosophila Myc as a potential partner of insulin receptor (InR) that conferred additive rescue against poly(Q) induced neurodegeneration. Comprehensive analyses demonstrated InR and Myc to confer additive rescue against several events of pathogenesis, including aggregation of expanded poly(Q) containing proteins, transcriptional dysregulation, upsurge of cell death cascades, etc. Also, the synergistic rescue efficiency of InR and Myc was equally efficient in mitigating poly(Q) induced structural and functional deficits. The study also demonstrates that Myc functions downstream of InR signalling cascade to deliver rescue against human poly(Q) mediated toxicity in Drosophila disease models. In conclusion, the present study suggests that InR and Myc have the potential to be developed as a combinatorial therapeutic approach against human poly(Q) diseases.