Pathophysiological Alterations Research Articles

Probiotics Combined with Metformin Improves Sperm Parameters in Obese Male Mice through Modulation of Intestinal Microbiota Equilibrium.

The decline in sperm parameters among obese males has attracted significant scholarly interest. The intestinal microbiota plays a crucial role in obesity, and investigating the intestinal-reproductive axis may offer a novel molecular approach to addressing the decline in male sperm parameters caused by obesity. To clarify whether probiotics, either alone or in conjunction with metformin, can enhance sperm parameters in obese male mice and assess the underlying mechanisms involved.6-week-old male mice were constructed as obese models. Probiotics and metformin were used as intervention conditions. Changes in inflammatory factors and ROS content were detected by ELISA, morphological changes in testicular and colon tissues were observed by H&E staining, changes in intestinal microbiota abundance were detected by 16SrRNA gene sequencing, and changes in metabolites such as blood glucose, blood lipids, and lipopolysaccharide were detected by biochemical testing to investigate the mechanism of probiotics, metformin, and their combination to ameliorate reproductive impairment in obese male mice. Our results revealed that high-fat diet would result in reduced testicular spermatogenic tubule hierarchy, decreased spermatogenic cell counts, decreased sperm concentration and motility, and altered abundance of intestinal microbiota, whereas the combination of probiotics and metformin could restore high-fat-mediated pathophysiological alterations thereby ameliorating spermatogenic disorders in mice.The combination of probiotics and metformin can attenuate inflammation and oxidative stress, while enhancing androgen production to improve testicular spermatogenic function by re-construction intestinal microbiota equilibrium in HFD mice.

Immunological Profiles, Oxidative Stress Biomarkers and Plasma Cholinesterase Activities in Patients with Immune-Mediated Inflammatory Diseases Treated in a Clinic in Duhok, Iraq

Abstract Aim The purpose of the present study was to measure the levels of selected plasma biochemical variables among cases of immune-mediated inflammatory diseases (IMIDs), other than rheumatoid arthritis, treated in a clinic in the city of Duhok, Iraq, since such information is scarce in the region. Materials and Methods A case-control study on IMIDs patients treated in a clinic in Duhok, Iraq, was performed from February 2022 to June 2023. A total of 29 patients of both genders with IMIDs and 61 healthy controls were recruited at the Duhok Center for Rheumatic Diseases and Medical Rehabilitation, Duhok, Iraq. The laboratory tests conducted on plasma samples from IMIDs patients and healthy controls included measurements of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, malondialdehyde (MDA), total antioxidant status (TAS) and cholinesterase (ChE) activity. Results No significant differences were found in gender distribution, age, and body mass index between the IMIDs patients and healthy controls. The majority of patients (69%) received conventional therapy combined with biologic agents, whereas the remaining patients (31%) received only conventional medications. The IMIDs identified among the 29 patients were Behcet’s disease (27.6%), ankylosing spondylitis (24.1%), inflammatory bowel diseases (24.1%), psoriatic arthritis (10.3%), systemic lupus erythematosus (6.9%) and psoriasis (6.9%). Conventional therapy used was mostly azathioprine (44.8%) and methotrexate (17.2%), whereas biological therapy included mostly etanercept (27.6%) and adalimumab (24.1%). The values of CRP, IL-6 and TNF-Į among the IMIDs patients were not significantly different from those of the controls. The oxidative stress biomarker MDA was elevated in IMID patients (2.93 ± 1.106 —mol/L vs. 2.52 ± 0.478) at a p value of 0.064 (though not significant). The TAS level (1.21 ± 0.422 mmol Trolox Equiv./L vs. 1.00 ± 0.338, p = 0.022) and plasma ChE activity (1.18 ± 0.50 ¨ pH/20 min vs. 0.83 ± 0.30, p = 0.001) were significantly higher in IMIDs patients compared to controls. Conclusions The data suggest that oxidative stress and changes in plasma ChE activity might be a part of the pathophysiological alterations among IMIDs patients. Therapeutic drug monitoring and its clinical outcome as well as response of IMIDs patients to anti-ChE agents are worth of further in depth exploration and pursuing. They are essential for better diagnosis, treatment, and management of IMIDs.

Protein-Energy Malnutrition and Its Progression in Dialysis Patients in West Delhi Centre: A Prospective Study

Background: There is a high prevalence of protein-energy malnutrition in patients with chronic renal failure who are undergoing maintenance hemodialysis. Apart from this the pathogenic mechanisms of malnutrition are complex and involve an interplay of multiple pathophysiologic alterations including decreased appetite, decreased nutrient intake and dialysis related abnormalities. Methods: The study subjects were patients of CKD 5 (MHD) of age 18 to 60 years enrolled from Anjuman Medical centre in West Delhi. Total 30 subjects (15 males and 15 females) were enrolled from Dialysis centre and their basic demographic profile socio economic status, dietary habits and physical activity details were recorded. Dietary nutrient (calories, protein, fats, carbohydrates, sodium, potassium, phosphorus and fluid) was calculated by Diet Cal version 10.0 software using a 3-day dietary recall and analysed was done using SPSS software version 21.0. Nutritional status were measured at baseline , 2 months and 3 months. Knowledge, Attitude, practice and Quality of life also recorded at 1 month and at 3 months after nutritional counselling. Results: The average BMI, weight, and height of males were (24.2 kg/m2, 67.6 kg, and 166 cm) and females were (22.2 kg/m2, 54.8 kg, and 158 cm) respectively. Blood pressure was 129±13 systolic and 79±10 mmHg diastolic. 23.3% had pallor, and 60% of patients were moderate and 33.3% were severely malnutrition. Handgrip was 21.7±6.9 kg. Protein intake changed from 52±15.9 to 73.2±11.4 in males and 47.8±50.4 to 57.0±13.7g in females after three months of the study. And energy improved from 1477±333 to 2253±494 in males and 1201±255 to 2106±346 kcal in females. Similarly, fat and phosphorus intake improved from 49.2±37.9 to 56.5±17.9 (p>0.080) and 728.9±287.7 to 1160.0±290.1 (p>0.000) respectively. While KAP was (8.5±2.0, 75.3±10.6 and 25.8±2.3) respectively and QoL also improved from 27.0±4.0 to 30.9±2.7 after 3 months of the study. Conclusion: After 3 months of study, QoL and KAP significantly improved. Further, there were significant changes in intake of energy, protein and phosphorus in all dialysis patients. In nutritional status weight, MUAC and handgrip showed significant increase result. Blood pressure, pallor and MIS score also improved.

Three-dimensional choroidal characteristics in different subtypes of central serous chorioretinopathy using swept-source optical coherence tomography angiography.

To assess choroid vascular characteristics in four subtypes of central serous chorioretinopathy (CSC) eyes under the new classification system. There were 83 subjects in total for analysis including 16 individuals with acute CSC, 13 with non-resolving CSC, 12 with recurrent CSC, 16 with chronic CSC, and 26 healthy control eyes. We utilized the integrated software of SS-OCTA to acquire measurements of the central choroidal thickness (CT), the choriocapillaris perfusion area (CCPA), three-dimensional choroidal vascularity index (CVI) and three-dimensional choroidal vessel volume (CVV). The SNK-q test was conducted for pairwise comparisons among four subgroups of CSC and healthy control eyes. A multiple linear regression model was employed to investigate the relationship between CVI, CCPA and other factors. CT, CVI, and CCPA of the chronic CSC subgroup were significantly lower than the other three CSC subgroups. Lower CVI was significantly correlated with the subgroup of chronic CSC (β = -0.140, P = 0.016), lower CT (β = 0.0014, P < 0.01), and higher CCPA (β = -0.141, P < 0.01). Lower CCPA was significantly correlated with the subgroup of chronic CSC (β = -0.937, P < 0.01), diabetes (β = -0.118, P = 0.015), higher CVV (β = -0.414, P = 0.014), and higher CVI (β = -0.764, P < 0.01). This is the first study to evaluate the choroidal characteristics of four subtypes of CSC under the new classification system in detail. It seems that chronic CSC displays distinct pathophysiological alterations in choroidal characteristics. NCT05687422.

Ischemic Stroke Induces ROS Accumulation, Maladaptive Mitophagy, and Neuronal Apoptosis in Minipigs.

Reactive oxygen species (ROS)-induced adaptive/maladaptive mitophagy plays an essential role in the pathophysiology of acute ischemic stroke (AIS). However, most studies have been conducted using rodent models, which limits their clinical application. In this study, we aimed to develop porcine models of permanent stroke and observe the pathophysiological alterations caused by acute ischemic stroke, focusing on ROS-induced mitophagy. Miniature pigs were subjected to lateral frontotemporal electrocoagulation, which resulted in permanent middle cerebral artery occlusion. We investigated global brain damage and mechanisms of adaptive/maladaptive mitophagy caused by ROS and global brain inflammation after AIS. An early neuroinflammatory response was observed in the ipsilateral hemisphere. ROS levels were significantly elevated in the ipsilateral hemisphere and slightly elevated in the contralateral hemisphere. ROS accumulation may be attributed to the increased production and impaired elimination of ROS. In addition, mitophagy and apoptosis were detected in the ischemic core, which may be attributed to ROS accumulation. We propose "distinct-area targeting" interventions aimed at maladaptive mitophagy within the ischemic core of the infarct hemisphere, which may provide new therapeutic targets for the treatment of AIS.

A WFS1 variant disrupting acceptor splice site uncovers the impact of alternative splicing on beta cell apoptosis in a patient with Wolfram syndrome.

Wolfram syndrome 1 (WS1) is an inherited condition mainly manifesting in childhood-onset diabetes mellitus and progressive optic nerve atrophy. The causative gene, WFS1, encodes wolframin, a master regulator of several cellular responses, and the gene's mutations associate with clinical variability. Indeed, nonsense/frameshift variants correlate with more severe symptoms than missense/in-frame variants. As achieving a genotype-phenotype correlation is crucial for dealing with disease outcome, works investigating the impact of transcriptional and translational landscapes stemming from such mutations are needed. Therefore, we sought to elucidate the molecular determinants behind the pathophysiological alterations in a WS1 patient carrying compound heterozygous mutations in WFS1: c.316-1G>A, affecting the acceptor splice site (ASS) upstream of exon 4; and c.757A>T, introducing a premature termination codon (PTC) in exon 7. Bioinformatic analysis was carried out to infer the alternative splicing events occurring after disruption of ASS, followed by RNA-seq and PCR to validate the transcriptional landscape. Patient-derived induced pluripotent stem cells (iPSCs) were used as an in vitro model of WS1 and to investigate the WFS1 alternative splicing isoforms in pancreatic beta cells. CRISPR/Cas9 technology was employed to correct ASS mutation and generate a syngeneic control for the endoplasmic reticulum stress induction and immunotoxicity assays. We showed that patient-derived iPSCs retained the ability to differentiate into pancreatic beta cells. We demonstrated that the allele carrying the ASS mutation c.316-1G>A originates two PTC-containing alternative splicing transcripts (c.316del and c.316-460del), and two open reading frame-conserving mRNAs (c.271-513del and c.316-456del) leading to N-terminally truncated polypeptides. By retaining the C-terminal domain, these isoforms sustained the endoplasmic reticulum stress response in beta cells. Otherwise, PTC-carrying transcripts were regulated by the nonsense-mediated decay (NMD) in basal conditions. Exposure to cell stress inducers and proinflammatory cytokines affected expression levels of the NMD-related gene SMG7 (>twofold decrease; p<0.001) without eliciting a robust unfolded protein response in WFS1 beta cells. This resulted in a dramatic accumulation of the PTC-containing isoforms c.316del (>100-fold increase over basal; p<0.001) and c.316-460del (>20-fold increase over basal; p<0.001), predisposing affected beta cells to undergo apoptosis. Cas9-mediated recovery of ASS retrieved the canonical transcriptional landscape, rescuing the normal phenotype in patient-derived beta cells. This study represents a new model to study wolframin, highlighting how each single mutation of the WFS1 gene can determine dramatically different functional outcomes. Our data point to increased vulnerability of WFS1 beta cells to stress and inflammation and we postulate that this is triggered by escaping NMD and accumulation of mutated transcripts and truncated proteins. These findings pave the way for further studies on the molecular basis of genotype-phenotype relationship in WS1, to uncover the key determinants that might be targeted to ameliorate the clinical outcome of patients affected by this rare disease. The in silico predicted N-terminal domain structure file of WT wolframin was deposited in the ModelArchive, together with procedures, ramachandran plots, inter-residue distance deviation and IDDT scores, and Gromacs configuration files (doi/10.5452/ma-cg3qd). The deep-sequencing data as fastq files used to generate consensus sequences of AS isoforms of WFS1 are available in the SRA database (BioProject PRJNA1109747).

Pathophysiology, molecular mechanisms, and genetics of atrial fibrillation.

The development of atrial fibrillation (AF) is a highly complex, multifactorial process involving pathophysiologic mechanisms, molecular pathway mechanisms and numerous genetic abnormalities. The pathophysiologic mechanisms including altered ion channels, abnormalities of the autonomic nervous system, inflammation, and abnormalities in Ca2 + handling. Molecular pathway mechanisms including, but not limited to, renin-angiotensin-aldosterone (RAAS), transforming growth factor-β (TGF-β), oxidative stress (OS). Although in clinical practice, the distinction between types of AF such as paroxysmal and persistent determines the choice of treatment options. However, it is the pathophysiologic alterations present in AF that truly determine the success of AF treatment and prognosis, but even more so the molecular mechanisms and genetic alterations that lie behind them. One tiny clue reveals the general trend, and small beginnings show how things will develop. This article will organize the development of these mechanisms and their interactions in recent years.

High Behavioral Reactivity to Novelty as a Susceptibility Factor for Memory and Anxiety Disorders in Streptozotocin-Induced Neuroinflammation as a Rat Model of Alzheimer's Disease.

Individual differences in responsiveness to environmental factors, including stress reactivity and anxiety levels, which differ between high (HR) and low (LR) responders to novelty, might be risk factors for development of memory and anxiety disorders in sporadic Alzheimer's disease (sAD). In the present study, we investigated whether behavioral characteristics of the HR and LR rats, influence the progression of sAD (neuroinflammation, β-amyloid peptide, behavioral activity related to memory (Morris water maze) and anxiety (elevated plus maze, white and illuminated open field test) in streptozotocin (STZ)-induced neuroinflammation as a model of early pathophysiological alterations in sAD. Early (45 days) in disease progression, there was a more severe impairment of reference memory and higher levels of anxiety in HRs compared with LRs. Behavioral depression in HRs was associated with higher expression of β-amyloid deposits, particularly in the NAcS, and activation of microglia (CD68+ cells) in the hypothalamus, as opposed to less inflammation in the hippocampus, particularly in CA1, compared with LRs in late (90 days) sAD progression. Our findings suggest that rats with higher behavioral activity and increased responsivity to stressors show more rapid progression of disease and anxiety disorders compared with low responders to novelty in the STZ-induced sAD model.

Dynamic Expression of Genes Encoding Ubiquitin Conjugating Enzymes (E2s) During Neuronal Differentiation and Maturation: Implications for Neurodevelopmental Disorders and Neurodegenerative Diseases.

Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h, Ube2b, and Aktip. Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i, the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases.

Pathogenesis and Clinical Characteristics of Hereditary Arrhythmia Diseases.

Hereditary arrhythmias, as a class of cardiac electrophysiologic abnormalities caused mainly by genetic mutations, have gradually become one of the most important causes of sudden cardiac death in recent years. With the continuous development of genetics and molecular biology techniques, the study of inherited arrhythmias has made remarkable progress in the past few decades. More and more disease-causing genes are being identified, and there have been advances in the application of genetic testing for disease screening in individuals with disease and their family members. Determining more refined disease prevention strategies and therapeutic regimens that are tailored to the genetic characteristics and molecular pathogenesis of different groups or individuals forms the basis of individualized treatment. Understanding advances in the study of inherited arrhythmias provides important clues to better understand their pathogenesis and clinical features. This article provides a review of the pathophysiologic alterations caused by genetic variants and their relationship to disease phenotypes, including mainly cardiac ion channelopathies and cardiac conduction disorders.

Chronic unpredictable stress during adolescence exerts sex-specific effects on depressive-like behavior and neural activation triggered by tail suspension test

During adolescence, acute stress can modify neuronal excitability in various brain regions, leading to negative behavioral outcomes. However, the impact of chronic stress during adolescence on neuronal responses to acute stimuli remains unclear. To address this, we subjected adolescent mice to 12 days of chronic unpredictable stress (CUS). Anxiety and depressive behaviors were evaluated, along with changes in c-Fos expression, which is one of the most widely used markers of neuronal activation. By comparing c-Fos immunoreactivity between the CUS and control groups both before and after the tail suspension test (TST), we found that adolescent CUS induced depressive behaviors in male mice, but not in female mice. Adolescent CUS primarily affected the excitability of neurons in the infralimbic cortex (IL), the dorsomedial and dorsolateral area of the bed nucleus of the stria terminalis (BNST), and the ventral hippocampus CA3. TST exerted a significant main effect on the density of c-Fos+ neurons in the prelimbic cortex (PL), infralimbic cortex (IL), cingulate areas 1 and 2 (Cg1, Cg2), the lateral septum (LS), BNST, and lateral habenular (LHb). Furthermore, the excitability of neurons in the paraventricular thalamic nucleus (PVT) was impacted by sex. These data suggest that adolescent CUS elicits region- and sex-specific modifications in TST-induced c-Fos expression, establishing a theoretical basis for understanding the pathophysiological alterations in mood disorders following adolescent stress.

Comprehensive quantitative magnetic resonance imaging assessment of skeletal muscle pathophysiology in golden retriever muscular dystrophy: Insights from multicomponent water T2 and extracellular volume fraction.

Quantitative MRI and MRS have become important tools for the assessment and management of patients with neuromuscular disorders (NMDs). Despite significant progress, there is a need for new objective measures with improved specificity to the underlying pathophysiological alteration. This would enhance our ability to characterize disease evolution and improve therapeutic development. In this study, qMRI methods that are commonly used in clinical studies involving NMDs, like water T2 (T2H2O) and T1 and fat-fraction (FF) mapping, were employed to evaluate disease activity and progression in the skeletal muscle of golden retriever muscular dystrophy (GRMD) dogs. Additionally, extracellular volume (ECV) fraction and single-voxel bicomponent water T2 relaxometry were included as potential markers of specific histopathological changes within the tissue. Apart from FF, which was not significantly different between GRMD and control dogs and showed no trend with age, T2H2O, T1, ECV, and the relative fraction of the long-T2 component, A2, were significantly elevated in GRMD dogs across all age ranges. Moreover, longitudinal assessment starting at 2months of age revealed significant decreases in T2H2O, T1, ECV, A2, and the T2 of the shorter-T2 component, T21, in both control and GRMD dogs during their first year of life. Notably, insights from ECV and bicomponent water T2 indicate that (I) the elevated T2H2O and T1 values observed in dystrophic muscle are primarily driven by an expansion of the extracellular space, likely driven by the edematous component of inflammatory responses to tissue injury and (II) the significant decrease of T2H2O and T1 with age in control and GRMD dogs reflects primarily the progressive increase in fiber diameter and protein content during tissue development. Our study underscores the potential of multicomponent water T2 relaxometry and ECV to provide valuable insights into muscle pathology in NMDs.

The Implications of Aging on Vascular Health.

Vascular aging encompasses structural and functional changes in the vasculature, significantly contributing to cardiovascular diseases, which are the leading cause of death globally. The incidence and prevalence of these diseases increase with age, with most morbidity and mortality attributed to myocardial infarction and stroke. Diagnosing and intervening in vascular aging while understanding the mechanisms behind age-induced vascular phenotypic and pathophysiological alterations offers the potential for delaying and preventing cardiovascular mortality in an aging population. This review delves into various aspects of vascular aging by examining age-related changes in arterial health at the cellular level, including endothelial dysfunction, cellular senescence, and vascular smooth muscle cell transdifferentiation, as well as at the structural level, including arterial stiffness and changes in wall thickness and diameter. We also explore aging-related changes in perivascular adipose tissue deposition, arterial collateralization, and calcification, providing insights into the physiological and pathological implications. Overall, aging induces phenotypic changes that augment the vascular system's susceptibility to disease, even in the absence of traditional risk factors, such as hypertension, diabetes, obesity, and smoking. Overall, age-related modifications in cellular phenotype and molecular homeostasis increase the vulnerability of the arterial vasculature to structural and functional alterations, thereby accelerating cardiovascular risk. Increasing our understanding of these modifications is crucial for success in delaying or preventing cardiovascular diseases. Non-invasive techniques, such as measuring carotid intima-media thickness, pulse wave velocity, and flow-mediated dilation, as well as detecting vascular calcifications, can be used for the early detection of vascular aging. Targeting specific pathological mechanisms, such as cellular senescence and enhancing angiogenesis, holds promise for innovative therapeutic approaches.

Precisely Engineering a ROS‐Regulatable Decellularized Matrix to Rejuvenate Endogenous Repair for Heart Valve Remodeling in Diabetic Cohort

AbstractThe reconstruction of a heart valve through in situ tissue engineering remains a formidable challenge, particularly for patients with diabetes mellitus, because the pathophysiological alterations associated with diabetes substantially impair the cardiovascular system's intrinsic repair capacity. In this study, reactive oxygen species (ROS) regulation are integrated into the fabrication of pro‐endothelialization interfaces to counteract the adverse repair environment. Specifically, a heparin‐mimicking alginate‐derived glycopeptide and the natural ROS scavenger melanin are modified onto the surface of a decellularized extracellular matrix (dECM). This tailored interface significantly enhances endothelial cell (EC) adhesion while reducing platelet adhesion. The incorporation of melanin effectively suppresses ROS elevation in ECs and macrophages under hyperglycemic conditions. Consequently, this intervention promotes EC rejuvenation by enhancing proliferation, migration, and anti‐apoptotic capabilities, while concurrently attenuating the release of inflammatory and pro‐fibrotic factors by macrophages. The dECM is intravascularly implanted in a diabetic rabbit model after being fabricated into a covered stent, demonstrating favorable remodeling characteristics such as enhanced endothelialization and reduced fibrotic deposition. This scaffold design, specifically tailored to the pathological conditions of diabetes, offers a precise biomaterial strategy for in situ heart valve tissue engineering.

Melatonin attenuates intermittent hypoxia-induced cognitive impairment in aged mice: The role of inflammation and synaptic plasticity

Intermittent hypoxia (IH), a major pathophysiologic alteration in obstructive sleep apnea syndrome (OSAS), is an important contributor to cognitive impairment. Increasing research suggests that melatonin has anti-inflammatory properties and improves functions related to synaptic plasticity. However, it is unclear whether melatonin has a protective effect against OSAS-induced cognitive dysfunction in aged individuals and the involved mechanisms are also unclear. Therefore, in the study, the effects of exposure to IH alone and IH in combination with daily melatonin treatment were investigated in C57BL/6 J mice aged 18 months. Assessment of the cognitive ability of mice in a Morris water maze showed that melatonin attenuated IH-induced impairment of learning and memory in aged mice. Enzyme-linked immunosorbent assay, polymerase chain reaction, and western blotting molecular techniques showed that melatonin treatment reduced the levels of the proinflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α, decreased the levels of NOD-like receptor thermal protein domain associated protein 3 and nuclear factor kappa-B, lowered the levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and increased the levels of the synaptic proteins, activity-regulated cytoskeleton-associated protein, growth-associated protein-43, postsynaptic density protein 95, and synaptophysin in IH-exposed mice. Moreover, electrophysiological results showed that melatonin ameliorated the decline in long-term potentiation induced by IH. The results suggest that melatonin can ameliorate IH-induced cognitive deficits by inhibiting neuroinflammation and improving synaptic plasticity in aged mice.

The Tao of Copper Metabolism: From Physiology to Pathology.

As a transitional metal, copper plays a crucial role in maintaining the normal physiological activities of mammals. The intracellular copper concentration is meticulously regulated to maintain extremely low levels through homeostatic regulation. Excessive accumulation of free copper in cells can have deleterious effects, as observed in conditions such as Wilson's disease. Moreover, data accumulated over the past few decades have revealed a crucial role of copper imbalance in tumorigenesis, progression and metastasis. Recently, cuproptosis, also known as copper-induced cell death, has been proposed as a novel form of cell death. This discovery offers new prospects for treating copperrelated diseases and provides a promising avenue for developing copper-responsive therapies, particularly in cancer treatment. We present a comprehensive overview of the Yin- Yang equilibrium in copper metabolism, particularly emphasising its pathophysiological alterations and their relevance to copper-related diseases and malignancies.

Non-Alcoholic Fatty Liver Disease and Coronary Artery Disease: A Bidirectional Association Based on Endothelial Dysfunction

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is regarded as a liver manifestation of metabolic syndrome. It is linked to insulin resistance, obesity, and diabetes mellitus, all of which increase the risk of cardiovascular complications. Endothelial dysfunction (EnD) constitutes the main driver in the progression of atherosclerosis and coronary artery disease (CAD). Several pathophysiological alterations and molecular mechanisms are involved in the development of EnD in patients with NAFLD. Our aim is to examine the association of NAFLD and CAD with the parallel assessment of EnD, discussing the pathophysiological mechanisms and the genetic background that underpin this relationship. This review delves into the management of the condition, exploring potential clinical implications and available medical treatment options to facilitate the deployment of optimal treatment strategies for these patients.

Diabetes mellitus and female sexual response: what do animal models tell us?

One of the less explored effects of diabetes mellitus (DM) is female sexual dysfunction. Females of different species have been used as models. To analyze the information of animal models of DM and female sexual response (FSR). The literature of FSR in models of DM was reviewed. Paradigm- and diabetes-dependent changes have been found in various aspects of the FSR. Females in a type 1 DM (DM1) model show a decrease in the number of proestrus events, and ovariectomized females treated with sex hormones have been used. In these females, a reduction in lordosis has been reported; in proceptivity, the data are contradictory. These females present a decrease in sexual motivation that was restored after exogenous insulin. In the type 2 DM (DM2) model, females show regular estrous cycles, normal levels of lordosis behavior, and, depending on the paradigm, decreased proceptivity. These females display normal preference for sexually active males or their olfactory cues when having free physical contact; they lose this preference when tested in paradigms where physical interaction is precluded. Preclinical data showing the high deleterious effects of a DM1 model and the less drastic effects under a DM2 model are in accordance with clinical data revealing a much higher prevalence of sexual dysfunction in women with DM1 than DM2. The main strength is the analysis of the changes in various components of FSR in 2 models of DM. The main limitation is the difficulty in extrapolating the data on FSR from rats to women and that most studies focus on evaluating the impact of severe or chronic-moderate hyperglycemia/hyperinsulinemia on the sexual response, without considering other pathophysiologic alterations generated by DM. Females with severe hyperglycemia have a decrease in FSR, while those with moderate hyperglycemia show much less drastic effects.

Caracterización de los pacientes atendidos con accidente ofídico en el Hospital Regional de la Orinoquía

Introduction: an ophidian accident is an intoxication due to snakebite venom inoculation. In Colombia, venomous snakes belong to the Viperidae, Elpidae and Colubridae genus. The bite causes tissue damage and characteristic clinical manifestations, including variable local and systemic pathophysiological alterations. Objective: to characterize patients with ophidian accidents treated at Hospital Regional de la Orinoquia (HORO) of Yopal, Colombia. Materials and methods: an observational, descriptive, cross-sectional, retrospective study, was conducted. All patients with snakebites who attended HORO between January 1, 2014, and May 30, 2020, were included. Results: 571 patients affected by an ophidian accident were identified; 70.1% were males; the minimum age at occurrence was 2 years and the maximum age, 89 years; most cases occurred in 2018 (19.5%). These accidents happened more often when walking along trails (31.2%) and in agricultural activities (29.6%). Bites predominantly involve the lower limbs (70.2%). Conclusions: ophidian accidents are a major public health problem, due to their frequency and outcomes. They are featured by tissue lesions and pathophysiological alterations, which can lead to critical illness and death.

A novel mouse model reproducing frontal alterations related to the prodromal stage of dementia with LEWY bodies

BackgroundDementia with Lewy bodies (DLB) is the second most common age-related neurocognitive pathology after Alzheimer's disease. Animal models characterizing this disease are lacking and their development would ameliorate both the understanding of neuropathological mechanisms underlying DLB as well as the efficacy of pre-clinical studies tackling this disease. MethodsWe performed extensive phenotypic characterization of a transgenic mouse model overexpressing, most prominently in the dorsal hippocampus (DH) and frontal cortex (FC), wild-type form of the human α-synuclein gene (mThy1-hSNCA, 12 to 14-month-old males). Moreover, we drew a comparison of our mouse model results to DH- and FC- dependent neuropsychological and neuropathological deficits observed in a cohort of patients including 34 healthy control subjects and 55 prodromal-DLB patients (males and females). ResultsOur study revealed an increase of pathological form of soluble α-synuclein, mainly in the FC and DH of the mThy1-hSNCA model. However, functional impairment as well as increase in transcripts of inflammatory markers and decrease in plasticity-relevant protein level were exclusive to the FC. Furthermore, we did not observe pathophysiological or Tyrosine Hydroxylase alterations in the striatum or substantia nigra, nor motor deficits in our model. Interestingly, the results stemming from the cohort of prodromal DLB patients also demonstrated functional deficits emanating from FC alterations, along with preservation of those usually related to DH dysfunctions. ConclusionsThis study demonstrates that pathophysiological impairment of the FC with concomitant DH preservation is observed at an early stage of DLB, and that the mThy1-hSNCA mouse model parallels some markers of this pathology.