Pathological Conditions Research Articles

Oral administration of coenzyme Q10 ameliorates memory impairment induced by nicotine-ethanol abstinence through restoration of biochemical changes in male rat hippocampal tissues.

Substance abuse among adolescents has become a growing issue throughout the world. The significance of research on this life period is based on the occurrence of neurobiological changes in adolescent brain which makes the individual more susceptible for risk-taking and impulsive behaviors. Alcohol and nicotine are among the most available drugs of abuse in adolescents. Prolonged consumption of nicotine and alcohol leads to drug dependence and withdrawal which induce various dysfunctions such as memory loss. Coenzyme Q10 (CoQ10) is known to improve learning and memory deficits induced by various pathological conditions such as Diabetes mellitus and Alzheimer's disease. In the present study we investigated whether CoQ10 treatment ameliorates memory loss following a nicotine-ethanol abstinence. Morris water maze and novel object recognition tests were done in male Wistar rats undergone nicotine-ethanol abstinence and the effect of CoQ10 was assessed on at behavioral and biochemical levels. Results indicated that nicotine-ethanol abstinence induces memory dysfunction which is associated with increased oxidative and inflammatory response, reduced cholinergic and neurotrophic function plus elevated Amyloid-B levels in hippocampi. CoQ10 treatment prevented memory deficits and biochemical alterations. Interestingly, this ameliorative effect of CoQ10 was found to be dose-dependent in most experiments and almost equipotential to that of bupropion and naloxone co-administration. CoQ10 treatment could effectively improve memory defects induced by nicotine-ethanol consumption through attenuation of oxidative damage, inflammation, amyloid-B level and enhancement of cholinergic and neurotrophic drive. Further studies are required to assess the unknown side effects and high dose tolerability of the drug in human subjects.

Targeting the autophagy-miRNA axis in prostate cancer: toward novel diagnostic and therapeutic strategies.

Since prostate cancer is one of the leading causes of cancer-related death, a better understanding of the molecular pathways guiding its development is imperative. A key factor in prostate cancer is autophagy, a cellular mechanism that affects both cell survival and death. Autophagy is essential in maintaining cellular homeostasis. Autophagy is a physiological mechanism wherein redundant or malfunctioning cellular constituents are broken down and recycled. It is essential for preserving cellular homeostasis and is implicated in several physiological and pathological conditions, including cancer. Autophagy has been linked to metastasis, tumor development, and treatment resistance in prostate cancer. The deregulation of miRNAs related to autophagy appears to be a crucial element in the etiology of prostate cancer. These miRNAs influence the destiny of cancer cells by finely regulating autophagic mechanisms. Numerous investigations have emphasized the dual function of specific miRNAs in prostate cancer, which alter autophagy-related pathways to function as either tumor suppressors or oncogenes. Notably, miRNAs have been linked to the control of autophagy and the proliferation, apoptosis, and migration of prostate cancer cells. To create customized therapy approaches, it is imperative to comprehend the dynamic interplay between autophagy and miRNAs in prostate cancer. The identification of key miRNAs provides potential diagnostic and prognostic markers. Unraveling the complex network of lncRNAs, like PCA3, also expands the repertoire of molecular targets for therapeutic interventions. This review explores the intricate interplay between autophagy and miRNAs in prostate cancer, focusing on their regulatory roles in cellular processes ranging from survival to programmed cell death.

Overcoming traps and pitfalls leading to misinterpretation of normal EEG variants and variation of the background activity.

Normal EEG variants, especially the epileptiform variants, can be challenging to interpret because they often have sharp contours and may be confused with "epileptic" interictal activities. However, they can be recognized by the fact that "most spikes or sharp wave discharges of clinical import are followed by a slow wave or a series of slow deflections" (Maulsby, 1971).If there is no wave after the spike, electroencephalographers should be suspicious of artifacts and normal EEG variants. Most normal EEG variants display a single rhythm with the same frequency within the pattern and the morphology remains stable throughout the entire EEG recording with repetition of the same pattern. In case of doubt or difficulties with a standard EEG, it is recommended to undergo an EEG that includes sleep stages with or without sleep deprivation. Finally, epileptiform is an ambiguous term corresponding to an electroencephalographic trait. Epileptiform does not imply a pathological condition, including epilepsy. The clinical context remains the most paramount in the diagnosis of epilepsy. In this article, we propose a set of rules and guidelines to identify normal EEG variants in EEG tracings and normal variation of the background activity. It is not easy to accurately assign a specific/precise name to all EEG activity, but with an orderly approach to EEG that involves using a set of criteria, nonepileptic activity can be identified.

Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications.

Mitophagy, a specialised form of autophagy, selectively targeting damaged or dysfunctional mitochondria, and is crucial for maintaining cellular homeostasis and mitochondrial quality control. Dysregulation of mitophagy contributes to various pathological conditions, including cancer, neurodegenerative and cardiovascular diseases. This review presents a comprehensive analysis of the molecular mechanisms, regulatory pathways, and interplay with other cellular processes governing mitophagy, emphasizing its importance in physiological and pathological contexts. We explore the PINK1/Parkin-mediated and receptor-mediated mitophagy pathways, encompassing BNIP3/NIX, FUNDC1, and Bcl2-L-13. Additionally, we discuss post-translational modifications and cellular signalling pathways modulating mitophagy, as well as the connection between mitophagy and ageing, highlighting the decline in mitophagy efficiency and its impact on age-related pathologies. The review also investigates mitophagy's role in human diseases such as cancer, myocardial ischemia-reperfusion injury, Parkinson's, and Alzheimer's disease. We assess the potential of mitophagy-targeting therapeutic strategies, focusing on the development of dietary therapies, small molecules, drugs, and gene therapy approaches that modulate mitophagy levels and efficiency for treating these diseases and dysfunctions commonly observed in ageing individuals. In summary, this review offers an extensive overview of the molecular mechanisms and regulatory networks involved in mitophagy, its association with autophagy, and implications in human health and disease. By examining the potential of mitophagy-modulating therapies in disease and non-disease settings, we aim to inspire further research to develop innovative treatment strategies for various pathological conditions linked to mitochondrial dysfunction and to ageing.

A Review on Indole-triazole Molecular Hybrids as a Leading Edge in Drug Discovery: Current Landscape and Future Perspectives.

Molecular hybridization is a rational design strategy used to create new ligands or pro-totypes by identifying and combining specific pharmacophoric subunits from the molecular struc-tures of two or more known bioactive derivatives. Molecular hybridization is a valuable technique in drug discovery, enabling the modulation of unwanted side effects and the creation of potential dual-acting drugs that combine the effects of multiple therapeutic agents. Indole-triazole conju-gates have emerged as promising candidates for new drug development. The indole and triazole moieties can be linked through various synthetic strategies, such as click chemistry or other cou-pling reactions, to generate a library of diverse compounds for biological screening. The achieva-ble structural diversity with indole-triazole conjugates offers avenues to optimize their pharmaco-kinetic and pharmacodynamic attributes, amplifying their therapeutic efficacy. Researchers have extensively tailored both indole and triazole frameworks with diverse modifications to compre-hend their impact on the drug's pharmacokinetic and pharmacodynamic characteristics. The cur-rent review article endeavours to explore and discuss various research strategies to design indole-triazole hybrids and elucidate their significance in a variety of pathological conditions. The in-sights provided herein are anticipated to be beneficial for the researchers and will likely encour-age further exploration in this field.

Potential therapeutic effects of crocin.

Crocin, a natural bioactive compound derived from saffron (Crocus sativus) and other Crocus genera, has gained significant attention recently due to its potential therapeutic properties. The multifaceted nature of crocin's biological effects has piqued the interest of researchers and health enthusiasts, prompting further investigations into its mechanisms of action and therapeutic applications. This review article comprehensively explores the emerging evidence supporting crocin's role as a promising ally in protecting against metabolic disorders. The review covers the molecular mechanisms underlying crocin's beneficial effects and highlights its potential applications in preventing and treating diverse pathological conditions. Understanding the mechanisms through which crocin exerts its protective effects could advance scientific knowledge and offer potential avenues for developing novel therapeutic interventions. As we uncover the potential of crocin as a valuable ally in the fight against disorders, it becomes evident that nature's palette holds remarkable solutions for enhancing our health.

Acupoint Sensitivity in Health and Disease: A Systematic Review.

Introduction: The concept of acupoints is a key defining feature of acupuncture, yet the scientific basis of acupoints remains unclear. In recent years, there has been an emerging body of animal studies demonstrating an association between cutaneous sensitivity and visceral pathophysiology, through which acupoints over the skin are sensitized in pathologic conditions. Several studies with humans have also been conducted to assess whether the sensitivity of acupoints is distinct in healthy versus clinical populations. However, no systematic review has been conducted to collate and synthesize the status and quality of human studies on this topic. Methods: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Literature search was performed by combining variations of search terms related to acupoints and pain sensitivity in PubMed, EMBASE, and Alt HealthWatch (EBSCOHost). Screening of titles and abstracts and review of full-text articles for eligibility were performed by two independent investigators. Using a predefined template, information on subject characteristics, pathologic conditions, names of assessed acupoints, and relevant main findings were extracted from the included studies. The methodological quality of included studies was assessed using a modified Newcastle-Ottawa Scale (NOS) for case-control studies. A quality assessment checklist was also developed by the present authors to examine the quality of reporting of experimental variables that were considered important for evaluating acupoint sensitivity. Results: A total of 3453 studies were identified from the database search, of which 11 met the eligibility criteria to be included in this review. Six studies examined the mechanical sensitivity of body acupoints, and the remaining five studies examined the mechanical sensitivity of auricular points. Overall, findings suggest that the sensitivity of acupoints may be distinct in healthy versus clinical populations. However, there were various potential sources of bias and substantial heterogeneity across included studies in clinical conditions and acupoints. Conclusion: There is at present insufficient evidence to support or refute that acupoints in humans are sensitized in pathologic conditions. There were various methodological issues, including small sample size and poor reporting of experimental design and variables, which limit the ability to draw a definitive conclusion on this topic. It is also largely unclear whether it is the general body regions rather than specific acupoints that may be sensitized, as most studies did not include nonacupoint location(s) for comparison. Thus, further rigorous research is warranted.

Effect of verbascoside against acute kidney injury induced by rhabdomyolysis in rats.

Rhabdomyolysis is a pathological condition caused by muscle tissue degradation. In this condition, intracellular contents enter the bloodstream, and acute kidney injury (AKI) develops. Verbascoside (VB) is one of the most common phenylethanoid glycosides and has antioxidant and anti-inflammatory effects. This study investigated the effects of VB on AKI induced by rhabdomyolysis in rats. Male Wistar rats were divided into six groups (n = 6): (1) control group (normal saline), (2) 50% glycerol (10 ml/kg, IM, single injection, only on the first day), (3)-(5) 50% glycerol (same as group 2) + VB (30, 60, and 100 mg/kg, IP, 4 days), and (6) VB (100 mg/kg). Serum and kidney tissue samples were collected on day 5. Subsequently, serum creatinine (Cr), blood urea nitrogen (BUN), renal glutathione (GSH), malondialdehyde (MDA), lipocalin associated with neutrophil gelatinase (NGAL), tumor necrosis factor-alpha (TNF-α), and pathological changes were investigated. The injection of glycerol elevated levels of kidney damage markers, including Cr and BUN in serum, MDA, TNF-α, and NGAL, along with a reduction in GSH levels in the kidney tissue. The administration of VB (100 mg/kg) significantly lowered the levels of these markers, indicating the therapeutic effect of VB against AKI caused by rhabdomyolysis. Histopathological examinations revealed enhanced myoglobin cast formation and tubular necrosis in the glycerol group, which was reduced in rats that received VB, although this reduction did not reach statistical significance. VB can reduce rhabdomyolysis-induced AKI through its anti-inflammatory and antioxidant effects and decrease kidney damage severity.

Smelly interactions: host-borne volatile organic compounds triggering behavioural responses in mosquitoes, sand flies, and ticks.

Volatile organic compounds (VOCs) are chemicals emitted as products of cell metabolism, which reflects the physiological and pathological conditions of any living organisms. These compounds play a key role as olfactory cues for arthropod vectors such as mosquitoes, sand flies, and ticks, which act in the transmission of pathogens to many animal species, including humans. Some VOCsmay influence arthropod behaviour, e.g.,host preference and oviposition site selection for gravid females. Furthermore, deadly vector-borne pathogens such as Plasmodium falciparum and Leishmania infantum are suggested to manipulate the VOCs profile of the host to make them more attractive to mosquitoes and sand fly vectors, respectively. Under the above circumstances, studies on these compounds have demonstrated their potential usefulness for investigating the behavioural response of mosquitoes, sand flies, and ticks toward their vertebrate hosts, as well as potential tools for diagnosis of vector-borne diseases (VBDs). Herein, we provide an account for scientific data available on VOCs to study the host seeking behaviour of arthropod vectors, and their usefulness as attractants, repellents, or tools for an early diagnosis of VBDs.

Notch Signaling: An Emerging Paradigm in the Pathogenesis of Reproductive Disorders and Diverse Pathological Conditions

Notch Signaling: An Emerging Paradigm in the Pathogenesis of Reproductive Disorders and Diverse Pathological Conditions

Regulation of mitochondrial function by FOXOs in ischemic stroke and Alzheimer’s disease

Transcriptional control is a pivotal mechanism governing various cellular processes. FOXO proteins, a subgroup of the forkhead family of transcription factors, play a key role in determining cell fate. The localization and function of FOXO proteins are regulated by post-translational modifications to control target gene expression, with a pronounced impact on various aspects of mitochondrial function, including mitochondrial dynamics, biogenesis, and quality control. Mitochondria stand out as the primary target of FOXO transcription factors, which recruit downstream signaling factors to govern mitochondrial processes. Essential signaling pathways are modulated by FOXOs, exemplified by their regulation of mitochondrial biogenesis through SIRT1-Pgc1a and NRF1-TFAM, as well as their influence on mitochondrial dynamics involving Mfn1, Mfn2, Drp1, and Fis1. Furthermore, FOXOs demonstrate the ability to upregulate and downregulate genes that serve as modulators in oxidative and apoptosis cascades. The functional role of FOXO proteins is highly context-dependent, varying with cell type, organ, and specific FOXO isoform. Notably, FOXOs emerge as prominent players in various pathological conditions, including ischemic conditions, neurodegenerative diseases, cancer, and metabolic disorders. Unraveling the complex role of FOXOs in mammalian cell pathology positions them as promising therapeutic targets receptive to pharmacological treatment. This review aims to provide insights into the intricate roles of FOXOs in mitochondria, illuminating their potential as therapeutic targets amenable to pharmacological intervention in diverse pathological contexts, particularly in ischemic stroke and Alzheimer’s disease.

MAPP unravels frequent co-regulation of splicing and polyadenylation by RNA-binding proteins and their dysregulation in cancer

Maturation of eukaryotic pre-mRNAs via splicing and polyadenylation is modulated across cell types and conditions by a variety of RNA-binding proteins (RBPs). Although there exist over 1,500 RBPs in human cells, their binding motifs and functions still remain to be elucidated, especially in the complex environment of tissues and in the context of diseases. To overcome the lack of methods for the systematic and automated detection of sequence motif-guided pre-mRNA processing regulation from RNA sequencing (RNA-Seq) data we have developed MAPP (Motif Activity on Pre-mRNA Processing). Applying MAPP to RBP knock-down experiments reveals that many RBPs regulate both splicing and polyadenylation of nascent transcripts by acting on similar sequence motifs. MAPP not only infers these sequence motifs, but also unravels the position-dependent impact of the RBPs on pre-mRNA processing. Interestingly, all investigated RBPs that act on both splicing and 3’ end processing exhibit a consistently repressive or activating effect on both processes, providing a first glimpse on the underlying mechanism. Applying MAPP to normal and malignant brain tissue samples unveils that the motifs bound by the PTBP1 and RBFOX RBPs coordinately drive the oncogenic splicing program active in glioblastomas demonstrating that MAPP paves the way for characterizing pre-mRNA processing regulators under physiological and pathological conditions.

Macrophage PET imaging in mouse models of cardiovascular disease and cancer with an apolipoprotein-inspired radiotracer

Macrophages are key inflammatory mediators in many pathological conditions, including cardiovascular disease (CVD) and cancer, the leading causes of morbidity and mortality worldwide. This makes macrophage burden a valuable diagnostic marker and several strategies to monitor these cells have been reported. However, such strategies are often high-priced, non-specific, invasive, and/or not quantitative. Here, we developed a positron emission tomography (PET) radiotracer based on apolipoprotein A1 (ApoA1), the main protein component of high-density lipoprotein (HDL), which has an inherent affinity for macrophages. We radiolabeled an ApoA1-mimetic peptide (mA1) with zirconium-89 (89Zr) to generate a lipoprotein-avid PET probe (89Zr-mA1). We first characterized 89Zr-mA1’s affinity for lipoproteins in vitro by size exclusion chromatography. To study 89Zr-mA1’s in vivo behavior and interaction with endogenous lipoproteins, we performed extensive studies in wildtype C57BL/6 and Apoe-/- hypercholesterolemic mice. Subsequently, we used in vivo PET imaging to study macrophages in melanoma and myocardial infarction using mouse models. The tracer’s cell specificity was assessed by histology and mass cytometry (CyTOF). Our data show that 89Zr-mA1 associates with lipoproteins in vitro. This is in line with our in vivo experiments, in which we observed longer 89Zr-mA1 circulation times in hypercholesterolemic mice compared to C57BL/6 controls. 89Zr-mA1 displayed a tissue distribution profile similar to ApoA1 and HDL, with high kidney and liver uptake as well as substantial signal in the bone marrow and spleen. The tracer also accumulated in tumors of melanoma-bearing mice and in the ischemic myocardium of infarcted animals. In these sites, CyTOF analyses revealed that natZr-mA1 was predominantly taken up by macrophages. Our results demonstrate that 89Zr-mA1 associates with lipoproteins and hence accumulates in macrophages in vivo. 89Zr-mA1’s high uptake in these cells makes it a promising radiotracer for non-invasively and quantitatively studying conditions characterized by marked changes in macrophage burden.

The Role of the Gap Junction Protein Connexin in Adrenal Gland Tumorigenesis

Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their role in the pathogenesis of different diseases as well as tumorigenesis, invasion and metastases. The expression pattern and possible role of connexins (Cxs), as major GJ proteins, under both physiological and pathological conditions in the adrenal gland, were evaluated in this review. The databases Web of Science, PubMed and Scopus were searched. Studies were evaluated if they provided data regarding the connexin expression pattern in the adrenal gland, despite current knowledge of this topic not being widely investigated. Connexin expression in the adrenal gland differs according to different parts of the gland and depends on ACTH release. Cx43 is the most studied connexin expressed in the adrenal gland cortex. In addition, Cx26, Cx32 and Cx50 were also investigated in the human adrenal gland. Cx50 as the most widespread connexin, along with Cx26, Cx29, Cx32, Cx36 and Cx43, has been expressed in the adrenal medulla with distinct cellular distribution. Considerable effort has recently been directed toward connexins as therapeutically targeted molecules. At present, there exist several viable strategies in the development of potential connexin-based therapeutics. The differential and hormone-dependent distribution of gap junctions within adrenal glands, the relatively large gap junction within this gland and the increase in the gap junction size and number following hormonal treatment would indicate that gap junctions play a pivotal role in cell functioning in the adrenal gland.

A comprehensive review on role of magnetic resonance imaging in the precise measurement of corpus callosum

Magnetic Resonance Imaging (MRI) has emerged as a powerful and non-invasive imaging technique, playing a pivotal role in neuroimaging research and clinical diagnosis. This comprehensive review explores the significance of MRI in the precise measurement of the corpus callosum, a key structure connecting the two hemispheres of the brain. The corpus callosum plays a crucial role in inter hemispheric communication and is implicated in various neurological and psychiatric disorders. The review begins by elucidating the anatomy and functions of the corpus callosum, emphasizing its importance in facilitating seamless communication between the cerebral hemispheres. Subsequently, the paper delves into the historical evolution of MRI techniques and how advancements have enhanced the visualization and measurement capabilities of the corpus callosum. A detailed examination of various MRI modalities, including structural MRI, diffusion tensor imaging (DTI), and functional MRI, is presented in the context of corpus callosum analysis. Structural MRI provides high-resolution images for accurate morphological assessments, while DTI offers insights into white matter microstructure and fiber tractography, allowing for a more comprehensive understanding of the corpus callosum's integrity. The review also highlights the role of MRI in investigating alterations in the corpus callosum associated with neurological disorders such as multiple sclerosis, epilepsy, and neurodevelopmental disorders. Additionally, the paper explores how functional MRI contributes to understanding the functional connectivity and inter hemispheric interactions mediated by the corpus callosum. Challenges and limitations in the measurement of the corpus callosum using MRI are discussed, including methodological considerations, image artifacts, and potential sources of variability. The review concludes by outlining future directions in corpus callosum imaging research, including the integration of advanced imaging techniques, artificial intelligence, and large-scale multi-center studies to enhance the precision and reliability of measurements.In summary, this comprehensive review underscores the pivotal role of MRI in advancing our understanding of the corpus callosum, providing valuable insights into both normal brain function and pathological conditions. The continual evolution of MRI techniques holds promise for further refining the assessment of the corpus callosum, ultimately contributing to improved diagnostic accuracy and therapeutic interventions in neurological and psychiatric disorders.

Focused ultrasound as a treatment modality for gliomas

Ultrasound waves were initially used as a diagnostic tool that provided critical insights into several pathological conditions (e.g., gallstones, ascites, pneumothorax, etc.) at the bedside. Over the past decade, advancements in technology have led to the use of ultrasound waves in treating many neurological conditions, such as essential tremor and Parkinson’s disease, with high specificity. The convergence of ultrasound waves at a specific region of interest/target while avoiding surrounding tissue has led to the coined term “focused ultrasound (FUS).” In tumor research, ultrasound technology was initially used as an intraoperative guidance tool for tumor resection. However, in recent years, there has been growing interest in utilizing FUS as a therapeutic tool in the management of brain tumors such as gliomas. This mini-review highlights the current knowledge surrounding using FUS as a treatment modality for gliomas. Furthermore, we discuss the utility of FUS in enhanced drug delivery to the central nervous system (CNS) and highlight promising clinical trials that utilize FUS as a treatment modality for gliomas.

Laser Doppler Fluximetry in Cutaneous Vasculature: Methods for Data Analyses

Introduction: Acquisition of a deeper understanding of microvascular function across physiological and pathological conditions can be complicated by poor accessibility of the vascular networks and the necessary sophistication or intrusiveness of the equipment needed to acquire meaningful data. Laser Doppler fluximetry (LDF) provides a mechanism wherein investigators can readily acquire large amounts of data with minor inconvenience for the subject. However, beyond fairly basic analyses of erythrocyte perfusion (fluximetry) data within the cutaneous microcirculation (i.e., perfusion at rest and following imposed challenges), a deeper understanding of microvascular perfusion requires a more sophisticated approach that can be challenging for many investigators. Methods: This manuscript provides investigators with clear guidance for data acquisition from human subjects for full analysis of fluximetry data, including levels of perfusion, single- and multiscale Lempel-Ziv complexity (LZC) and sample entropy (SampEn), and wavelet-based analyses for the major physiological components of the signal. Representative data and responses are presented from a recruited cohort of healthy volunteers, and computer codes for full data analysis (MATLAB) are provided to facilitate efforts by interested investigators. Conclusion: It is anticipated that these materials can reduce the challenge to investigators integrating these approaches into their research programs and facilitate translational research in cardiovascular science.

The deletion of AQP4 and TRPV4 affects astrocyte swelling/volume recovery in response to ischemia-mimicking pathologies

IntroductionAstrocytic Transient receptor potential vanilloid 4 (TRPV4) channels, together with Aquaporin 4 (AQP4), are suspected to be the key players in cellular volume regulation, and therefore may affect the development and severity of cerebral edema during ischemia. In this study, we examined astrocytic swelling/volume recovery in mice with TRPV4 and/or AQP4 deletion in response to in vitro ischemic conditions, to determine how the deletion of these channels can affect the development of cerebral edema.MethodsWe used three models of ischemia-related pathological conditions: hypoosmotic stress, hyperkalemia, and oxygenglucose deprivation (OGD), and observed their effect on astrocyte volume changes in acute brain slices of Aqp4–/–, Trpv4–/– and double knockouts. In addition, we employed single-cell RT-qPCR to assess the effect of TRPV4 and AQP4 deletion on the expression of other ion channels and transporters involved in the homeostatic functioning of astrocytes.ResultsQuantification of astrocyte volume changes during OGD revealed that the deletion of AQP4 reduces astrocyte swelling, while simultaneous deletion of both AQP4 and TRPV4 leads to a disruption of astrocyte volume recovery during the subsequent washout. Of note, astrocyte exposure to hypoosmotic stress or hyperkalemia revealed no differences in astrocyte swelling in the absence of AQP4, TRPV4, or both channels. Moreover, under ischemia-mimicking conditions, we identified two distinct subpopulations of astrocytes with low and high volumetric responses (LRA and HRA), and their analyses revealed that mainly HRA are affected by the deletion of AQP4, TRPV4, or both channels. Furthermore, gene expression analysis revealed reduced expression of the ion transporters KCC1 and ClC2 as well as the receptors GABAB and NMDA in Trpv4–/– mice. The deletion of AQP4 instead caused reduced expression of the serine/cysteine peptidase inhibitor Serpina3n.DiscussionThus, we showed that in AQP4 or TRPV4 knockouts, not only the specific function of these channels is affected, but also the expression of other proteins, which may modulate the ischemic cascade and thus influence the final impact of ischemia.

IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis

Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α’s endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is evolutionarily conserved. Genetic deficiency and pharmacological inhibition of IRE1α have similar effects in inhibiting ferroptosis and reducing renal ischemia–reperfusion injury in mice. Our findings reveal a previously unidentified role of IRE1α to regulate ferroptosis and suggests inhibition of IRE1α as a promising therapeutic strategy to mitigate ferroptosis-associated pathological conditions.

Analyzing the correlation between body composition variables and cellular phase angle via computerized bioelectrical impedance analysis (BIA)

Background: Various diseases and pathological conditions, as well as inflammatory processes, either in isolation or in combination with advanced age, can lead to significant alterations in body composition. This study investigates the correlation between various body composition metrics and the cellular Phase Angle (PhA) through Computerized Bioelectrical Impedance Analysis (BIA) in a diverse age group of individuals ranging from 18 to 80 years. Objective: Our aim was to explore the interplay between body composition variables such as Body Mass Index, Lean Body Mass, Skeletal Muscle Mass, and their potential influence on the cellular integrity as indicated by PhA. Methods: Utilizing a dataset of 199 participants, we employed both linear and advanced machine learning models, including Random Forest regression, to analyze the predictive relationships and variable importance within our body composition metrics. Results: Initial analyses revealed strong correlations between mass-related measures and suggested complex relationships with the PhA, an indicator of cellular health and membrane integrity. The Random Forest model significantly outperformed simple linear regression in predicting PhA, emphasizing the nonlinear nature of these relationships and the importance of a comprehensive approach in body composition assessment. Conclusion: Our findings highlight the nuanced interactions between body composition variables and their collective impact on cellular health as measured by PhA. This study underscores the potential of utilizing PhA alongside traditional metrics for a more nuanced understanding of body composition and its implications for health. Future research should continue to leverage advanced statistical and machine learning techniques to further elucidate these complex relationships, with implications for nutritional, sports medicine, and biomedical fields. Initial analyses revealed strong correlations between mass-related measures and suggested complex relationships with the Phase Angle, an indicator of cellular health and membrane integrity. The Random Forest model significantly outperformed simple linear regression in predicting PhA, emphasizing the nonlinear nature of these relationships and the importance of a comprehensive approach in body composition assessment. Our findings highlight the nuanced interactions between body composition variables and their collective impact on cellular health as measured by PhA. This study underscores the potential of utilizing PhA alongside traditional metrics for a more nuanced understanding of body composition and its implications for health. Future research should continue to leverage advanced statistical and machine learning techniques to further elucidate these complex relationships, with implications for nutritional, sports medicine, and biomedical fields.