Stress Pathways Research Articles

Transcriptome Analysis Reveals the Key Genes and Pathways for Growth, Ion Transport, and Oxidative Stress in Post-Larval Black Tiger Shrimp (Penaeus monodon) Under Acute Low Salt Stress.

As an abiotic stress factor, salinity significantly affects the physiological activities of crustaceans. In this study, transcriptome sequencing was used to evaluate the mechanism of ion transport and the physiological response of black tiger shrimp (Penaeus monodon) under low salt stress. Four hundred post larval (PL) stage P. monodon were distributed in eight experimental tanks and exposed to 3 or 5 ppt salt concentrations for 96h. Low salinity significantly reduced the survival rate of shrimp but simultaneously activated the activity of ion transporter enzymes Na+/K+-ATPase (NKA) and Ca2+/Mg2+-ATPase), the expression of NKA, galectin 10, and cytochrompe c peroxidase genes, and the activity and expression of antioxidant-related genes (superoxide dismutase, catalase, heat shock protein 60). Low salt stress activated the urea cycle but significantly inhibited glutathione metabolization-related indicators (glutamate dehydrogenase, glutaminase, glutamic acid). RNA-seq analysis identified 221 differentially expressed genes (78 up-regulated and 143 down-regulated). Quantitative real-time PCR and RNA-seq results of 11 of them were consistent, illustrating the validity of the transcriptomic predictions. Gene set enrichment analysis results showed that calcium ion transmembrane transport, calmodulin binding, the stress-activated protein kinase signaling cascade, and regulation of the cytosolic calcium ion concentration process were significantly enriched. These results showed that low salt stress activated the calcium-dominated ion transport pathway and promoted molting growth of P. monodon. They also indicate that there is potential for larval rearing shrimp under low salt conditions.

Therapeutic Potential of Rosmarinic Acid in Tramadol-Induced Hepatorenal Toxicity: Modulation of Oxidative Stress, Inflammation, RAGE/NLRP3, ER Stress, Apoptosis, and Tissue Functions Parameters.

Tramadol (TRM), a widely used opioid analgesic for moderate to severe pain, is associated with liver and kidney toxicity at high doses or prolonged use. This study investigates the protective role of rosmarinic acid (RA), a natural phenolic compound known for its antioxidant, anti-inflammatory, and cell-protective properties, against TRM-induced hepatorenal toxicity. Thirty-five male Wistar rats were divided into five groups: Control, TRM, RA, TRM+RA25, and TRM+RA50. Rats received TRM (50 mg/kg) and RA (25 or 50 mg/kg), with liver and kidney function tests, oxidative stress, inflammation, ER stress, apoptosis, and tissue damage indicators assessed through qRT-PCR, ELISA, Western blotting, H&E, and immunohistochemical analysis. TRM induced liver and kidney dysfunctions, evident from increased ALT, AST, ALP, urea, creatinine, nephrin, TIM-1 and 8-OHdG levels, along with activated oxidative stress, inflammation, ER stress, and apoptosis pathways. RA significantly reduced these effects, ameliorating histologic and immunohistochemical markers of tissue damage and inflammation. RA demonstrates therapeutic potential by mitigating TRM-induced hepatorenal toxicity and preserving tissue integrity.

A septo-hypothalamic-medullary circuit directs stress-induced analgesia.

Stress is a potent modulator of pain. Specifically, acute stress due to physical restraint induces stress-induced analgesia (SIA). However, where and how acute stress and pain pathways interface in the brain are poorly understood. Here, we describe how the dorsal lateral septum (dLS), a forebrain limbic nucleus, facilitates SIA through its downstream targets in the lateral hypothalamic area (LHA) of mice. Taking advantage of transsynaptic viral-genetic, optogenetic, and chemogenetic techniques, we show that the dLS→LHA circuitry is sufficient to drive analgesia and is required for SIA. Furthermore, our results reveal that the dLS→LHA pathway is opioid-dependent and modulates pain through the pro-nociceptive neurons in the rostral ventromedial medulla (RVM). Remarkably, we found that the inhibitory dLS neurons are recruited specifically when the mice struggle to escape under restraint and, in turn, inhibit excitatory LHA neurons. As a result, the RVM neurons downstream of LHA are disengaged, thus suppressing nociception. Together, we delineate a poly-synaptic pathway that can transform escape behavior in mice under restraint to acute stress into analgesia.

Impact of Nanoparticles on Oxidative Stress and Inflammatory Pathways in Human Prostate Cancer

Prostate cancer is one of the most prevalent cancers among men and is fueled by oxidative stress and inflammation that drive tumor progression and resistance to therapy. Production of reactive oxygen species (ROS) and pro-inflammatory cytokine such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) establish a pro-tumor microenvironment. Iron oxide nanoparticles are believed to be promising micro/nano therapy agents because NPs such as ferric oxide (Fe2O3) play a critical role in antioxidant and anti-inflammatory events. Herein, we examine influences of NPs on oxidative stress and inflammatory pathways in prostate cancer models. NP treatment was used for cells exposed to oxidative and inflammatory stressors. We measured a variety of key markers including ROS, MDA, GSH, and activities of antioxidant enzymes (catalase [CAT] and superoxide dismutase [SOD]). The levels of inflammatory cytokines were determined by widely used biochemical methods and spectrophotomedically. This resulted in significant reduction in ROS and MDA (oxidative damage markers) and significant elevation in the reduced GSH levels and these results were supported by the increased levels of antioxidant enzymes namely catalase (CAT) and superoxide dismutase (SOD) activity in NP-treated. Moreover, NPs also inhibited inflammation by downregulating the release of cytokines, such as TNF-α and IL-6. These effects suggest that NPs are capable of restoring oxidative homeostasis and suppressing inflammation, ultimately leading to a more tumor-hostile microenvironment. Abstract Nanoparticles that alleviate oxidative stress and overwrite inflammation pathways synergistically offer two critical blockade points in prostate cancer therapy to counter plasma phase-induced cellular malfunctions required for tumor progression. These results reinforce the prospect of NP as complements to cancer therapy. Optimizing NP formulations could improve their efficacy and safety for potential clinical applications in the future and provide new approaches for improving prostate cancer treatment. CuO NPs with Anti-cancer Effect on Prostate Cancer: In Vivo Study Oxidative Stress along with Inflammation as Potential Pathogenesis Prostate Cancer Responsive Ferric Oxide Nanoparticles Release ROS Assist in Treating Prostate Cancer.

Cannabis vaping elicits transcriptomic and metabolomic changes in inflammatory, oxidative stress and cancer pathways in human bronchial epithelial cells.

The increasing shift from cannabis smoking to cannabis vaping is largely driven by the perception that vaping to form an aerosol represents a safer alternative to smoking and is a form of consumption appealing to youth. Herein, we compared the chemical composition and receptor-mediated activity of cannabis smoke extract (CaSE) to cannabis vaping extract (CaVE) along with the biological response in human bronchial epithelial cells. Chemical analysis using HPLC and GC/MS revealed that cannabis vaping aerosol contained fewer toxicants than smoke; CaSE and CaVE contained teratogens, carcinogens, and respiratory toxicants. A bioluminescence resonance energy transfer (BRET)-based biosensor detected the receptor-mediated activity of the extracts, primarily driven by Δ9-THC concentration. RNA- sequencing showed both CaSE and CaVE induced similar transcriptional responses, significantly upregulating genes within pathways related to inflammation, cancer, and cellular stress. This was paralleled by downregulation of pathways related to lipid synthesis and metabolism similarly from both CaSE and CaVE. Targeted metabolomics revealed significant changes in metabolites involved in lipid and membrane metabolism, energy production, nucleotide/DNA/RNA pathways, and oxidative stress response, suggesting potential impairment of lung epithelial cell repair and function. Additionally, the upregulation of 5-hydroxymethylcytosine (5hmC) indicates epigenetic changes potentially contributing to inflammation, oxidative stress, and an increased risk of cancer. These findings challenge the notion that cannabis vaping is risk-free, highlighting an urgent need for comprehensive research into its respiratory health effects. This comparison of cannabis consumption methods offers insights that could inform public health policies and raise consumer awareness regarding the potential risks of inhaling cannabis aerosol.

Constructing a model of the factors related to the job wellbeing of preschool teachers in China: a grounded theory study

IntroductionAs educational management research evolves, leadership styles are increasingly recognized as crucial managerial skills. Among various leadership approaches, empowering leadership has been found to significantly enhance employee job performance and satisfaction. However, there is limited research exploring the relationship between empowering leadership and the job wellbeing of preschool teachers in the educational sector.MethodsThis study examines the relationship between empowering leadership and preschool teachers' job wellbeing using the Job Demands-Resources (JD-R) model. Semi-structured interviews were conducted with 12 preschool teachers and 12 kindergarten leaders in China. The qualitative data collected were analyzed using grounded theory to identify themes and construct a systematic model.ResultsThe findings suggest that empowering leadership of kindergarten principals is positively related to preschool teachers' job wellbeing. This relationship is mediated through stress pathways, such as work pressure and burnout, as well as through enhanced organizational support and a positive work environment. Furthermore, empowering leadership influences teachers' personal motivation and work engagement, which in turn impacts their job wellbeing.DiscussionThe study highlights the importance of empowering leadership in improving preschool teachers' wellbeing. By addressing stress factors, enhancing organizational support, and promoting personal motivation, empowering leadership can foster a more supportive and engaging work environment. These findings have practical implications for leadership practices in early childhood education settings.

Bioinformatic analysis of ferroptosis related biomarkers and potential therapeutic targets in vitiligo

Vitiligo is a complex autoimmune skin disorder characterized by depigmentation and immune dysregulation. To elucidate the role of ferroptosis-related genes (FRGs) in vitiligo, we conducted a comprehensive analysis of gene expression data from the GSE53146 and GSE65127 datasets obtained from the GEO database. We identified 31 differentially expressed FRGs (DE-FRGs), with 21 genes upregulated and 10 downregulated. Functional enrichment analysis revealed that these DE-FRGs are significantly involved in oxidative stress, immune regulation, and vitiligo-associated signaling pathways. Utilizing machine learning approaches, including LASSO and SVM-RFE, we identified four key marker genes (ALOX5, SNCA, SLC1A4, and IL33) with strong diagnostic potential. Immune landscape analysis demonstrated that these marker genes influence immune cell composition, particularly showing correlations with CD8 + T cells and regulatory T cells. Furthermore, drug-gene interaction analysis proposed potential therapeutic targets, while ceRNA network analysis uncovered intricate regulatory relationships involving miRNAs and lncRNAs. Collectively, our findings provide novel insights into the molecular mechanisms underpinning vitiligo and suggest new avenues for diagnostic and therapeutic development.

Investigation of the Mesencephalic Astrocyte Derived Neurotrophic Factor-Endoplasmic Reticulum Stress Pathway in Mood Disorders.

Bipolar disorder (BD) has been associated with impaired cellular resilience. Recent studies have shown abnormalities in the unfolded protein response (UPR) in BD. The UPR is the cellular response to endoplasmic reticulum (ER) stress. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a trophic factor, decreases ER stress by modulating the UPR. The objective of this study is to investigate the MANF-ER stress pathway in BD and major depressive disorder (MDD) compared to healthy controls (HC). MANF protein concentration and MANF and GRP78 gene expression were assessed in peripheral blood from individuals with BD, MDD and HC (protein: 40 BD, 55 MDD, 55 HC; gene expression: 52 BD, 61 MDD, 69 HC). MANF protein and gene expression along with GRP78 gene expression were also analyzed in postmortem brain tissue (20 BD, 20 MDD, 19 HC). MANF protein was quantified using an ELISA assay while quantitative polymerase chain reaction was used for MANF and GRP78 gene expression. Peripheral MANF protein levels were reduced in individuals with BD in a depressive state compared to controls (p=0.031) and euthymic BD participants (p=0.013). No significant differences in MANF or GRP78 gene expression were observed in BD irrespective of mood state, or MDD compared to HC (all p>0.05). No differences were observed regarding MANF/GRP78 protein or gene expression levels in postmortem tissue (p>0.05). Individuals with BD who were in an acute depressive phase were found to have reduced peripheral MANF levels potentially signifying abnormal UPR and supporting the notion that BD is associated with increased ER stress.

Exploring Chemoprevention in Colorectal Cancer for Patients with Inflammatory Bowel Disease: Mechanisms of Action and Clinical Aspects.

Background: Inflammatory bowel diseases (IBDs) have been associated with a higher risk of colorectal cancer (CRC) development and chronic colonic inflammation seems to have a critical role in the pathogenesis of CRC in patients suffering from IBD. In respect to that, surveillance colonoscopy at regular intervals is recommended in patients with colitis. Objective: This review aims to explore the chemopreventive potential of a range of agents, including mesalazine, thiopurines, anti-TNF agents, statins, ursodeoxycholic acid, aspirin, folic acid, and nutraceuticals. Results: These agents target inflammation, oxidative stress, and oncogenic pathways, thereby offering the potential to reduce the risk of CRC in patients with IBD. Anti-TNF agents, such as infliximab and adalimumab, not only reduce colonic inflammation, but also play a protective role against CRC by lessening the carcinogenic effects associated with prolonged inflammatory processes. Furthermore, mesalazine and thiopurines have demonstrated established efficacy, while newer biologics, including interleukin inhibitors, show promising advancements. Although nutraceuticals and dietary interventions require further clinical validation, they offer additional possibilities for non-pharmacological prevention. Conclusion: Despite progress, knowledge gaps persist regarding the long-term safety, optimal dosing, and combined use of these agents. A significant reduction in the incidence of CRC in patients with IBD could be achieved by advancing chemoprevention and personalizing strategies.

The Triad of Risk: Linking MASLD, Cardiovascular Disease and Type 2 Diabetes; From Pathophysiology to Treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.

Pharmacodynamic Mechanisms of Cicadae Periostracum in Parkinson's Disease: A Metabolomics-Based Study.

Cicadae Periostracum (CP) is a traditional Chinese animal-derived medicine with the potential to treat Parkinson's disease (PD). This study aims to explore the pharmacodynamic mechanisms of CP against PD-based on metabolomics technology and provide a theoretical basis for developing new anti-PD medicine. First, MPP+-induced SH-SY5Y cells were used to evaluate the anti-PD activity of CP. In the animal study, an MPTP-induced PD mouse model was employed to assess CP's therapeutic effects. Immunofluorescence (IF) staining and Western blotting (WB) were used to evaluate its neuroprotective activity on neurons. A Serum metabolomics analysis was conducted to examine CP's regulatory effects on metabolites and to identify vital metabolic pathways. Finally, cellular experiments were performed to validate the critical pathways. Cellular activity experiments demonstrated that CP mitigates MPP+-induced SH-SY5Y cytotoxicity, inhibits apoptosis, and restores mitochondrial homeostasis. Animal experiments revealed that CP significantly alleviates dyskinesia in PD mice, enhances motor performance, and restores neuronal integrity while reducing α-synuclein (α-syn) aggregation in the striatum (STR), showing its strong anti-PD effect. Metabolomic analysis revealed that CP can significantly improve the metabolic disorders of ten biomarkers that are mainly involved in amino acid metabolism and fatty acid β-oxidation and are closely related to oxidative stress pathways. Finally, pathway verification was performed, and the results show that CP exerted neuroprotective effects against PD through the dual signaling pathways of Bcl-2/Bax/Caspase-3 and Nrf2/HO-1. This study provides a comprehensive strategy for elucidating the mechanisms by which CP exerts its therapeutic effects against PD, highlighting its potential in developing anti-PD drugs.

Systems analysis of long-term heat stress responses in the C4 grass Setaria viridis.

Many C4 plants are used as food and fodder crops and often display improved resource use efficiency compared to C3 plants. However, the response of C4 plants to future extreme conditions such as heatwaves is less understood. Here, Setaria viridis, an emerging C4 model grass, was grown under long-term high temperature stress for two weeks (42°C, compared to 28°C). This resulted in stunted growth, but surprisingly had little impact on leaf thickness, leaf area-based photosynthetic rates and bundle sheath leakiness. Dark respiration rates increased and there were major alterations in carbon and nitrogen metabolism in the heat-stressed plants. Abscisic acid and indole-acetic acid-amino acid conjugates accumulated in the heat-stressed plants, consistent with transcriptional changes. Leaf transcriptomics, proteomics and metabolomics analyses were carried out and mapped onto the metabolic pathways of photosynthesis, respiration, carbon/nitrogen metabolism and phytohormone biosynthesis and signaling. An in-depth analysis of correlations between transcripts and their corresponding proteins revealed strong differences between groups in the strengths and signs of correlations. Overall, many stress signaling pathways were upregulated, consistent with multiple signals leading to reduced plant growth. A systems-based model of the plant response to long-term heat stress is presented based on the oxidative stress, phytohormone and sugar signaling pathways.

Brucella abortus transcriptional regulator ArsR6 inhibits host pyroptosis via BAB_RS28760 by triggering the endoplasmic reticulum stress pathway.

Pyroptosis, which is accompanied by inflammatory responses, is critical for pathogen clearance. However, the mechanism through which Brucella evades host pyroptosis remains unclear. The transcriptional regulator ArsR6 maintains bacterial intracellular homeostasis and possibly influences host cell death. However, whether ArsR6 acts on cellular pyroptosis is unknown. Therefore, we investigated pathogen-host interactions within macrophages infected with Brucella abortus (B. abortus), and found that ArsR6 is crucial for inhibiting host cell pyroptosis after B. abortus infection. The downstream target gene, BAB_RS28760 of ArsR6 was screened using chromatin immunoprecipitation sequencing. BAB_RS28760 belongs to the BA14K protein family and is strongly immunoreactive and induces humoral and cellular immune responses in the host during infection. Deleting ArsR6 in B. abortuspromotes pyroptosis and enhancs the intracellular survival of B. abortus. In addition, ArsR6 negatively regulated its target gene BAB_RS28760, whereas BAB_RS28760 deletion downregulated cellular pyroptosis by inhibiting endoplasmic reticulum stress and decreasing the intracellular survival of B. abortus. Our results reveal for the first time that Brucella ArsR6 reduces endoplasmic reticulum stress activation by negatively regulating its downstream target genes, thus inhibiting host cell pyroptosis. Our study provides new insights into the pathogenic mechanisms of Brucella, which can provide potential selectivity for the development of anti-Brucella therapies.

Oxytocin ameliorates lipopolysaccharide-induced acute orchitis model: interplay of oxidative stress and inflammatory pathways.

Lipopolysaccharide (LPS), a constituent of the outer membrane of Gram-negative bacteria, is a powerful inducer of systemic inflammation and has been extensively utilized in experimental models to simulate inflammatory responses and septic disorders. Recent research indicates that oxytocin (OXY), a neuropeptide typically linked to social bonding and reproductive functions, may influence inflammatory processes. This work examines the impact of OXY on LPS-induced testicular damage, aiming to elucidate its therapeutic potential in addressing inflammatory disorders and broadening the comprehension of its functions beyond conventional neuroendocrine roles. Eighteen male albino rats were divided into three groups; the control group received no treatment; the LPS group received 0.5mL of saline solution containing 5mg/kg LPS intraperitoneally (orchitis model); and the LPS + OXY group received LPS and OXY (0.1mg/kg) intraperitoneally every 12h for 72h. Animals subjected to LPS were found to have severe orchitis, as evidenced by increased oxidative stress and surging inflammatory mediators (TNF-α, IL-1β, and IL-6), with declined IL-10 levels. Besides, LPS increased the malondialdehyde (MDA) and decreased the glutathione (GSH) levels, inducing an oxidative stress cascade. In addition, there are dramatic increases in the TLR4, MyD88, NF-κB, and PK2/PKR1 protein expression levels. All these events could alter the sperm count, morphology, and testicular architecture. Interestingly, OXY could mitigate LPS-induced oxidative damage and inflammation in testicular tissue alongside restoring the disrupted sperm count, motility, and morphology. This therapeutic potential of OXY might be accounted for by its anti-inflammatory, antioxidant, and antiapoptotic activities.

Exploring the Potential of Malvidin and Echiodinin as Probable Antileishmanial Agents Through In Silico Analysis and In Vitro Efficacy.

Leishmaniasis, a neglected tropical disease caused by Leishmania species, presents serious public health challenges due to limited treatment options, toxicity, high costs, and drug resistance. In this study, the in vitro potential of malvidin and echioidinin is examined as antileishmanial agents against L. amazonensis, L. braziliensis, and L. infantum, comparing their effects to amphotericin B (AmpB), a standard drug. Malvidin demonstrated greater potency than echioidinin across all parasite stages and species. Against L. amazonensis, malvidin's IC50 values were 197.71 ± 17.20 µM (stationary amastigotes) and 258.07 ± 17 µM (axenic amastigotes), compared to echioidinin's 272.99 ± 29.90 μM and 335.96 ± 19.35 μM. AmpB was more potent, with IC50 values of 0.06 ± 0.01 µM and 0.10 ± 0.03 µM. Malvidin exhibited lower cytotoxicity (CC50: 2920.31 ± 80.29 µM) than AmpB (1.06 ± 0.12 µM) and a favorable selectivity index. It reduced infection rates by 35.75% in L. amazonensis-infected macrophages. The in silico analysis revealed strong binding between malvidin and Leishmania arginase, with the residues HIS139 and PRO258 playing key roles. Gene expression analysis indicated malvidin's modulation of oxidative stress and DNA repair pathways, involving genes like GLO1 and APEX1. These findings suggest malvidin's potential as a safe, natural antileishmanial compound, warranting further in vivo studies to confirm its therapeutic efficacy and pharmacokinetics in animal models.

The Unexplored Role of Connexin Hemichannels in Promoting Facioscapulohumeral Muscular Dystrophy Progression.

DUX4 is typically a repressed transcription factor, but its aberrant activation in Facioscapulohumeral Muscular Dystrophy (FSHD) leads to cell death by disrupting muscle homeostasis. This disruption affects crucial processes such as myogenesis, sarcolemma integrity, gene regulation, oxidative stress, immune response, and many other biological pathways. Notably, these disrupted processes have been associated, in other pathological contexts, with the presence of connexin (Cx) hemichannels-transmembrane structures that mediate communication between the intracellular and extracellular environments. Thus, hemichannels have been implicated in skeletal muscle atrophy, as observed in human biopsies and animal models of Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Dysferlinopathies, suggesting a potentially shared mechanism of muscle atrophy that has not yet been explored in FSHD. Despite various therapeutic strategies proposed to manage FSHD, no treatment or cure is currently available. This review summarizes the current understanding of the mechanisms underlying FSHD progression, with a focus on hormones, inflammation, reactive oxygen species (ROS), and mitochondrial function. Additionally, it explores the potential of targeting hemichannels as a therapeutic strategy to slow disease progression by preventing the spread of pathogenic factors between muscle cells.

Data Mining Approach to Melatonin Treatment in Alzheimer's Disease: New Gene Targets MMP2 and NR3C1.

Melatonin is a hormone released by the pineal gland that regulates the sleep-wake cycle. It has been widely studied for its therapeutic effects on Alzheimer's disease (AD), particularly through the amyloidosis, oxidative stress, and neuroinflammation pathways. Nevertheless, the mechanisms through which it exerts its neuroprotective effects in AD are still largely unknown. Data mining was used to identify potential gene targets that link melatonin's effects to AD pathways, yielding a comprehensive view of the underlying molecular mechanisms. We identified 3397 genes related to AD from DisGeNet and 329 melatonin gene targets from ChEMBL, which revealed 223 overlapping genes and the potential shared pathways. These genes were used to construct a protein-protein interaction (PPI) network comprising 143 nodes and 823 edges, which demonstrated significant PPI enrichment. A cluster analysis highlighted two key clusters centered on MMP2 and NR3C1, with both genes playing crucial roles in steroid hormone signaling, apoptosis, and monoamine neurotransmission. Gene Ontology (GO) enrichment and KEGG pathway analyses further elucidated their involvement in critical pathways, for instance, steroid hormone signaling and apoptosis regulation, significantly influencing AD pathology through mechanisms such as extracellular matrix remodeling, epigenetic modifications, and neuroinflammation. Our findings emphasize MMP2 and NR3C1 as important gene targets for future research on melatonin treatment in AD, paving the way for further investigations into their roles in AD pathophysiology.

Hypusinated and unhypusinated isoforms of the translation factor eIF5A exert distinct effects in models of pancreas development and function.

Hypusination of eukaryotic translation initiation factor 5A (eIF5A) is essential for its role in translation elongation and termination. Although the function of hypusinated eIF5A (eIF5AHyp) in cellular proliferation is well-characterized, the role of its unhypusinated form (eIF5ALys) remains unclear. We hypothesized that eIF5ALys exerts independent, negative effects on cellular replication and metabolism, distinct from the loss of eIF5AHyp. To test this hypothesis, we utilized zebrafish and mouse models with inducible knockdowns of deoxyhypusine synthase (DHPS) and eIF5A to investigate their roles in cellular growth. Gene expression analysis via RNA sequencing and morphometric measurements of pancreas and β-cell mass were performed to assess phenotypic changes and identify affected biological pathways. Loss of DHPS in zebrafish resulted in significant defects in pancreatic growth, accompanied by changes in gene expression related to mRNA translation, neurogenesis, and stress pathways. By contrast, knockdown of eIF5A had minimal impact on pancreas development, suggesting that the effects of DHPS loss are not solely due to the lack of eIF5AHyp. In mice, β cell-specific deletion of DHPS impaired β cell mass expansion and glucose tolerance, while eIF5A deletion had no statistically significant effects. These findings provide evidence for an independent role for eIF5ALys in regulating developmental and functional responses in pancreas health and disease.

The gut-brain axis: Unveiling the impact of xenobiotics on neurological health and disorders.

The Gut-Brain Axis (GBA) is a crucial link between the gut microbiota and the central nervous system. Xenobiotics, originating from diverse sources, play a significant role in shaping this interaction. This review examines how these compounds influence neurotransmitter dynamics within the GBA. Environmental pollutants can disrupt microbial populations, impacting neurotransmitter synthesis-especially serotonin, gamma-aminobutyric acid (GABA), and dopamine pathways. Such disruptions affect mood regulation, cognition, and overall neurological function. Xenobiotics also contribute to the pathophysiology of neurological disorders, with changes in serotonin levels linked to mood disorders and imbalances in GABA and dopamine associated with anxiety, stress, and reward pathway disorders. These alterations extend beyond the GBA, leading to complications in neurological health, including increased risk of neurodegenerative diseases due to neuroinflammation triggered by neurotransmitter imbalances. This review provides a comprehensive overview of how xenobiotics influence the GBA and their implications for neurological well-being.

Targeted delivery of a selenium-sulfa compound via cationic starch microparticles: Modulation of oxidative stress and pain pathways in fibromyalgia-like symptoms in mice

Cationic starch microparticles (CStMPs) loaded with 4-amino-3 -(phenylselenyl)benzenesulfonamide (4-APSB) were prepared and investigated in a model of fibromyalgia (FM) induced by intermittent cold stress (ICS) in male and female Swiss mice. The CStMPs/4-APSB were characterized by Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy-dispersive X-ray (EDX) spectroscopy, zeta potential, and particle size measurements, providing information about their chemical composition, surface charge, morphology/microstructure, and size (1.50 ± 0.5 μm). Following ICS exposure, the animals were treated with free 4-APSB (1 mg/kg), CStMPs/4-APSB (containing 0.13 mg of 4-APSB per mg of microparticles), or CStMPs, from days 5 to 10. The results revealed the successful incorporation of 4-APBS in the CStMPs. Free 4-APSB and CStMPs/4-APSB reversed nociceptive- and depressive-related behaviors in male and female mice exposed to ICS, attenuating the hallmark symptoms of FM. Those treatments (free 4-APSB and CStMPs/4-APSB) normalized the monoamine oxidase (MAO)-A activity in the cerebral cortex and the oxidative damage, providing the correct functioning of the enzyme Ca2+ -ATPase in the cerebral cortex and hippocampus of mice exposed to ICS. The CStMPs/4-APSB modulated the oxidative stress markers, specifically in the spinal cord of mice - an anatomical region intricately linked to pain pathways.