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The present study elucidates the efficacy of the neuropeptide neurotensin/NTS analog PD149163 in ameliorating chronic thyroid inflammation and metabolic endotoxemia induced by E. coli endotoxin lipopolysaccharide/LPS. NTS, a gastrointestinal-tract tri-decapeptide, has anti-inflammatory and anti-oxidative effects. Swiss-albino mice (female/7-8 weeks/25 ± 2.5 g) were divided into six groups: GI/control; GII and GIII were treated with 50 and 100 μg/kg bw of PD149163, respectively, for 4 weeks. GIV-VI was injected with LPS (1 mg/kg bw; 5 days), followed by PD149163 exposure to GV/END+PD50 (50 μg/kg bw) and GVI/END+PD100 (100 μg/kg bw) for 4 weeks. Both the LPS and PD149163 were given intraperitoneally. PD100 treatment has shown efficacy in counteracting chronic thyroid inflammation, metabolic endotoxemia and hormonal impairments. The LPS-induced histopathological alterations in thyroid and visceral adipose tissue are characteristics of inflammation, ameliorated following PD100 supplementation. LPS-exposure elevates cytokines (IL-6/TNF-α), apoptotic protein/CAS3, adipokine/leptin and decreases IL-10, Bcl-2 and NTS, indicating inflammation and cellular apoptosis, normalised by PD100. Supplementation with PD100 reduces LPS-mediated increase in acute-phase protein/CRP and anti-thyroid peroxidase/TPO antibodies in plasma and tissue. The LPS-induced hormonal impairment of the HPT axis (TSH/T4/T3) and metabolic endotoxemia, reflected in altered triglycerides (TAG)/total cholesterol (TC)/high and low-density lipoproteins (HDL-c/LDL-c), were also counteracted by PD100. Molecular docking predicted that LPS/LBP may compete with T3 for its receptors (TRα/TRβ) and can disrupt the thyroid receptor's functioning. Also, docking of PD149163-LBP suggests that PD149163 directly binds to LBP, thereby inhibiting LPS-LBP interaction and attenuating LPS-induced effects. Thus, PD149163 emerges as a potential modulator of endotoxemia-induced thyroid inflammation, hormonal imbalance, and metabolic dysfunction by inhibiting LPS-LBP interaction and downstream signalling.
Thrombospondin-1 (TSP-1) is a matricellular glycoprotein involved in the regulation of angiogenesis, immune responses, and extracellular matrix remodeling within the tumor microenvironment. Its overexpression and interaction with receptor CD47 have been associated with tumor progression and resistance to therapy. In contrast to CD47/SIRPα blockade, which is constrained by hematological and immunotoxic adverse effects, selective inhibition of the TSP-1/CD47 interaction axis may represent a mechanistically distinct and potentially safer therapeutic approach. TAX2, a 12-amino-acid cyclic peptide, was designed as an orthosteric antagonist of this interaction. Its non-clinical profile was characterized through cross-species binding assays, receptor selectivity profiling, pharmacokinetic and biodistribution analyses in rodents and dogs, in vitro off-target and cytokine release assays, and GLP-compliant toxicology studies. Human pharmacokinetics were predicted using multiple species allometric scaling. TAX2 demonstrated binding to TSP-1 from human, rodent, and canine origin, without measurable interference with CD47/SIRPα signaling under the conditions tested. The peptide exhibited rapid plasma clearance (1-4 h), dose-proportional exposure, and detectable signal in TSP-1-rich tissues and tumor-associated regions in biodistribution studies. No relevant off-target activity or unexpected immunostimulatory effects were observed. TAX2 was well tolerated at doses up to 400 mg/kg in rats and 100 mg/kg in dogs, with no hematological or systemic toxicity, and exposures exceeding the projected clinical range. Overall, these findings establish a translational non-clinical framework for TAX2 as a first-in-class TSP-1/CD47 antagonist with cross-species-reactivity and a favorable pharmacokinetic and safety profile2.
Doxorubicin-induced cardiotoxicity (DIC) features cardiomyocyte loss and maladaptive remodeling. Mitochondrial damage, oxidative stress, autophagy, and different types of cell death, including ferroptosis, pyroptosis, and apoptosis, are recognized as the principal biological mechanisms contributing to DIC, in which disrupted mitochondrial dynamics play a pivotal role. The role of long noncoding RNAs (lncRNAs) in DIC is becoming more well understood; however, the function of TGFB2-AS1 remains unclear. Here, DIC was established in doxorubicin-treated male C57BL/6 mice and in doxorubicin-treated AC16/HL-1 cardiomyocytes. TGFB2-AS1 expression and subcellular localization were determined, and gain- and loss-of-function analyses were performed. Flow cytometry was used to quantify apoptosis and intracellular reactive oxygen species (ROS), and apoptosis-associated proteins and mitochondrial dynamics regulators were assessed by immunoblotting. Mitochondrial morphology was visualized using MitoTracker staining. Bone morphogenic protein 7 (BMP7) signaling was evaluated via recombinant BMP7 supplementation and BMP7 knockdown. Cardiac structure and injury were evaluated by echocardiography and histology. TGFB2-AS1 expression was markedly upregulated in DIC models, and TGFB2-AS1 overexpression exacerbated doxorubicin-induced hypertrophy, apoptosis, ROS accumulation, and mitochondrial fragmentation, whereas TGFB2-AS1 silencing partially reversed these effects. Mechanistically, TGFB2-AS1 knockdown restored BMP7/Smad1/5/9- inhibitor of DNA binding protein 2 (Id2) signaling, and BMP7 depletion attenuated the cardioprotective effects of TGFB2-AS1 silencing. Consistently, BMP7 supplementation mitigated cardiomyocyte apoptosis and Drp1-associated mitochondrial fission in vitro and improved doxorubicin-induced remodeling in vivo through the activation of BMP7/Smad signaling. Collectively, TGFB2-AS1 promotes DIC by suppressing BMP7/Smad/Id2 signaling and enhancing mitochondrial fission, positioning TGFB2-AS1 as a candidate intervention point.
Information on childhood cancer burden is crucial for effective cancer policy planning. Unfortunately, observed paediatric cancer data are not available in every country, and previous global burden estimates have not discretely reported several common cancers of childhood. We aimed to inform efforts to address childhood cancer burden globally by analysing results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, which now include nine additional cancer causes compared with previous GBD analyses. GBD 2023 data sources for cancer estimation included population-based cancer registries, vital registration systems, and verbal autopsies. For childhood cancers (defined as those occurring at ages 0-19 years), mortality was estimated using cancer-specific ensemble models and incidence was estimated using mortality estimates and modelled mortality-to-incidence ratios (MIRs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the standard life expectancy at the age of death. Prevalence was estimated using survival estimates modelled from MIRs and multiplied by sequelae-specific disability weights to estimate years lived with disability (YLDs). Disability-adjusted life-years (DALYs) were estimated as the sum of YLLs and YLDs. Estimates are presented globally and by geographical and resource groupings, and all estimates are presented with 95% uncertainty intervals (UIs). Globally, in 2023, there were an estimated 377 000 incident childhood cancer cases (95% UI 288 000-489 000), 144 000 deaths (131 000-162 000), and 11·7 million (10·7-13·2) DALYs due to childhood cancer. Deaths due to childhood cancer decreased by 27·0% (15·5-36·1) globally, from 197 000 (173 000-218 000) in 1990, but increased in the WHO African region by 55·6% (25·5-92·4), from 31 500 (24 900-38 500) to 49 000 (42 600-58 200) between 1990 and 2023. In 2023, age-standardised YLLs due to childhood cancer were inversely correlated with country-level Socio-demographic Index. Childhood cancer was the eighth-leading cause of childhood deaths and the ninth-leading cause of DALYs among all cancers in 2023. The percentage of DALYs due to uncategorised childhood cancers was reduced from 26·5% (26·5-26·5) in GBD 2017 to 10·5% (8·1-13·1) with the addition of the nine new cancer causes. Target cancers for the WHO Global Initiative for Childhood Cancer (GICC) comprised 47·3% (42·2-52·0) of global childhood cancer deaths in 2023. Global childhood cancer burden remains a substantial contributor to global childhood disease and cancer burden and is disproportionately weighted towards resource-limited settings. The estimation of additional cancer types relevant in childhood provides a step towards alignment with WHO GICC targets. Efforts to decrease global childhood cancer burden should focus on addressing the inequities in burden worldwide and support comprehensive improvements along the childhood cancer diagnosis and care continuum. St Jude Children's Research Hospital, Gates Foundation, and St Baldrick's Foundation.
Over-the-counter (OTC) medicines are frequently used during pregnancy. As these medicines are often used without medical supervision, accessible and reliable safety information is essential. However, finding reliable and understandable information on the safety of these medicines during pregnancy is often experienced as difficult. Hence, there is a need for a new easily accessible electronic health (eHealth) tool that empowers women to actively seek information to support safer self-medication practices during pregnancy and breastfeeding. This study aimed to describe the development and dissemination process of a Dutch mobile app providing reliable safety information on OTC medicines during pregnancy and breastfeeding using a development and formative evaluation approach. The app was developed over a 2-year project comprising 5 phases, including preparation, development, preimplementation, implementation, and evaluation. Mixed-method strategies, including questionnaires, focus groups, and user feedback rounds, were applied to involve the target population in the development process. Medicine safety information in the app was based on the latest scientific evidence. First-year app-usage outcomes included app downloads, usage patterns, and information-seeking behavior. Input from 253 potential users formed the foundation for the development of the MediMama app (Netherlands Pharmacovigilance Centre Lareb), with users expressing a need for clear, reliable, and easily accessible information on medication safety during pregnancy and breastfeeding. The app was launched on Mother's Day 2024 and provides safety information on over 250 OTC medicines, including supplements and herbal remedies, across 27 medicine categories. Promotion occurred through multiple online and offline channels. During its first year, the MediMama app was downloaded 22,415 times, with an average of 370 unique daily users, indicating substantial user engagement. Information on paracetamol (acetaminophen) and nasal sprays was most frequently accessed, reflecting the need for information on commonly used OTC medicines among the target population. One year after its launch, the MediMama app is considered a promising tool in maternity care, meeting the target population's need for accessible OTC medicine safety information. The app aims to support informed decision-making, contributing to safer medication use during pregnancy and breastfeeding. Further research is required to evaluate the effectiveness of the implementation strategy, as well as the app's impact on maternal medication use behaviors and health outcomes.
Ghrelin is a peptide hormone consisting of 28 amino acids, characterized by octanoylation, and is primarily secreted by gastric X/A-like cells and is recognized as the sole circulating orexigenic hormone. Ghrelin, via its receptor growth hormone secretagogue receptor 1a, modulates key biological functions such as appetite, growth hormone release, glucose regulation, gastrointestinal motility, cardiovascular activity, immune, and stress reactivity. The characteristics of O-octanoyl substitution at Ser3 are not only crucial for receptor activation, but this alteration also makes it susceptible to enzymatic breakdown and therefore leads to a short plasma half-life, bridging both therapeutic possibilities and pharmacological constraints. This review summarizes the structural features of ghrelin, its receptor biology, and its significant physiological and pharmacological actions, particularly its differential effects on the hypothalamic pituitary adrenal axis and stress behaviors. We also discussed the hurdles associated with ghrelin-based treatments, and, therefore, briefly mentioned new delivery methods that could potentially address issues with pharmacokinetics and targeting constraints. There are numerous potential clinical applications, including metabolic disorders, gastrointestinal disease, neurodegeneration, chronic pain, psychiatric disorders, and wasting syndromes. The limitations, such as metabolic adverse effects, receptor desensitization, differential effects, and safety considerations, were critically evaluated. In translational pharmacology, ghrelin is a potential but challenging target that requires careful integration of physiopharmacological knowledge with prudent treatment design.
Anti-nerve growth factor (NGF) monoclonal antibodies (mAbs) have emerged as a promising new class of analgesics, offering potential benefits in managing particular painful musculoskeletal (MSK) conditions. However, their long-term safety remains uncertain, leading to regulatory non-approval of these agents. This study aims to evaluate the efficacy and safety of individual anti-NGF mAbs compared to other analgesics when treating chronic MSK pain. Our literature search included PubMed, Scopus, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov through April 25th, 2025. Articles eligible for inclusion were randomized controlled trials (RCTs) comparing one of the human anti-NGF mAbs to other interventions in adults with chronic MSK pain. Primary outcomes evaluated were changes from baseline in pain, physical function, and patient global assessment (PGA) scores, as well as risks of adjudicated arthropathies (AAs) and abnormal peripheral sensation (APS). We used the Cochrane Risk of Bias 2 (RoB-2) tool to assess risk of bias. Pairwise and network meta-analyses were performed using random-effects models. Treatments were ranked using the cumulative ranking curve (SUCRA), and a multi-criteria decision analysis with Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) was applied to integrate all efficacy and safety outcomes. Statistical analyses were conducted in R (v4.3.1) using the meta, netmeta, gemtc, and Multi-Criteria Decision Aiding (MCDA) packages. A total of 29 studies, involving 27,747 patients with osteoarthritis or chronic low back pain, were included in this analysis. Compared to placebo, fasinumab showed the highest improvements in pain (standardized mean difference [SMD] - 0.40, 95% CI [- 0.52, - 0.29], p < 0.001) and physical function (SMD - 0.42, 95% CI [- 0.53, - 0.31], p < 0.001), followed by tanezumab (pain: SMD - 0.36, 95% CI [- 0.44, - 0.28], p < 0.001; function: SMD - 0.39, 95% CI [- 0.47, - 0.31], p < 0.001). For safety, both fasinumab and tanezumab demonstrated a significant risk for AAs (risk ratio [RR] 4.7, 95% CI [3.61, 6.13], p < 0.001; and RR 3.84, 95% CI [2.07, 7.14], p < 0.001, respectively) and APS (RR 1.99, 95% CI [1.49, 2.65], p < 0.001; and RR 2.46, 95% CI [1.93, 3.14], p < 0.001, respectively) relative to placebo. While fulranumab was less effective (pain: SMD - 0.25, 95% CI [- 0.42, - 0.07], p < 0.01; function: SMD - 0.25, 95% CI [- 0.43, - 0.07], p < 0.01), it showed better overall safety against placebo relative to both agents, demonstrating a significant risk only for APS events (RR 1.78, 95% CI [1.09, 2.92], p < 0.05). Anti-NGF mAbs, particularly fasinumab and tanezumab, are associated with the greatest levels of pain relief and functional improvement over placebo within this analysis. However, these benefits are counterbalanced by significant risks of joint-related adverse events. Implementation of strict safety protocols is essential when considering these agents for further evaluation. PROSPERO ID: CRD420251104612.
AimTo assess whether the timing of atogepant administration influences its tolerability and effectiveness over 12 weeks in patients with episodic and chronic migraine in a real-world setting.MethodsThis is a post-hoc analysis of the STAR study, a prospective, Italian, multicenter study evaluating atogepant 60 mg for migraine prevention. Data were collected at baseline (T0) and after the first 12 weeks (T3) of treatment. Patients were grouped by administration timing (morning vs. evening) and by administration with or without food. Changes in monthly headache days (MHDs), monthly migraine days (MMDs), and Migraine Disability Assessment (MIDAS) were measured. Tolerability was evaluated via adverse events (AEs). Linear mixed-effects models (LMMs) were used.ResultsEighty-one patients (86% females, mean age 50.8 ± 13.7 years) were included. At T3, MMDs decreased from 16.6 to 9.7 (p < 0.001) and MHDs from 19.8 to 11.9 (p < 0.001); 60% of patients achieved ≥50% reduction in MMDs. AEs occurred in 34 (42%) participants. Atogepant was taken in the morning by 57% and in the evening by 43% of patients. Fifty-seven out of 81 participants (70.4%) took atogepant with food. No significant differences in MMDs, MHDs, or AEs emerged between morning and evening users. Evening users had higher baseline MIDAS scores (estimated marginal means [EMMs]: 69.9 vs. 39.9, p = 0.034) that showed a greater reduction compared to morning users (F(1,63) = 6.29, p = 0.015), reaching similar final scores after 12 weeks (EMMs: 25.1 vs. 23.8). No difference in atogepant effectiveness and tolerability according to intake with or without food, except for a reduction in MHDs for patients who took atogepant without food (EMMs from 21.3 to 9.9 vs with food: EMMs from 18.4 to 12.7; F(1,79) = 8.553, p = 0.005).ConclusionsAtogepant significantly reduced migraine burden over 12 weeks in a real-world setting. Overall, the timing of atogepant administration did not affect its effectiveness or tolerability. However, a greater reduction in MIDAS scores was observed among evening users. Whether this reflects a pharmacological advantage or a ceiling effect remains unclear. Taking atogepant without food was associated with a significantly greater reduction in MHDs, whereas changes in MMDs and MIDAS scores did not differ between groups. Long-term and dedicated studies are needed to evaluate and confirm these findings.Trial RegistrationThe main study (STAR) was preregistered on clinicaltrial.gov, NCT06414044.
This longitudinal study investigated the differential composition of the nasopharyngeal microbiome in patients presenting different COVID-19 infectious phenotypes and its evolution during convalescence, with a focus on post-acute sequelae of SARS-CoV-2 (PASC) and its potential microbiome-related mechanisms. Microbiota composition was assessed for a cohort of healthy participants (n = 25), influenza patients (n = 24), and patients with moderate (n = 50) and severe (n = 57) COVID-19. Samples were collected at two time points: during the acute infection phase and at approximately 3-month follow-up. From collected nasopharyngeal swab samples, metagenomics using shotgun sequencing was performed and the microbiota composition was analyzed. Alpha and beta diversity analyses revealed no significant differences in overall community diversity between patient groups across visits. However, differential abundance testing identified specific species, such as Dolosigranulum pigrum and various Corynebacterium species, whose profiles correlated with PASC development. Furthermore, the analysis of microbial co-associations identifies commensal species, including D. pigrum and Corynebacterium species, which are less abundant in patients who develop PASC, consistent with a potential protective role suggested by experimental studies but not proven by our observational data. Antibiotic use was associated with lower levels of key protective taxa, which may increase susceptibility to PASC in case of superinfection. These findings highlight the potential importance of the nasopharyngeal microbiome in acute COVID-19 disease outcomes and suggest that preserving or restoring a balanced respiratory microbiome could mitigate the risk of COVID-19 persistent symptoms and PASC development. Our results may set the stage for future clinical interventions involving probiotics or microbial-derived metabolites to promote respiratory health post-COVID-19.IMPORTANCEThis study highlights the importance of bacteria naturally found in the upper respiratory tract, particularly the nasopharynx (the nasopharyngeal microbiome), in shaping how severely COVID-19 affects patients and whether they experience persistent symptoms, also called long-COVID or post-acute sequelae of SARS-CoV-2 (PASC). By examining microbiome samples from healthy people, influenza patients, and individuals with COVID-19 during acute and convalescent phases, we found that certain commensal bacteria, namely, Dolosigranulum pigrum and Corynebacterium species, were less abundant in individuals who developed long-COVID and more abundant in those who fully recovered. We also observed that antibiotic treatment was associated with lower abundances of these commensal taxa, in turn coinciding with a higher frequency of PASC. These findings suggest that the composition of the nasopharyngeal microbiome is associated with recovery trajectories after COVID-19 and motivate future research into treatments aimed toward the microbiome to improve respiratory health following infection.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05557539.
Chronic aluminum (Al) exposure has been implicated as a significant environmental risk factor in the development and progression of neurodegenerative diseases. This study aimed to investigate the Al maltolate (Al-Malt) induced cellular stress responses in SH-SY5Y cells in vitro by evaluating the changes in endoplasmic reticulum (ER) stress related markers and NMDAR2B levels, and to assess the modulatory effects of coenzyme Q10 (CoQ10). Cellular viability and metabolic activity following exposure to Al-Malt were assessed using the MTT assay. NMDAR2B levels were measured by the ELISA, while GRP78 and CHOP mRNA expression levels, which are ER stress biomarkers, were analyzed by the RT-PCR. 250 and 500 μ Al-Malt exposure resulted in reduced cellular viability and metabolic activity by approximately ∼18% and ∼ 30% respectively. GRP78 mRNA expression increased ∼2.2 and ∼ 2.6 fold, while CHOP mRNA expression increased by ∼1.86 and ∼ 2.31 fold at 250 and 500 μ Al-Malt, respectively. NMDAR2B levels decreased by approximately ∼26% and ∼ 40% compared to control. CoQ10 pretreatment attenuated these cellular responses. These findings suggest an association between Al exposure, ER stress related responses, and alterations in NMDAR2B levels in an in vitro neuronal model, and indicate that CoQ10 may modulate Al-induced cellular stress. However, further studies using primary neuronal cultures and in vivo models are warranted to validate and extend these results.
Non-small cell lung cancer (NSCLC) continues to impose a significant global mortality burden, due to limited therapies, drug resistance, and treatment-related toxicity. Exosomes offer promise for the targeted delivery of therapeutic agents. Exosomes were isolated from bovine colostrum and characterized for size, polydispersity index, and surface charge. Celastrol (CEL) was loaded onto exosomes (ExoCEL), and Folic Acid (FA)-functionalized exosomes (FA-ExoCEL) and validated using fluorescence quenching and protease sensitivity assay. Anticancer activity was assessed in NSCLC cell lines using colony formation, cell migration and uptake assays. Transcriptomic (RNA-seq) and protein analysis were performed to analyze gene expression changes. Biodistribution, oral uptake and potential toxicity were evaluated in wild-type mice, while oral antitumor efficacy was tested in orthotopic lung tumor models comparing CEL, ExoCEL and FA-ExoCEL. Synergistic activity with paclitaxel was assessed in chemoresistant cells. Exosomes were isolated, characterized and efficiently loaded with CEL. ExoCEL demonstrated superior antiproliferative effects in NSCLC cell lines and enhanced potency in drug-resistant A549TR cells compared to free CEL. ExoCEL significantly inhibited colony formation and cell migration in a dose-dependent manner. RNA Seq and protein analyses showed that CEL and ExoCEL reversed TGF-β-induced EMT, restored epithelial markers, suppressed mesenchymal, oncogenic and extracellular matrix related markers. In orthotopic lung tumor models, FA-ExoCEL achieved approximately 80-90% tumor inhibition, outperforming both free CEL and ExoCEL. Oral delivery of FA-ExoCEL resulted in efficient gastrointestinal uptake, selective tumor targeting, recovery of exosomal markers in circulation and no observed systemic toxicity. CEL exhibited strong synergy with paclitaxel, with exosomal delivery further enhancing paclitaxel efficacy in resistant cells. FA-ExoCEL represents a safe, scalable, and effective oral therapeutic strategy for NSCLC. By combining exosome-mediated delivery with folate-targeted tumor accumulation, this platform enhances CEL bioavailability, and improves antitumor efficacy, supporting its translational potential for lung cancer therapy.
Aspartame is a widely consumed artificial sweetener that undergoes rapid metabolic conversion to phenylalanine, aspartic acid, and methanol, metabolites that may contribute to oxidative stress and inflammatory responses under conditions of metabolic vulnerability. This study evaluated whether nanoencapsulation using chitosan nanoparticles could modulate systemic metabolite exposure and attenuate metabolite-associated biological stress responses. Aspartame-loaded chitosan nanoparticles (Asp@CS-NPs) were prepared by ionic gelation and characterized for physicochemical properties, release kinetics, and pharmacokinetic behavior. Nanoencapsulation produced sustained release profiles and significantly reduced peak plasma concentrations (Cmax) and systemic exposure (AUC) of phenylalanine compared with free aspartame, indicating altered toxicokinetic behavior. In a glucocorticoid-induced metabolic dysfunction and osteoporosis rat model, reduced metabolite exposure was associated with attenuation of oxidative stress biomarkers, suppression of pro-inflammatory cytokines, preservation of hepatic and renal function, and improvement in metabolic and skeletal endpoints. These effects were accompanied by normalization of redox-sensitive signaling markers, suggesting mitigation of metabolite-induced oxidative and inflammatory cascades. Collectively, the findings indicate that nanoencapsulation can influence toxicokinetic parameters and downstream toxicodynamic responses associated with metabolite exposure. This approach provides a framework for toxicokinetic modulation, whereby controlled absorption reduces peak metabolite exposure and downstream stress responses without altering the intrinsic properties of the parent compound.
Atomoxetine, a drug used in the treatment of Attention Deficit/Hyperactivity Disorder, acts by increasing the availability of neurotransmitters, which can act on the male genital system. The effects of this substance on Leydig cells, which are responsible for testosterone production, have not been described. This study aimed to investigate the in vitro effects of atomoxetine hydrochloride (250, 1000 or 1750 ng/mL) on DNA damage (4 h), gene expression (12h), and after 24 h, cell viability and death, oxidative profile, cytokines and testosterone levels, and the colony-forming capacity in TM3 Leydig cells. Although cell viability was not altered, a reduction in testosterone biosynthesis, an increase in apoptosis and necrosis, a decrease in clonogenic capacity, and an increase in DNA damage were observed at higher concentrations. An alteration in the redox profile was noted, evidenced by a decrease in reduced glutathione and catalase enzyme activity, an increase in total, oxidized, and S-transferase glutathione enzymes, in addition to superoxide dismutase activity and increased lipid peroxidation. Genes involved in apoptotic pathways (BAX, Tp53) were upregulated, as were those related to oxidative stress (HO-1 and Nrf2). Conversely, the androgen receptor gene (AR), especially at the concentration of 1000 ng/mL, downregulated. Furthermore, there was a reduction in IL-33 levels. Even without directly compromising cell viability, possibly due to a limitation of the MTT test, or altering levels of TNF-α and IL-1β, atomoxetine hydrochloride caused important functional alteration in Leydig cells through oxidative stress, genotoxicity, and cytostatic effects, with potential implications for male reproductive function.
Alpha-terpineol (α-terpineol), a ubiquitous monoterpenoid alcohol found in numerous essential oils, is widely employed in cosmetics, perfumes, and aromatic therapies. Despite its extensive application, concerns regarding its potential reproductive and developmental toxicity remain inadequately characterized, particularly concerning specific teratogenic effects and underlying molecular mechanisms. This study presents novel findings, demonstrating that α-terpineol exposure during the critical organogenesis period significantly induces developmental toxicity in Wistar rat fetuses. α-terpineol was administered at the doses of 0, 75, 150, and 300 mg/kg with a dose volume of 5 mL/kg. We report dose-dependent embryotoxic and teratogenic effects, including reduced fetal weight and a spectrum of severe skeletal malformations such as anophthalmia, club foot, micrognathia, phocomelia, and irregularities in the vertebral column, ribs, and limb bones. Crucially, our comprehensive gene expression analysis revealed statistically significant alterations in the expression patterns of HOXD13 and GDF11, two pivotal genes essential for skeletal patterning and limb development. The observed downregulation of these genes suggests a potential molecular association into α-terpineol-induced teratogenesis. These findings underscore the significant developmental risks associated with α-terpineol exposure during pregnancy and provides insights into potential molecular changes underlying its teratogenic potential, warranting further investigation into human health implications and the establishment of safe exposure limits for this widely used compound.
Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI), largely driven by mitochondrial dysfunction and oxidative stress. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) detoxifies lipid peroxidation-derived reactive aldehydes; however, its role in APAP-induced hepatotoxicity, particularly in light of the high prevalence of ALDH2 deficiency in East Asian populations, remains incompletely understood. Fasted wild-type (WT) and ALDH2 knockout (KO) mice were challenged with APAP (500 mg/kg). Liver injury was evaluated by histopathological analysis, serum aminotransferase levels, and survival. Intestinal barrier integrity, gut microbiota composition (16S rRNA sequencing), fecal bile acid profiles (LC-MS/MS), and hepatic Nrf2 signaling were systematically examined. ALDH2 deficiency markedly exacerbated APAP-induced liver injury, as evidenced by extensive hepatic necrosis, elevated serum ALT and AST levels, and reduced survival. KO mice exhibited compromised intestinal barrier function, characterized by reduced expression of Claudin-1 and ZO-1 and increased accumulation of 4-hydroxynonenal. Gut microbiota analysis revealed pronounced microbial instability and a significant depletion of Lactobacillus, which was negatively correlated with the severity of liver injury. Consistently, fecal bile acid profiling demonstrated increased levels of tauro-β-muricholic acid in KO mice, which positively correlated with liver damage and inversely correlated with Lactobacillus abundance. Mechanistically, APAP robustly induced hepatic Nrf2-dependent antioxidant gene expression in WT mice, whereas this adaptive response was markedly blunted in ALDH2-deficient mice. Collectively, ALDH2 deficiency heightens susceptibility to APAP-induced ALI by impairing Nrf2-mediated antioxidant defenses and disrupting the gut-liver axis. These findings identify ALDH2 as a critical determinant of APAP sensitivity and a potential therapeutic target.
Radiofrequency radiation (RFR), widely emitted from modern wireless devices, has raised questions regarding its possible impact on male reproductive health. In this comparative study, we examined the redox and apoptotic responses of TM3 Leydig cells following exposure to mobile phone radiation, as well as 2450 MHz, and 1800 MHz frequencies for 15, 30, 45, 60, 90 & 120 min, and redox imbalance was assessed by quantifying nitric oxide (NO) and intracellular superoxide (SO) levels. Apoptotic cell percentages were evaluated by dual labeling with Annexin V-FITC/PI using flow cytometry. Mobile phone and 2450 MHz exposures induced biphasic alterations in NO levels, while 1800 MHz exposure resulted in a sustained reduction in NO. SO levels increased progressively in a time- and frequency-specific manner. Apoptotic analysis revealed early apoptotic activation in mobile and 2450 MHz groups, whereas 1800 MHz exposure led to delayed but sustained late-stage apoptosis. These findings demonstrate that RFR triggers redox imbalance and apoptosis in TM3 cells, with effects varying by frequency and exposure duration. This comparative analysis underscores the biological risks of chronic low-intensity RFR exposure and highlights the growing concerns about RFR-associated testicular stress and its implications for male reproductive toxicity.
The brain undergoes profound molecular and structural changes during the aging process, resulting in the development of neurodegeneration, cognitive impairment, and increased vulnerability to chronic diseases. At the cellular level, brain aging is characterized by oxidative damage, genomic instability, and chronic low-grade inflammation known as inflammaging. Central to this process is Sirtuin 1 (SIRT1), a NAD+-dependent class III histone deacetylase, known for its regulatory role in chromatin remodeling, oxidative stress responses, mitochondrial biogenesis, and neuroplasticity. Recent research has identified SIRT1 as a molecular target capable of reversing or attenuating several hallmarks of aging, particularly within the central nervous system (CNS). This narrative review critically evaluates the emerging evidence surrounding the geroprotective effects of SIRT1 activators, which exert dual actions, senomorphic and senolytic, via modulation of signaling pathways, thereby reducing neuronal senescence, enhancing autophagy, and mitigating inflammatory responses. The discussion also addresses the region-specific role of SIRT1 across the brain, particularly in the hippocampus and hypothalamus, which are essential for memory, energy homeostasis, and resilience to stress. Additionally, this review explores how SIRT1 depletion during aging contributes to the development of synaptic dysfunction, impaired cognitive function, and susceptibility to neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The therapeutic potential of SIRT1 activators is supported by preclinical and early clinical studies, suggesting their value in preventing or delaying brain aging. Thus, SIRT1 could be a promising pharmacological target for age-associated brain disorders, warranting more robust translational studies to validate these findings in humans.
This study investigated an intranasal nose-to-brain delivery strategy to repurpose ondansetron (OND) for anxiety management using PLGA nanoparticles co-loaded with superparamagnetic iron oxide nanoparticles (SPIONs) and incorporated into a Carbopol 940 mucoadhesive gel. Nanoparticles were optimized using an I-optimal experimental design evaluating PLGA concentration and surfactant type. The optimized SPION/OND-PLGA nanoparticles showed a small particle size (141.547 ± 1.31 nm), narrow size distribution (PDI = 0.235 ± 0.002), relatively high zeta potential (-34.307 ± 0.53 mV), and satisfactory encapsulation efficiency (42.09 ± 1.34%). The developed nanogel exhibited acceptable organoleptic properties, shear-thinning behavior, sustained drug release, and enhanced ex vivo nasal permeability, with OND permeation values of 996.96 ± 6.53 μg, 621.92 ± 7.54 μg, and 317.87 ± 2.88 μg per cm2 within 6 h for the nanogel,SPION/PLGA NPs and aqueous solution, respectively. In vivo behavioral studies (open field test and elevated plus maze) demonstrated significant anxiolytic activity in all OND-treated groups, with superior efficacy for the magnetically targeted nanogel. Neurochemical and biochemical analysis indicated a monoaminergic-dominant anxiolytic profile, increased BDNF expression, and improved oxidative stress status. Molecular docking revealed strong OND binding to 5-HT5A and 5-HT3A receptors. Overall, magnetic intranasal nanocarriers substantially enhanced the anxiolytic and neuroprotective efficacy of ondansetron.
Vitamin D is one of the most popular supplements worldwide, yet its appropriate dosage and full impact on health of humans and animals are still debatable. In this study, 30 pigs were divided into three groups, differing in the amount of vitamin D in the diet (Group A - no supplementation, group B-5000 IU/Kg of vitamin D, and group C 10000 IU/Kg). After 3 months of fattening, animals were slaughtered, and samples of jejunum (the longest part of the small intestine in pigs) and colon were collected for transcriptome analysis. Comparison of the transcriptomes between jejunum and colon identified 3872 Differentially Expressed Genes (DEGs). In contrast, transcriptomic changes under the influence of vitamin D were subtle in both parts of the intestine. RNA-seq results showed that vitamin D supplementation with 5000 IU/Kg enhanced the expression of 7 genes in the jejunum and one gene (MEP1B) in the colon (FDR < 0.05, base mean > 10, and log2fold change>0.6), while supplementation with 10,000 IU/Kg increased the expression of one gene (OASL) in the jejunum. No DEGs with FDR < 0.05 were identified after supplementation with 10,000 IU/kg of vitamin D in the colon, however qPCR analysis showed that genes connected to cell cycle control (PLK1, PLK3, KIF4A, KIFC1, AURKB) are upregulated in this group. Gene Set enrichment analysis of the whole RNA-seq dataset revealed that among the most affected by vitamin D processes are that connected to immunity, especially antiviral response in the jejunum, and that connected to cell cycle control in the colon. Despite the use of very high dietary vitamin D doses, no evidence of overt intestinal toxicity was observed at the transcriptomic level. Nevertheless, the activation of molecular pathways involved in calcium handling and cell cycle regulation suggests that prolonged exposure to supraphysiological vitamin D levels may trigger adaptive responses whose long-term consequences remain unknown.