Journal of Physiology and Pharmacology最新文献

Butylparaben (BP) is a chemical commonly used as a preservative, but it is an endocrine-disrupting chemical (EDC) with estrogenic activity in humans when exposed through various routes. Although the adverse effects of BP have been confirmed, the neurodevelopmental toxicity of BP is still unclear. The neurotoxic effects of BP were confirmed in vitro, leading to an investigation of its impact on the neurodevelopment of mouse offspring in this study. BP caused a reduction in cell viability (IC₅₀=3.56x10^-4 M) and neural differentiation (ID₅₀=6.14x10^-4 M) in a developmental neurotoxicity test using 46C mouse neural progenitor cells, confirming its neurotoxic potential. A behavioral evaluation was carried out on the offspring mice. The pups were exposed to BP from early pregnancy (embryo day 10.5) until the weaning day (postnatal day 20), as their mothers were orally administered BP at doses of 50 or 100 mg/kg/day. The effects of BP on the offspring's behavior were studied. Male offspring exposed to BP showed impaired memory (novel object recognition and Morris water maze tests; p<0.05 or lower), and suggested social deficits (three-chamber test). Female offspring demonstrated increased compulsive behavior (marble burying test; p<0.05), impaired memory (Morris water maze; p<0.001) and reduced spontaneous locomotion (open field test; p<0.05). Gene expression analysis revealed elevated levels of AChE and NMDAr mRNA in a sex-dependent manner (p<0.05 or lower). These findings support that BP induces neurodevelopmental toxicity via cholinergic and glutamatergic disruption, suggesting its potential risk even at sub-toxic doses.

Endothelin-1 (ET-1) contributes to control of blood pressure (BP) and body fluid homeostasis. Blocking prohypertensive ET-1 receptors appeared promising treatment but the critical disturbing side-effect was oedema. Epoxyeicosatrienoic acids (EETs) have natriuretic and vasodilatory activity, hence they could find some therapeutical potential for patients with hypertension and end organ damage. We evaluated the effectiveness of atrasentan (ATR) combined with 14,15-EET analog, EET-A, on BP, kidney function and heart morphology, and ATR-dependent oedema in conscious spontaneously hypertensive rats (SHR). Systolic (SBP), mean and diastolic BP were measured by telemetry in SHR receiving in drinking water: ATR (5 mg/kg/day; n=6), EET-A (10 mg/kg/day; n=6), ATR+EET-A (n=6) or control solvent (C; n=5) for two weeks. Urine and blood sampling, and 24-h observations in metabolic cages were performed weekly. At the end animals were euthanized and organs were harvested. In the second protocol effectiveness of single intragastric drug application on renal electrolyte and water transport was tested. After two weeks of ATR+EET-A treatment SBP decreased significantly more (-13±2 mmHg; p<0.05) than after ATR alone (-3±1 mmHg). Decreases in plasma sodium (-9 mmol/l) and osmolality (-3 mosm/l) were significant in ATR group only, associated with the greatest increase in body weight. In ATR+EET-A and EET-A alone groups organ weights were significantly lower than with ATR alone. Our results suggest that addition of EET-A prolongs the hypotensive effect of ATR and prevents post-ATR water retention. Importantly, EET-A given orally, alone or combined with ATR, shows strong cardio- and renoprotective activity.

This study was designed to reveal the profound association between follicular fluid vitamin D (25(OH)D) levels and the health status of women with polycystic ovary syndrome (PCOS), with the aim of laying a solid scientific foundation for the development of more precise treatment strategies for PCOS. By exploring the correlation between follicular 25(OH)D level and endocrine function, ovarian function and insulin resistance in women with PCOS, it is hoped that the potential value of this level in clinical practice can be realized. From June 2021 to March 2024, 153 women with infertility mainly due to PCOS were selected. According to the Rotterdam criteria, they were divided into phenotypes A-D, with 72 cases (47.06%), 36 cases (23.53%), 18 cases (11.76%), and 27 cases (17.65%), respectively. Forty-six healthy controls with gender and age matching were included. Endocrine function was evaluated by measuring follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and dehydroepiandrosterone sulfate. Ovarian function (ovarian volume and number of follicles) and insulin resistance index (HOMA-IR) were also assessed. PCOS patients with different phenotypes were divided into vitamin D deficiency (VDD) group (<20 ng/mL) and non-VDD group (≥20 ng/mL) according to 25(OH)D levels. The correlation between follicular fluid 25(OH)D and differential clinical features was evaluated. We found that 25(OH)D in follicular fluid of PCOS women was lower than that of controls (P<0.001). Phenotype A and B had higher LH and LH/FSH than phenotype D (P<0.05) and were hyperandrogenic, whereas phenotype D had normal or low androgens and no hyperandrogenic symptoms (P<0.05). In terms of ovarian function, PCOS women with phenotypes A, C, and D had large ovarian volumes, with more follicular fluid in A and C than in B (P<0.05). There were no significant differences in FBG, HOMA-IR, insulin sensitivity and follicular fluid 25-(OH)D among the four groups (P>0.05). In the phenotype A and B cohorts, the LH/FSH ratio, ovarian volume, and HOMA-IR of the VDD group were higher than those of the non-VDD group. There was a weak and negative correlation between follicular fluid 25(OH)D and LH/FSH levels and HOMA-IR, and a moderate correlation with ovarian volume. To sum up: PCOS women have lower follicular fluid 25(OH)D. When VDD is present, patients with phenotype A and B have higher levels of insulin resistance characteristics. Although follicular fluid 25-(OH)D does not show statistically significant differences across the different PCOS phenotypic cohorts, specific phenotypes A and B exhibit more pronounced insulin resistance profiles in those individuals with VDD.

The pH gradient inversion is one of the characteristic features of cancer cells. The acidic environment outside the tumor and the alkaline inside cancer cells significantly affect its growth and ability to metastasize and reduce the effectiveness of therapy. In this study, we examined the effect of the alkaline pH on the viability of colorectal cancer (CRC) cells Caco-2 and Ht-29, and normal human fibroblasts BJ-CRL-2522 as a control cell line. Moreover, we analyzed the expression level of 3 genes at different pH: pro-apoptotic BAX, proliferation marker MKI67, and pH-sensitive receptor GPR4 using the RT-qpCR method. We demonstrated increased Ht-29 cell viability at alkaline pH, with simultaneous morphological changes, and decreased Caco-2 cell viability at pH above 9. The expression of BAX, GPR4 was upregulated in Ht-29 and BJ cells cultured at alkaline pH, whereas in Caco-2 cells the expression was significantly different between conditions. MKI67 expression was slightly increased in HT-29 and BJ, while decreased in Caco-2 cells. Our study shed new light on the cellular processes occurring under the influence of alkalization, but it is difficult to assess what role alkalization may play in the potential therapy of CRC, therefore, further studies are necessary.

The aim of the study was to investigate the underlying molecular mechanisms by which Naloxone enhances neurological function after ischemic stroke (IS). The permanent middle cerebral artery occlusion (PMCAO) model was utilized to simulate ischemic stroke in mice. Neurological function was assessed through behavioral scoring, and infarct volume as well as brain water content were measured to evaluate the extent of ischemic damage. Histopathological changes in the hippocampus were analyzed using hematoxylin and eosin staining, while neuronal apoptosis was quantified using TUNEL staining. An oxygen-glucose deprivation (OGD) injury model was established in HT22 cells, with cell viability assessed by MTT assay, apoptosis measured by flow cytometry, and lactate dehydrogenase release used to evaluate cellular toxicity. Proinflammatory cytokines were measured by enzyme-linked immunosorbent assay. The miR-30a-5p and Follistatin-like 1 (FSTL1) were quantified by RT-qPCR, and Western blotting was performed to detect FSTL1 protein levels as well as key apoptotic markers. Bioinformatic analysis, luciferase reporter assays, and RNA pulldown assays were conducted to confirm the direct interaction between miR-30a-5p and FSTL1. We found that Naloxone demonstrated a dose-dependent improvement in neurological function in PMCAO mice, as evidenced by reduced infarct volume, diminished cerebral edema, and attenuation of neuronal apoptosis and inflammation. Naloxone treatment significantly enhanced the viability of HT22 cells subjected to OGD, while also reducing apoptosis and inflammatory damage. Furthermore, Naloxone upregulated miR-30a-5p expression, and this upregulation contributed to the amelioration of OGD-induced cellular injury. The protective effects of Naloxone were partially reversed by silencing miR-30a-5p. miR-30a-5p directly targeted FSTL1, and silencing FSTL1 mitigated the reversal effect of miR-30a-5p inhibition on Naloxone's neuroprotective action. We conclude that Naloxone exerts its neuroprotective effects in ischemic stroke by upregulating miR-30a-5p, which inhibits the expression of FSTL1, ultimately improving neurological function and reducing brain injury in ischemic stroke models.

Periodontitis is a complex disease, depending on genetic and environmental factors. In its early stage, a local response of the innate immune system takes place, resulting in a release of neutrophils, whose activation is evoked by endogenous chemokines, a subtype of cytokines family. In this review, the immunological activity of as well as essential participation of cytokines in the induction and modulation of effector mechanisms in the pathogenesis of periodontitis was described. The characteristics of genetic polymorphisms in the promoter regions for cytokine transcription was given, as well as those of functional polymorphisms in the cytokine genes. Strong genetic association with the production intensity of pro- and anti-inflammatory cytokines was shown, and their dysregulated expression was related to inflammatory reactions within the tissues of the stomatognathic system. It is assumed that the incidence of periodontal diseases may arise from genetically polymorphic gene variants. Knowledge in this area will facilitate development of cytokine-targeted immunotherapies, which may constitute a promising way to cure periodontitis and in which a lot of hope currently has been placed. To undertake novel optimal strategy of treatment seems to be inevitable in respect to minimal side effects that can be provided to living organism.

Neutrophil infiltration of the intestinal mucosa correlates closely with disease activity in ulcerative colitis (UC). This study aimed to investigate the contribution of reactive oxygen species (ROS) to disease severity in UC. Sixty-four subjects were enrolled, including 35 patients with active UC (18 males, 17 females; mean age: 38.1±13.6 years) and 29 healthy controls (15 males, 14 females; mean age: 42.7±11.3 years). Clinical disease activity was classified according to the Truelove and Witts' index. Mucosal biopsy samples were analyzed for oxidative stress markers: malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPO) and myeloperoxidase (MPO). Patients with UC had significantly higher mucosal levels of MPO, GPO, SOD, and MDA compared to controls (p=0.0001, 0.02, 0.001, and 0.03, respectively). When stratified by disease activity, mild, moderate, and severe UC groups exhibited progressively elevated MPO and antioxidant enzyme levels relative to controls. ROC analysis demonstrated that MDA and MPO levels had moderate discriminatory power for high disease activity (AUROC=0.74 and 0.79, respectively). All oxidative markers positively correlated with disease activity index (MDA: r=0.34, p=0.006; GPO: r=0.43, p=0.0001; MPO: r=0.59, p=0.0001; SOD: r=0.43, p=0.0001). Multivariate logistic regression identified MPO and SOD as independent predictors of disease activity. Elevated levels of ROS and associated antioxidant enzymes are significantly associated with clinical disease activity in UC. These findings support the potential therapeutic value of antioxidant-based strategies in UC management.

All-trans retinoic acid (ATRA), a potent natural, active metabolite of vitamin A, has a critical role in numerous biological processes, including lipid metabolism, adipocyte differentiation, and the immunological system. Increasing evidence from cellular and animal studies highlights its importance in cardiovascular diseases (CVD), acting through anti-atherogenic activity by inhibitory effects on thrombosis and inflammatory responses, modulating nitric oxide pathways, and inhibiting the proliferation and migration of arterial smooth muscle cells. ATRA mitigates endothelial dysfunction and reduces atherogenic plaque formation. It modulates oxidative stress, promotes endothelial repair, and limits cardiomyocyte hypertrophy, fibrosis, and apoptosis. The cardioprotective function of ATRA is also correlated with atrial natriuretic peptide activation. ATRA decreases the risk of obesity, improves insulin sensitivity, and reduces inflammation, the significant contributors to cardiovascular disease and metabolic disorders. This paper reviews ATRA's mechanisms in CVD pathology and its broader role as a cardioprotective agent, emphasizing its impact on inflammation, lipid metabolism, myocardial remodeling, and adipose tissue.

Acute-phase viral infections, such as COVID-19, trigger a complex interplay of proinflammatory and regulatory responses, influencing both tissue repair and damage. Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and platelet endothelial cell adhesion molecule-1 (PECAM-1) play crucial roles in immune activation, regulation, and homeostasis during infection. This study included adult patients hospitalized at the University Hospital in Cracow, Poland, with confirmed SARS-CoV-2 infection between January and June 2021. Blood samples were collected at three time points and categorized based on the time since symptom onset: first, second, or third week of infection. The objective was to assess serum levels of sICAM-1, sVCAM-1, and sPECAM-1 in relation to in-hospital mortality and key biochemical and clinical parameters. Among 276 patients (63% males) with a median age of 62 years, pneumonia was confirmed in 89% of cases, with an in-hospital mortality rate of 12.7%. Mortality was associated with advanced age (71(9) vs. 61(18) years p<0.001) and comorbidities such as hypertension, diabetes, chronic kidney disease, heart failure, and atrial fibrillation. Non-survivors exhibited significantly lower adhesion molecule levels. Median (IQR) concentrations in non-survivors vs. survivors, respectively, were at first week: sICAM-1: 279(114) vs. 399(328) ng/mL (p<0.001); sVCAM-1: 2944(2760) vs. 4670(3331) ng/mL (p<0.001); sPECAM-1: 15(6) vs. 17(7) ng/mL (p<0.05). Results for third week were: sICAM-1: 271(109) vs. 461(296) ng/mL (p<0.01); sVCAM-1: 1875(2034) vs. 1426(1194) ng/mL (p=0.054); sPECAM-1: 18(7) vs. 25(13) ng/mL (p<0.01). Proportionally, sVCAM-1 was highest at symptoms onset, while sICAM-1 and sPECAM-1 rose later. sICAM-1 positively correlated with interleukin-1α, sVCAM-1 was linked to pneumonia and inflammation, and sPECAM-1 negatively correlated with inflammatory markers and D-dimers. These findings highlight the dynamic role of adhesion molecules in COVID-19 and suggest their potential as biomarkers and therapeutic targets for optimizing treatment strategies.

Breast cancer remains a significant global health concern, with its molecular intricacies and the mechanistic role of tissue inhibitor of metalloproteinases-1 (TIMP1) still poorly understood. This study employed an integrated approach combining bioinformatic analyses and primary experimental validations to discover the complexities surrounding TIMP1 in breast cancer. Bioinformatic tools such as pan-cancer view, mRNA expression analysis, immune infiltrations, pathway enrichment, and functional annotations provided a clear perspective on TIMP1 in breast cancer. Gene expression by qPCR analysis for TIMP1 were conducted in MCF-7 and MDA-MB-231 and T47D cells and compared to normal breast cells, MCF-10A. Bioinformatic platform, The University of Alabama at Birmingham Cancer (UALCAN) data analysis underscored the diagnostic relevance of TIMP1, showing its upregulated mRNA expression across different stages and metastatic properties. Notably, the impact of breast cancer on immune cells was explored, revealing a direct influence of TIMP1 on CD4⁺, CD8⁺, and B cells, with strong correlations were observed. Kaplan-Meier (KM) survival analysis revealed that high TIMP1 expression correlates with poor prognosis in breast cancer patients, reinforcing its oncogenic potential. Furthermore, immunohistochemistry supported these findings, and protein-protein interaction analysis through STRING and CYTOSCAPE identified interconnected genes linked to TIMP1 in breast cancer. Enriched pathway analysis using KEGG pathways unveiled the potential involvement of TIMP1 in the phosphatidylinositol 3-kinases (PI3K) pathway and cell cycle regulation, further substantiating its oncogenic role. Experimental validation through siRNA silencing TIMP1 reduces cell growth and promotes G1 phase cell cycle arrest in MDA-MB-231 cells. In conclusion, this comprehensive study suggests that targeting TIMP1 in breast cancer could present a promising avenue for therapeutic development, highlighting its potential as a crucial player in the molecular landscape of breast cancer progression.