Journal of Physiology and Pharmacology最新文献

Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. RAD51 is associated with homologous recombination repair (HRR), a crucial DNA repair mechanism. This paper reports the development and efficacy of a novel targeted RAD51 degrader compound, TRD2, for treating TNBC. TRD2 is synthesized by linking a RAD51 binder to the ligand of the E3 ligase cereblon (CRBN). The results showed that TRD2 effectively reduces the RAD51 protein levels in TNBC cells and exhibits potent anticancer effects in vitro and in vivo. Mechanistic studies showed that TRD2 induces RAD51 ubiquitination and subsequent proteasomal degradation by binding to CRBN. Furthermore, TRD2 demonstrated significant tumor growth inhibition in a mouse xenograft model of TNBC. These findings highlight the potential of TRD2 as a promising therapeutic approach in TNBC, leveraging Proteolysis-targeting chimera (PROTAC) technology to degrade the overexpressed RAD51 protein selectively. The study emphasizes the importance of targeting DNA damage repair core proteins and suggests that TRD2 could overcome challenges posed by resistance to conventional therapies. Nevertheless, additional experiments will be needed to validate these observations and explore the potential impacts on other proteins and cancer types. Overall, this research introduces a novel strategy for TNBC treatment, addressing the limitations of current therapeutic options.

Air pollution is recognised as one of the primary environmental health hazards. The gas molecules including NO₂, CO, SO₂, O₃, particulate matter (PM₁₀, PM_2.5), and volatile organic compounds are being identified as particularly harmful. Despite this, a significant portion of the global population resides in areas with unsatisfactory air quality. Research suggests that air pollutants may act as endocrine disruptors, potentially interfering with thyroid function and contributing thyroid cancer development through oxidative stress, inflammation, and hormonal dysregulation. This paper reviews current literature on the effects of air pollution on thyroid function and thyroid cancer risk, focusing on epidemiological studies and mechanisms of endocrine disruption. Air pollutants are suspected endocrine disruptors that may interfere with thyroid function through receptor binding, hormone displacement, and disruptions in hormone transport, metabolism, and gene expression. Exposure to these pollutants, particularly during fetal development, can impair neonatal thyroid homeostasis, increasing the risk of hypothyroidism and long-term cognitive complications. Prolonged exposure to PM_2.5 has been associated with an increased risk of papillary thyroid cancer (PTC), particularly at higher concentrations and with long-term exposure. Elevated levels of NO₂ and O₃, as well as urban exposure to CO, have also been linked to a heightened risk of thyroid cancer. In contrast, an inverse relationship has been observed for PM₁₀ and SO₂. Additionally, studies suggest a potential association between PM_2.5 exposure and both increased risk and mortality of thyroid cancer, although multiple confounding factors must be considered. Air pollution with PM_2.5, NO₂, CO has also been found to affect thyroid hormone (TH) levels, but findings remain inconsistent, with relationships varying based on age, sex, and internal factors such as obesity. While evidence suggests a link between air pollution and thyroid dysfunction, as well as thyroid cancer risk, inconsistencies in findings highlight the need for further research. A deeper understanding of the mechanisms underlying these associations is crucial to assessing health risks and developing effective public health interventions.

Proper hydration is crucial for overall well-being. Insufficient water intake can disrupt homeostasis and lead to severe health issues. This observational study aimed to evaluate the prevalence of underhydration among mother-child pairs and to determine the effect of sociodemographic factors and nutritional status on underhydration. It utilized a questionnaire complemented by a urine osmolality test to assess hydration status. Underhydration was defined as an osmolality greater than 800 mOsm/kgH₂O. Two urine samples were collected from each child - one immediately after waking (first morning sample) and another at school in the afternoon - while only a first morning sample was requested from the mothers. Conducted between March and June 2018, the study involved 125 schoolchildren (77 boys and 48 girls) with a mean age of 10.25±1.63 years, and their 125 mothers with a mean age of 39.89±4.49 years, residing in the city and municipality of Niepolomice and Cracow (southern Poland). The urine osmolality tests revealed underhydration in 49.2% of children in the morning and in 51% during school hours. Statistical analysis of risk factors for underhydration in children did not reveal any significant associations with place of residence, age, sex, body mass index (BMI), and waist-to-height-ratio (WHtR). Among the mothers, 23.7% showed signs of underhydration. A significant association was observed between underhydration and mothers BMI (OR 4.42; 95% CI: 1.73-11.32), with those who were overweight or obese facing a more than fourfold higher risk of underhydration compared to those of normal weight. A significant positive association in morning urine osmolality (rSp=0.364; p=0.013) was observed exclusively in mother-daughter pairs, suggesting that daughters may mirror their mothers' hydration behaviors. This study highlights the importance of initiatives to enhance water intake among both children and their mothers, especially those with excess body weight.

This study aimed to explore the impact of hydroxysafflor yellow A (HSYA) on the proliferation, cell cycle, and apoptosis of Jurkat cells, serving as a representative model of T-cell acute lymphoblastic leukemia (T-ALL), and to explore the underlying molecular mechanism of its action. HSYA was administered to Jurkat cells. Cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8) assay, and flow cytometry was utilized to analyze cell cycle distribution and apoptosis. The expression levels of Notch1, c-Myc, and Hes1 at both mRNA and protein levels were assessed employing reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot techniques. HSYA hinders cell growth in a manner dependent on both time and dosage. The IC₅₀ (half-maximal inhibitory concentration) for HSYA to inhibit Jurkat cells was 99.08 μmol/L, 77.81 μmol/L and 59.05 μmol/L at 24, 48, and 72 hours, respectively. HSYA induced G0/G1 cell cycle arrest in Jurkat cells in a concentration-dependent manner. After exposure to different concentration of HSYA for 48 hours there was a notable increase in G1 phase cells (F=48.588, df=2, P<0.001) accompanied by decrease in S phase cells (F=66.637, df=2, P<0.001). After 48 hours of HSYA treatment, apoptosis in the experimental group was significantly up-regulated compared with the control group (F=98.09, df=2, P<0.001). After 48 hours of HSYA treatment with varying concentrations (50 and 100 μmol/L), the Jurkat cells exhibited significantly lower expression levels of Notch1, c-Myc, and Hes1 mRNA as compared to the control group (F=298.361, df=2, P<0.001 for comparison of Notch1 expression; F=173.332, df=2, P<0.001 for comparison of c-Myc expression; F=126.563, df=2, P<0.001 for comparison of Hes1 expression). HSYA can play an anti-leukemia effect by inhibiting Notch1 signaling pathway in T-ALL, and can be as a potential candidate for the treatment of T-ALL.

Obesity and type 2 diabetes are pathologies that are difficult to control, especially in older individuals; therefore, there is extensive research for the development of new hypoglycemic and lipid-lowering drugs, among them, insulin in diabetic patients has an immediate hypoglycemic effect. Some vanadium derivatives induce a decrease in body weight and blood concentrations of glucose, triglycerides, and cholesterol, after being administered for a few weeks in humans and in animal models with metabolic syndrome (MetS), which is called 'insulin-like effect' of vanadium compounds. The aim of this work is to analyse the immediate effects of vanadyl sulfate (VS) on blood glucose, triglycerides and cholesterol levels in old rats with MetS. MetS was induced in male Wistar rats by a high-fructose diet (HFD) for 20 weeks. Then, in week 22, rats were treated with one dose of VS, and at minutes 0, 15, 30, 60, 90, 120, 150, 180, and 24 hours later blood samples were taken for biochemistry analysis. VS in rats with MetS causes a slight blood glucose increase in the first 30 minutes and then drops to normal concentrations without causing hypoglycemia, remaining normal for 24 hours. Insulin decreases to normal levels. Cholesterol decreases progressively from the first 15 minutes, remaining low after 24 hours, while triglycerides increase slightly during the first three hours, but after 24 hours, it has decreased. VS in rats with MetS, causes a decrease in the consumption of sugared water and food from the first 24 hours.

Gingerol, the key active ingredient in ginger, is known for its numerous medicinal benefits. This research sought to explore, for the first time, Gingerol's potential to alleviate oxidative stress and apoptosis in the hearts of rats exposed to restraint stress (RS). Male albino rats were divided into four experimental groups, each comprising six rats: Group I (Control rats), Group II (Control rats given Gingerol), Group III (stressed rats) subjected to RS by being confined in restrainers for 2 hours daily for 21 days, and Group IV (stressed rats treated with Gingerol). After 21 days, the rats were sacrificed, and blood samples were taken via cardiac puncture for biochemical assays of lipid peroxidation (LPO), superoxide dismutase (SOD), reduced glutathione (GSH), and catalase (CAT). Heart tissues were meticulously collected for histological (hematoxylin and eosin staining) and biochemical assessments of oxidative stress and inflammation markers. Gingerol treatment in stressed rats enhanced their antioxidant defenses by decreasing LPO and increasing the levels of SOD, catalase CAT and GSH. Moreover, gingerol reduced the histopathological alterations caused by restraint stress in cardiac tissues, significantly lowering tumor necrosis factor-alpha (TNF-α), interleukin 1beta (IL-1β), and interleukin-6 (IL-6) levels. These results indicate that 6-Gingerol has antioxidant and anti-apoptotic effects, which can protect the rat heart against stress-induced oxidative damage.

Pyroptosis is increasingly recognized as crucial in sepsis development, but the specific roles of pyroptosis-related genes (PRGs) in sepsis remain underexplored. Gene expression profiles of sepsis and control samples were retrieved from the Gene Expression Omnibus (GEO) database for analysis (GSE57065, GSE95233). Differentially expressed genes (DEGs) were identified, followed by functional enrichment analysis. Weighted gene co-expression network analysis (WGCNA) was employed to identify genes associated with sepsis, with intersecting DEGs and PRGs highlighted via Venn diagrams. Hub genes were further analyzed across both the training and validation datasets (GSE65682) for differential expression, receiver operating characteristic (ROC) analysis, correlation analysis, and Kaplan-Meier (KM) survival analysis. Immune cell infiltration was evaluated in both datasets using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Machine learning approaches were applied to identify critical immune cell types involved in sepsis regulation, which were subsequently correlated with the hub genes. Single-cell RNA sequencing (scRNA-seq) analysis of sepsis samples was conducted using the GSE167363 dataset. Finally, Mendelian randomization (MR) was utilized to investigate causal relationships between exposures and outcomes. In results eight hub PRGs were identified, including NLRC4, PLCG1, TP53, AIM2, GZMB, GZMA, ELANE, and CASP5. Functional enrichment analysis implicated dysregulated immune responses in sepsis progression, aligning with established pathophysiological mechanisms. These eight key genes exhibited consistent expression patterns. Several genes (NLRC4, PLCG1, AIM2, GZMB, and ELANE) emerged as promising diagnostic biomarkers (AUC>0.85). Machine learning revealed that 15 immune cell types may play important roles in sepsis. Correlation analysis indicated a positive relationship between granzyme B (GZMB) and natural killer T (NKT) cells, a finding further corroborated by scRNA-seq analysis. In the validation cohort, GZMB and ELANE were linked to patient prognosis (p<0.05). MR analysis using the inverse variance weighting (IVW) method demonstrated a positive causal relationship between GZMB and NKT cells (OR=1.063, 95% CI=1.013-1.115, p=0.013). Moreover, elevated NKT cell levels were associated with a reduced risk of sepsis (OR=0.977, 95% CI=0.955-1.000, p=0.046), and NKT cells served as protective factors for 28-day mortality in sepsis (OR=0.938, 95% CI=0.881-0.997, p=0.040). This study provides a comprehensive analysis of the roles of PRGs and NKT cells in sepsis, offering valuable insights for diagnostic and therapeutic approaches in sepsis immunotherapy.

Non-small cell lung cancer (NSCLC) progression is aggressive carrying a high risk of death. In the disease, little is known about the mechanism of circRNA (circ)-C20orf11, and further in-depth studies are needed. First, circ-C20orf11 expression in NSCLC was assessed, and the effects of circ-C20orf11 on NSCLC cell proliferative, apoptotic, migratory, and invasive behaviors were detected after transfection. The targeting relationship between miRNA (miR)-495-3p and circ-C20orf11 or recombinant karyopherin alpha 2 (KPNA2) was validated. We found circ-C20orf11 expression was elevated in NSCLC, and depleting circ-C20orf11 or restoring miR-495-3p hindered proliferative, migratory, and invasive behaviors of NSCLC cells and stimulated apoptosis, while enhancing circ-C20orf11 or silencing miR-495-3p showed the opposite effect. Moreover, the circ-C20orf11 could promote KPNA2 expression by sponging miR-495-3p, and overexpressing KPNA2 impaired the effect of circ-C20orf11 silencing on NSCLC cells. We conclude that circ-C20orf11 accelerates NSCLC via the miR-495-3p/KPNA2 axis.

This research sought to determine the influence of esketamine (ESK) on hypoxia/reoxygenation (H/R) injury in cardiomyocytes by blocking autophagy via the transient receptor potential vanilloid type 1 (TRPV1)/ Ca²⁺/ calmodulin-dependent protein kinase β (CaMKKβ)/ adenosine monophosphate (AMP)-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) pathway. H9c2 cardiomyocytes were hypoxic for 4 h and reoxygenated for 6 h. H9c2 cells were pretreated with ESK (30 μg/ml) before hypoxia. H9c2 cells were transfected with plasmid vectors that interfered with TRPV1 or CaMKKβ, and the success of the transfections was verified by RT-qPCR. Cell viability was detected by MTT assay; apoptosis was detected by flow cytometry; intracellular Ca²⁺ concentration ([Ca²⁺]i) was assessed using fluorescent dye Fluo-3 AM/Pluronic F127, and LC3-I, LC3-II, Beclin-1, and CaMKKβ/AMPK/mTOR-related proteins were detected by Western blot. In results: ESK treatment inhibited H/R-induced cell injury, cellular autophagy, and [Ca²⁺]i elevation. Induction of autophagy or [Ca²⁺]i elevation attenuated the ameliorative effect of ESK on H/R-induced cell injury. Upregulating TRPV1 attenuated We conclude that ESK-induced protection against H/R injury, as well as reduced the effect on the CaMKKβ/AMPK/mTOR pathway. ESK attenuates H/R cardiomyocyte injury by hindering autophagy through the TRPV1/Ca²⁺/CaMKKβ/AMPK/mTOR pathway.

Increased levels of myostatin, a negative regulator of skeletal muscle development, have been shown in obesity and associated with dysregulated energy metabolism. There is growing interest on dietary factors behind muscle training, that regulate circulating myostatin levels. The aim of the study was to assess the effect of weight loss after a 3-month hypocaloric diet on plasma myostatin concentration in obese patients and to examine whether the myostatin level affects the effectiveness of the hypocaloric diet. The study involved 73 obese patients using hypocaloric (HCD) or control normocaloric (NCD) diet. Body weight and composition as well as biomarkers of glucose and lipid metabolism and plasma myostatin were measured before and after 3-month diet. The use of a 3-month hypocaloric diet, without changing of physical activity, markedly reduced BMI (-7.7% in HCD vs. -0.9% in NCD), body fat, influenced postprandial insulin sensitivity and improved plasma lipid profile. The dietary intervention did not influence muscle mass as well as plasma myostatin levels in the whole cohort, although the highest myostatin levels were normalized after 3 month to average values. Only the group with initially higher levels of myostatin (>21.18 ng/mL) achieved an improvement in carbohydrate metabolism. Results showed that obese patients who experienced a decrease in plasma myostatin concentration after a 3-month HCD had greater improvement in glucose metabolism, fasting and postprandial, than obese patients without reduction in circulating myostatin (correlations of Δ myostatin with Δ fasting glucose Rho=0.42, p<0.001; Δ myostatin with Δ glucose AUC OGTT Rho=0.33, p=0.005). In conclusion, increased circulating myostatin may be involved in the development of insulin resistance but does not significantly affect lipid complications in obese patients. A hypocaloric diet may only affect the highest myostatin values in obese individuals.