BMC Pharmacology & Toxicology最新文献

Drug-induced hepatotoxicity is a significant impediment to the use of doxorubicin, a commonly employed chemotherapeutic agent with established efficacy in cancer treatment. The present study aimed to determine the potential protective effects of agomelatine against doxorubicin hepatotoxicity in rat toxicity models. Thirty-two rats were divided into four groups: control (with saline administration), Doxo (with 40 mg/kg doxorubicin administration), Doxo + Ago20, and Doxo + Ago40 (with 20 and 40 mg/kg agomelatine administration and 40 mg/kg doxorubicin administration). On the day of 14 rats were sacrificed, samples were collected for comparison of immunohistochemical, hematological, and biochemical analysis. There were statistically significant differences between the study groups in terms of immunohistochemical, hematological, and biochemical parameters. Agomelatine administration reduced the TNF-alpha, and caspase-3, which increased by doxorubicin, and reversed levels of oxidative stress markers altered by doxorubicin (p < 0.05). Doxorubicin induces oxidative stress, apoptosis, and hepatotoxicity. Agomelatine may be favored as a primary antidepressant to mitigate hepatic damage induced by doxorubicin.

Objectives: To systematically evaluate the risk differences of hyponatremia induced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), stratify risks among individual drugs, and provide evidence-based guidance for clinical medication safety.

Methods: A systematic search was conducted across the Cochrane Library, PubMed, and Web of Science databases. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and the certainty of evidence was evaluated using the GRADE framework. A meta-analysis was performed to compare the event rates and odds ratios (ORs) of hyponatremia between SSRIs and SNRIs, followed by subgroup analysis and bias assessment.

Results: A total of 38 observational studies (including 30 cohort studies and 8 case-control studies) were included in this study. The overall event rate of hyponatremia with antidepressants was 6.03% (P < 0.001), with rates of 5.98% for SSRIs and 6.13% for SNRIs. Both drug classes significantly increased the risk of hyponatremia (SSRIs: OR = 2.158; SNRIs: OR = 2.270, P < 0.001), with SNRIs demonstrating a higher risk in clinically relevant hyponatremia (OR = 2.227, P < 0.001). Risk stratification among individual drugs revealed that fluoxetine (SSRIs) and venlafaxine (SNRIs) had the highest risk, while sertraline and duloxetine were associated with lower risks.

Conclusion: Both SSRIs and SNRIs significantly increase the risk of hyponatremia, with SNRIs posing a slightly higher risk. Clinicians should consider individual patient characteristics when selecting lower-risk medications and enhance serum sodium monitoring in high-risk populations.

Objective: Prostate cancer remains a prevalent global health challenge, with limited treatment options for advanced stages. There is a critical need to identify effective therapies through systematic integration of genomic and biological data.

Methods: We analyzed 10,911 single nucleotide polymorphisms (SNPs) in 554 genes from genome- and phenome-wide association studies to identify biological risk genes for prostate cancer. Bioinformatic analysis was used to map these genes to key pathways and potential drug targets. Drug repurposing opportunities were assessed through Connectivity Map (CMap) transcriptomic signature analysis in the PC3 prostate cancer cell line, with additional molecular docking studies to evaluate drug-target interactions.

Results: We identified 77 prostate cancer-associated genes. Drug repurposing analysis revealed 59 drugs targeting 13 genes, including 11 approved for prostate cancer and 22 in clinical or preclinical development. Notably, 26 candidate drugs had not been previously linked to prostate cancer. CMap analysis prioritized five candidates: estradiol-benzoate and estradiol-cypionate (targeting ESR2), which showed the highest CMap scores, danazol and oxymetholone (targeting AR), and selumetinib (targeting MAP2K1/MEK), each demonstrating potential to modulate key pathways in prostate cancer. Molecular docking analysis further supported these findings, revealing that estradiol-benzoate and estradiol-cypionate have strong predicted binding affinities for ESR2, while selumetinib robustly interacts with MAP2K1. Conversely, danazol and oxymetholone displayed weaker predicted binding, suggesting a more limited capacity for direct protein engagement.

Conclusions: Integrating genomics, bioinformatics, and molecular docking provides an effective strategy for identifying and prioritizing drug repurposing candidates in prostate cancer. Estradiol-benzoate, estradiol-cypionate, and selumetinib emerge as promising candidates, meriting further preclinical and clinical evaluation for advanced prostate cancer therapy.

Background: The aim of this study was to investigate baseline carboxyhemoglobin saturation (SpCO) values in smokers and to show the relationship between SpCO and age, years smoking, cigarettes per day, and nicotine dependence. We also analyzed the changes in carboxyhemoglobin in the body during active smoking.

Methods: This prospective cohort study involved 136 outdoor smokers and 60 controls who had never smoked. SpCO, heart rate (HR), and oxyhemoglobin saturation (SpO2) values were recorded with a CO-oximeter device before, during, and two minutes after smoking. Changes during active smoking were analyzed, and all parameters were compared between smoking and non-smoking groups. Age, BMI, years smoking, cigarettes per day, and Fagerström nicotine dependence (FTND) level were correlated with baseline SpCO.

Results: The mean age of smokers was 32.3 years (70.6% male; 22.79% with comorbidities), while the mean age of non-smokers was 36.7 years (38.3% male). The SpCO and HR were significantly higher during (p = 0.006, p < 0.001) and after (p = 0.015, p < 0.001) smoking than the pre-cigarette levels. There was a significant difference between smokers (3.07) and non-smokers (1.77) in terms of baseline SpCO (p < 0.001). Correlation analysis showed that age, years smoking, and nicotine dependence were positively correlated with baseline SpCO. In the ROC analysis, the AUC value for SpCO was 0.705 and the optimal cut-off value was 1.50. In addition, 83% of smokers had a baseline SpCO value below 5%.

Conclusion: In this study, the baseline SpCO values of smokers were found to be approximately 200% higher than those of non-smokers. In addition, SpCO and HR increased during active smoking. However, 83% of smokers had a baseline SpCO below 5% and just 2 (1.47%) smokers had a baseline SpCO value above 9%, suggesting that the intoxication level of 9% in smokers should be reconsidered.

Clinical trial number: Not applicable.

Background: Mitochondrial dysfunction and oxidative stress induced by overactivation of angiotensin II (Ang II) are major contributors to the progression of cardiovascular diseases (CVD). This study investigates the comparative effects of nebivolol, a third-generation β1-adrenergic blocker, and metoprolol, a second-generation β1-adrenergic blocker, on Ang II-induced mitochondrial impairment in H9c2 cardiomyoblasts.

Methods: Nebivolol and metoprolol mediated protective effects were demonstrated against Ang II-induced mitochondrial dysfunction in H9c2 cells. Intracellular reactive oxygen species (ROS) production was assessed by detecting 2',7'-dichlorofluorescein (DCF) fluorescence. Western blotting and Real-time PCR were used to quantify protein and mRNA levels, respectively.

Results: Our results showed that both nebivolol and metoprolol significantly attenuated Ang II-induced ROS generation and the expression of apoptotic and proinflammatory genes. However, nebivolol demonstrated higher efficacy than metoprolol in suppressing the expression of the proapoptotic marker BNIP3, while upregulating the antioxidant defense system and anti-apoptotic BCL2 expression. Additionally, nebivolol enhanced the mitochondrial biogenesis and fusion related gene expression.

Conclusion: In conclusion, both nebivolol and metoprolol effectively reduce oxidative stress and expression of proinflammatory genes in response to Ang II. However, nebivolol provides increased protection by restoring the antioxidant defense system and mitochondrial functions, highlighting its potential therapeutic advantage in Ang II-induced cardiac pathology.

Background: Nonspecific orbital inflammation (NSOI), also known as idiopathic orbital inflammation, comprises a heterogeneous group of immune-mediated disorders affecting orbital tissues, unified by the absence of a defined etiology. Lactotransferrin (LTF), an iron-binding glycoprotein, exerts potent antimicrobial activity by sequestering iron essential for microbial growth, and demonstrates broad-spectrum antibacterial, antiviral, and antifungal properties.

Methods: LTF was identified through the intersection analysis of common DEGs from datasets GSE58331 and GSE105149 from the GEO database, alongside immune-related gene lists from the ImmPort database, using Multiple Machine learning and WGCNA analysis. GSEA and GSVA were conducted with gene sets co-expressed with LTF. To further investigate the correlation between LTF and immune-related biological processes, the CIBERSORT algorithm and ESTIMATE method were employed to evaluate immune microenvironment characteristics of each sample. The expression levels of LTF were subsequently validated using GSE105149.

Results: Lasso and SVM-RFE algorithms pinpointed 28 hub genes. Enrichment analysis revealed that gene sets positively correlated with LTF were enriched in immune-related pathways. For biological function analysis in LTF, retina homeostasis, sensory perception of bitter taste, and tissue homeostasis were emphasized. Immune infiltration analysis indicated that Plasma cells and B cells naive were positively associated (That is, when the expression level of LTF increases, these immune cells also increase accordingly) with LTF, whereas B cells memory, Macrophages M2, Mast cells resting, Monocytes, NK cells activated, T cells regulatory (Tregs) were negatively associated with LTF. LTF demonstrated significant diagnostic potential in differentiating NSOI.

Conclusions: This study identifies LTF as a potential biomarker linked to NSOI, providing insights into its pathogenesis and offering new avenues for tracking disease progression.

Objective: This study aimed to investigate the possible hepatotoxic effect of chlorpyrifos ethyl, which may pose a potential danger to the environment and human health, on liver, oxidant and antioxidant parameters and the hepatoprotective role of geraniol against this effect.

Methods: Thirty-two Wistar albino male rats were included in the study. The study continued for 28 days. Rats were divided into four equal groups: Control, chlorpyrifos ethyl (CE), geraniol and CE + geraniol. CE was applied to induce liver injury, while geraniol was administered by oral gavage. To assess liver injury, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels were analyzed from blood serum samples. In addition, liver injury was assessed at the tissue level by analyzing malondialdehyde (MDA), total oxidant status (TOS), 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and oxidative stress index (OSI) in homogenate supernatants obtained from liver tissue. To determine the possible hepatoprotective effect of geraniol, it was examined whether the changes in these parameters returned to normal. In addition, catalase (CAT) and total antioxidant status (TAS) analyses were performed to assess antioxidant status. MDA, catalase CAT, TAS, TOS and 8-OHdG levels were analyzed by spectrophotometric methods.

Results: Parameters related to liver injury(ALT, AST, ALP, TOS, OSI, MDA and 8-OHdG) were higher, and TAS and CAT levels were lower in rats given only CE compared to the control group and the geraniol group. In this context, CE caused liver injury while also suppressing the antioxidant system. On the other hand, rats given CE + geraniol had lower liver injury-related parameters ALT, AST, ALP, TOS and OSI levels, and higher TAS and CAT levels than those given only CE. In this context, CE-induced liver injury was ameliorated with geraniol, and an increase was provided in the decreased antioxidant parameters.

Conclusion: Geraniol supplementation showed protective effects in ameliorating CE exposure-induced liver injury and antioxidant system suppression.

Background: Monosodium glutamate (MSG) is a common food additive that has been linked to oxidative stress and reproductive dysfunction. Lipopolysaccharide (LPS), a bacterial endotoxin, is known to induce systemic inflammation, leading to oxidative damage and hormonal disruption. This study investigated whether MSG exacerbates LPS-induced testicular toxicity in male Wistar rats via oxidative stress and endocrine dysfunction.

Methods: Twenty-eight male Wistar rats were divided into four groups (n = 7): control (distilled water), MSG (1500 mg/kg), LPS (250 µL/kg), and a combination of MSG + LPS. MSG was used in the background of LPS to model a real-life "double-hit" exposure where dietary and microbial toxins co-exist. We hypothesised that MSG would amplify LPS-induced reproductive damage through converging mechanisms such as ROS generation, antioxidant depletion, and hormonal dysregulation.

Results: Compared to control, MSG and LPS significantly reduced sperm count (MSG: p = 0.0001; LPS: p = 0.0001), motility (p = 0.0001; p = 0.0001), and viability (p = 0.0001; p = 0.0001), with more pronounced effects in the MSG + LPS group (p = 0.0001). The number of abnormal sperm cells was, however, increased significantly (p = 0.0001 for MSG; p = 0.0001 for LPS; p = 0.0009 for MSG + LPS). Serum testosterone (p = 0.0001 for MSG; p = 0.0001 for LPS; p = 0.0001 for MSG + LPS), FSH (p = 0.0001, 0.0001, 0.0001), and LH (p = 0.0001, 0.0001, 0.0001) were significantly decreased. Antioxidant enzymes/parameter SOD (p = 0.0001, 0.0001, 0.0001), CAT (p = 0.0001, 0.0001, 0.0001), GST (p = 0.0001, 0.0001, 0.0001), and GSH (p = 0.0001, 0.0001, 0.0001) were depleted, while TBARS levels increased significantly (p = 0.0001, 0.0001, 0.0001). Histological analysis revealed extensive structural damage in the MSG + LPS group.

Conclusions: These findings suggest that MSG potentiated LPS-induced testicular toxicity through oxidative stress and endocrine suppression, underscoring potential reproductive risks associated with combined dietary and inflammatory exposures.

Although considered safe and widely used, some natural remedies are responsible for health ailments to their users that deserve to be investigated. SAYE PLUS is one of the most widely used traditional recipes as antimalaria for decades and recently against Covid-19 in Burkina Faso and beyond, and is commonly regarded as safe to use. In the present study, sub-chronic toxicity tests were performed orally in Wistar rats at daily doses of 250, 500, and 1000 mg/kg for 90 days, following the guidelines of the Organization for Economic Cooperation and Development (OECD). The results revealed neither symptoms of toxicity nor mortality. Depending on the dose, time frame, or animal sex, compared with the control, SAYE PLUS powder caused a statistically significant reduction in the water and food consumption of the treated rats. Significantly increases in serum creatinine, total protein, hydrogen phosphate ion (PO₄²), and potassium ion (K⁺) levels were detected in females at all doses. Compared to control values, the male rats' glucose decreased while its PO₄^2- increased significantly at the daily dose of 1000 mg/kg of SAYE PLUS. Histopathological analysis revealed that the rat heart, lungs, liver, kidneys, and spleen histostructure were unaffected by sub-chronic exposure to SAYE PLUS up to 1000 mg/kg/d. The Findings provide some scientific information on the toxicological profile of the phytomedicine SAYE PLUS when administered in repeated doses for 90 days. However, they are limited by the absence of analysis of the animals' hematological parameters. Nevertheless, results show that for patient safety, it is not advisable to use SAYE PLUS for more than two consecutive weeks. Furthermore, herbal remedies need careful evaluation before or during their human use, especially when a new form of use other than the traditional one is proposed. Further long-term studies focusing on the hematological parameters and certain kidney and liver functional indicators will add the scientific merit and interest of the present work.

Background: Severe abdominal pain and multiple organ dysfunction are the hallmarks of acute pancreatitis (AP). Opioid medications are effective in alleviating AP patients' pain; however, they may exacerbate the severity of the condition.

Methods: This study investigated the potential of bone marrow mesenchymal stem cell-derived small extracellular vesicles (BMSC-sEVs) to inhibit the aggravation effect of opioids through the dual mechanism of gut microbiome-immune crosstalk through data mining and in vivo experiments.

Results: Genetic evidence suggests that opioid exposure is linked to gut microbiome dysbiosis, excessive inflammation, and susceptibility to AP. In the rat model, the inflammatory cell infiltration and pancreatic necrosis were exacerbated by the continuously increasing dose of morphine, while these effects were mitigated by antibiotic-driven microbial exhaustion. The primary point is that BMSC-sEVs has the potential to rectify the pancreatic injury that has been exacerbated by morphine by restoring the equilibrium of Bacteroidetes/Pleurophyla and inhibiting CCL3-mediated inflammation.

Conclusion: The gut microbiome-immune axis is the primary factor contributing to the aggravation of AP caused by opioids. BMSC-sEVs can be positioned as a novel drug for the treatment of AP, as it effectively regulates gut microbiome-immune crosstalk to coordinate analgesia and inflammation.