Drug and Chemical Toxicology最新文献

In this study, the protective effect of astaxanthin (AST) against cyclophosphamide (CP) induced adult rat heart damage was investigated. Eighteen rats were divided into 3 groups as Group 1: control, Group 2: cyclophosphamide and Group 3: cyclophosphamide + astaxanthin. The CP group, received a 200 mg/kg single dose intraperitoneal (i.p.) injection of CP on the seventh day of the experiment, while the control group received no treatment. For CP+AST group 25 mg/kg/day AST administered by oral gavage on days 1-7 and on the 7th day 200 mg/kg/day CP was administered by i.p injection. On the 8th day, the rats were sacrificed by exsanguination and the hearts were dissected. Histopathological examinations were performed by Hematoxylin&Eosin (H&E), Masson Trichrome and Periodic Acid-Schiff (PAS) staining methods; Annexin-V and Anti-NOX2/gp91phox analyzes were performed by flow cytometry. In histological evaluation of the CP Group; disruptions in cardiac histology and increased PAS(+) staining were observed. These findings were reduced in the CP+AST group compared to the CP group. According to flow cytometry measurements, there was an increase in Annexin-V and Anti-NOX2/gp91phox bound cells in the CP group. With the AST pretreatment, in the CP+AST group Annexin-V and Anti-NOX2/gp91phox bound cell level showed decrease. Based on our study's data, CP may alter cardiac histology and have a negative impact on apoptosis and oxidative damage processes. Astaxanthin may ameliorate these effects of CP on the heart. To enhance the assessment of this protective effect, we propose conducting future research utilizing varied dosages, application durations and advanced analytical techniques.

This study aims to elucidate the potential roles of commonly used plasticizers, including Diethyl Phthalate (DEP), Dimethyl Phthalate (DMP), and Dioctyl Phthalate (DOP), in the pathogenesis of Acute Myeloid Leukemia (AML). The focus is to highlight the complex interactions between these environmental chemicals and key molecular pathways involved in tumorigenesis. We employed network toxicology and molecular docking techniques to analyze the interactions between plasticizers and key proteins associated with AML. Utilizing databases such as The Cancer Genome Atlas (TCGA), we divided selected key genes from AML bone marrow samples into two groups based on gene expression and compared their survival analyses. Enrichment analysis was conducted to identify the biological pathways associated with these genes. The enrichment analysis underscored the association between the plasticizer-targeted genes and essential pathways in AML development, indicating a broad impact of plasticizers on various cancers, including hematologic malignancies. Subsequent expression analysis using TCGA data for AML demonstrated that these genes have significant statistical relevance to the survival in AML, confirming their critical roles in tumor biology. This study provides evidence that exposure to plasticizers could influence the pathogenesis of AML through interactions with key proteins and signaling pathways. By utilizing network pharmacology and protein interaction analysis, our findings emphasize the potential risks associated with plasticizers. These results highlight the necessity for further epidemiological and clinical research to fully understand the impact of plasticizer exposure on AML risk, thereby informing future preventive and therapeutic strategies.

Silymarin is an extract of Silybum marianum that is used traditionally for the treatment of several diseases. This study sought to evaluate the protective effects of silymarin on cobalt chloride (CoCl₂)-induced cardio-renal toxicities in rats. Forty rats were randomly divided into four groups of 10 rats each: control; 300 mg/kg CoCl₂; CoCl₂ + 100 mg/kg silymarin; and 100 mg/kg silymarin only. All administrations were done orally. At the end of the experimental period (seven days), blood pressure parameters, markers of oxidative stress, antioxidant defense status, renal function test, histopathology and immunohistochemical expressions were evaluated on the heart and kidney tissues. Silymarin significantly (p < 0.05) altered CoCl₂-induced alterations in blood pressure parameters, antioxidants and markers of oxidative stress, blood urea nitrogen and creatinine. Histopathological evaluation revealed area of infiltration of the myocardium by inflammatory cells and hemorrhages in the kidney of rats exposed to CoCl₂ without silymarin treatment, but these lesions were absent in the control and silymarin groups. Increased immunohistochemical expression of cardiac troponin I and matrix metalloproteinase-2 (MMP-2) was observed in the cardiac tissues of rats exposed to CoCl₂ without silymarin treatment. The immunohistochemical expression of cystatin C was heightened, while that of angiotensin-converting enzyme 2 (ACE2) was attenuated in the CoCl₂ untreated group compared with the control and silymarin groups. In conclusion, silymarin effectively mitigated the toxic effects of CoCl₂ on the heart and kidney tissues of rats due to its ability to positively modulate the activities of endogenous antioxidants and neutralize reactive oxygen species in cardiac and renal systems.

As a commonly used flame retardant in numerous products, it is inevitable that tris(2-chloroethyl)phosphate (TCEP) is released into the surrounding environment during its use. This process gives rise to potential environmental concerns that must be addressed. In recent years, there has been significant interest in the role of TCEP in the development of hyperuricemia (HUA). However, the specific mechanisms by which TCEP contributes to this condition remain to be fully elucidated. In this study, we have employed a combination of network toxicology and in vitro experiments to investigate the potential effects of TCEP on HUA and its mechanism of action. Through systematic analysis of GeneCards, OMIM, Swiss Target Prediction, and CHEMBL databases, a total of 242 TCEP-induced HUA targets were identified. Utilizing the STRING and DAVID databases further elucidated the core targets and associated signaling pathways of TCEP in relation to HUA. The molecular docking assay results demonstrated that TCEP exhibits binding activity with the selected targets. In vitro, our findings revealed that TCEP exacerbates HUA by amplifying the inflammatory response and upregulating the mRNA expression levels of GLUT9 and URAT1. The present study provides a new perspective and theoretical basis for the in-depth understanding of the molecular mechanism of TCEP affecting HUA, and helps to further understand the pathogenesis of HUA and the role of environmental factors.

The present study is aimed to evaluate the hepatoprotective role of N-acetyl cysteine (NAC) and vitamin E (VE), as potent antioxidants, against acrylamide (ACR)-induced hepatotoxicity via investigation of alterations in miRNA-34a, P53, Nrf2, and SIRT 1 hepatic expressions in addition to, changes in liver function tests, oxidative stress/antioxidant parameters, cytokines, histopathological analysis and immunohistochemical expressions of caspase 3. For this study, thirty-five male rats were randomly assigned into seven equal groups: group I (control), group II received ACR at dose 20 mg/kg b.wt., group III received NAC at dose 150 mg/kg b.wt., group IV received VE at a dose of 100 mg/kg b.wt., group V received NAC+ACR, group VI received VE+ACR and finally group VII received NAC+VE+ACR, for 28 days. ACR induced marked hepatic tissue damage as evident by severe alterations in hepatic biomarkers, in addition to histological and immunohistochemical pictures. This was accompanied by a significant elevation of hepatic MDA and apoptotic genes expressions, alteration in miRNA-34a and P53/Nrf2/SIRT1 pathway as well as cytokines. In contrast, marked depletion for antioxidant parameters was detected. These findings were confirmed with marked histological changes. Co-administration of NAC and VE significantly attenuated the hepatotoxic effects of ACR where liver parameters, oxidative status, genetic expressions, and liver histo-architecture were improved in comparison to ACR, NAC+ACR, and VE+ACR groups. NAC and/or VE had powerful antioxidants and could be used as an applicable hepatoprotective agent against oxidative damage mediated by ACR via regulation of miRNA-34a and P53/Nrf2/SIRT 1 signaling pathways.

Meloxicam is used in the treatment of clinical mastitis to promote milk production. Therefore, in the present investigation, acute and sub-acute dermal toxicity of our prototype film-forming topical dermal spray of meloxicam was carried out in addition to the dermal permeation rate. Implementing the OECD test norms, acute and repeated dose analyses were carried out in male and female groups of rats. Film-forming topical dermal spray of meloxicam released 68.62% of the drug over a 24-h period with a permeation rate of 22.58-µg/cm². The lethal dose 50 (LD₅₀) for film-forming topical dermal spray of meloxicam may be considered to be >2000 mg.kg^-1. Various hematological, biochemical and histopathological parameters were examined post-treatment in sub-acute toxicity. Film-forming dermal spray of meloxicam at low and moderate doses did not exhibit any adverse effects on the skin and mammary glands whereas the high dose had shown hyperplasia in the tubuloalveolar area of mammary glands. Hence, the"no observed adverse effect level (NOAEL) was considered to be 1000-mg.kg^-1 in experimental animals. The IC₅₀ value for blank film-forming topical dermal spray and meloxicam film-forming topical dermal spray was found to be 2.655-µg/mL, and 1.871-µg/mL, respectively, as compared to 229.18-µg/mL of meloxicam solution at 72 h against normal breast epithelial, MCF-10A cells. Hence, meloxicam film forming dermal spray retains the normal breast epithelial cell viability at low to moderate doses in both in vitro and in vivo applications. In conclusion, the moderate dose of film-forming dermal spray of meloxicam was found to be safe for topical use.

Myocardial infarction remains one of the leading causes of mortality and morbidity globally. While apigenin (AP), a trihydroxyflavone, and carvedilol, a beta blocker, have both been utilized in the treatment of cardiovascular diseases. There is a notable lack of comprehensive research or limited data regarding their combined cardioprotective activity. This gap emphasizes the need for further investigation into the potential synergistic effects of AP and carvedilol in the context of myocardial infarction. This study aims to evaluate the cardioprotective effect of AP and carvedilol in isoproterenol-induced myocardial infarction in rats. Male Sprague-Dawley rats were used and divided into five groups (n = 6). Isoproterenol (85 mg/kg/s.c.) was administered to induce myocardial infarction. AP (50 mg/kg/day/p.o) and carvedilol (5 mg/kg/day/p.o) were administered to rats for 14 days, along with Isoproterenol on the 15th and 16th days. Various parameters were estimated, including biochemical markers, cardiac markers, oxidative stress markers, antioxidants, and lipid profiles, to observe the effects of flavonoids and drugs. Administration of Isoproterenol showed changes in physical parameters, significantly elevated levels of serum biochemical markers, cardiac markers, oxidative stress markers, lipid profile, and decreased antioxidant enzymes. Treatment with AP and carvedilol diminished these changes very significantly. Histopathological examination of heart tissue in isoproterenol-induced rats showed necrotic lesions, which were reduced by the treatment with test drugs alone and in combination. Our study demonstrated that AP alone and in combination with carvedilol showed cardioprotective activity over isoproterenol-induced myocardial infarction in rats. Further investigations are needed to explore the underlying mechanism.

The increasing interest in bioactive compounds necessitates a thorough understanding of their in vivo safety profiles before they are developed as therapeutic drug leads. The present study aimed to evaluate acute and sub-acute toxicological effects of a compound mixture composed of garcinol, piperine, butyl oleate, pipnoohine, and bismurrayanimbine, combined in a molar mass ratio of 9:33:1:4:1 at the doses of 10 mg kg^-1, 25 mg kg^-1, and 50 mg kg^-1 in healthy Wistar rats, following Organization for Economic Co-operation and Development guidelines. A single oral dose of the compound mixture (10 mg kg^-1, 25 mg kg^-1, and 50 mg kg^-1) was administered, and the rats were closely observed over a subsequent 14-day period. Further, the compound mixture was administered orally at the same three doses to Wistar rats continuously for 28 days. The compound mixture at the three doses did not produce mortality or abnormal behavioral changes throughout the 14 days. No significant alterations in hematological parameters or biochemical markers such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and creatinine (p > 0.05) were observed. Histopathological analysis revealed no treatment-related changes in the hematoxylin and eosin-stained sections of the liver, kidney, heart, spleen, stomach, small intestine, and lung tissues. In conclusion, the oral administration of compound mixture at 10 mg kg^-1, 25 mg kg^-1, and 50 mg kg^-1 for 28 days was found to be safe in healthy Wistar rats via biochemical (liver enzymes, kidney function tests), hematological (full blood count analysis), and histological assessments of hematoxylin and eosin-stained tissue sections.

This study aims to evaluate the hepatoprotective effects of combined Saussurea costus and Glycyrrhiza glabra extracts against diethylnitrosamine (DEN)-induced hepatic damage in rats. In the present investigation, the in vivo experimental study involved forty-two male Albino Wistar rats allocated into seven groups of six rats in each. Group I served as the vehicle control (10% DMSO) and Group II was administered DEN at a concentration of 0.01% in drinking water. Group III received both DEN and silymarin at 25 mg/kg bw. Groups IV and V were treated with individual extracts of S. costus and G. glabra at 250 mg/kg bw, respectively. Groups VI and VII received combined lower (LDC) and higher doses (HDC) of both plant extracts i.e., 125 mg/kg bw and 250 mg/kg bw, respectively. The ultrasonographic evaluation revealed a significant increase in hepatic echotexture in the positive control group compared to ameliorative groups provided with various plant extract combinations depicting minimal changes comparable to the standard control i.e., rats provided with silymarin. Serum levels of ALT, AST, ALB, creatinine, and LPO indicating liver damage were diminished in the various treatment groups compared to group II receiving DEN only.

Therefore, the current study concluded that the higher combined dosage of the root extracts of S. costus and G. glabra i.e., 250 mg/kg bw each, demonstrated the hepatoprotective effect against DEN-induced liver damage in the rat model.

Fluoroquinolones (FQs) are potent, broad-spectrum bactericidal antibiotics commonly used to treat infections in both humans and animals. Despite their therapeutic efficacy, their potential reproductive toxicity remains a concern. This study aimed to evaluate the histological, immunohistochemical, and biochemical effects of three FQ derivatives-ciprofloxacin (CIP), levofloxacin (LVX), and moxifloxacin (MXF)-on the testicular tissue of rats over different time intervals. Seventy-two male Wistar albino rats were randomly divided into four groups (n = 18): Control, CIP (80 mg/kg), LVX (40 mg/kg), and MXF (40 mg/kg). Treatments were administered orally, and testicular samples were collected at three time points (Day 1, 7, and 14). Histopathological evaluation was performed using hematoxylin and eosin staining. Cyclooxygenase-2 (COX-2) expression was assessed immunohistochemically. Biochemical analyses included measurements of malondyaldehyde (MDA), adenosine deaminase (ADA), and acetylcholine esterase (AChE) levels. FQ exposure led to variable degrees of testicular degeneration and significantly increased COX-2 expression in the testis. MXF administration caused a time-dependent reduction in MDA levels. ADA activity was significantly elevated in the CIP group on Day 1 and in the LVX group on Day 14. AChE levels were notably increased in both the LVX and MXF groups on Day 1 compared to controls. These findings suggest that FQ derivatives may exert time-dependent degenerative and inflammatory effects on testicular tissue, highlighting their potential risk for male reproductive toxicity.