The existing study was conducted to evaluate the toxic potential of Acid Red 119 (AR 119) in fish by assessing DNA damage, biochemical alterations and histopathological changes in liver tissue after acute exposure. Fish were subjected to two sub-lethal concentrations of AR 119, (15.90 mg/L and 31.81 mg/L), alongside a control group (water only) for 96h. Samples of liver were harvested at 24, 48, 72 and 96h after acute exposure. Compared to the control group, fish exposed to AR 119 exhibited a significant, time-dependent increase in DNA damage. Additionally, oxidative stress measured by malondialdehyde (MDA) level was markedly higher in both exposed groups. Superoxide dismutase (SOD) and glutathione-S-transferase (GST) enzymatic activities were significantly reduced following acute exposure. Histopathological examination of liver tissues revealed distinct structural anomalies (sinusoid dilation, erythrocytic infiltration, congested portal vein, vacuolization) in exposed fish. Overall, the findings indicate that AR 119 induced genotoxic effects in , potentially mediated by oxidative stress mechanisms.

Occupational exposure to diesel particulate matter (DPM) poses significant risks of pulmonary injury, highlighting an urgent need for effective pharmacological intervention. This study aimed to systematically elucidate the protective mechanism of aspirin against DPM-induced lung injury by integrating computational and experimental approaches. Methodologically, network pharmacology utilizing SwissTargetPrediction and GeneCards identified PTGS2 as the core therapeutic target via Venn diagram analysis and topological screening. Molecular docking and dynamics simulations then confirmed the stable binding of aspirin to the PTGS2 catalytic pocket. Biological validation was conducted via colony formation assay and Western blot in A549 cells, which demonstrated aspirin's efficacy in mitigating DPM-induced cytotoxicity and suppressing inflammatory and apoptotic pathways. Furthermore, studies incorporating HE staining and protein analysis in a mouse model corroborated the protective role of aspirin against DPM-induced alveolar damage and inflammatory infiltration. Collectively, our findings validate PTGS2 as a critical therapeutic target of aspirin against DPM-induced lung injury and highlight the promise of pulmonary-targeted aspirin formulations to enhance therapeutic precision while reducing systemic toxicity. Future efforts should focus on advancing the clinical translation of inhalable aspirin and validating its long-term efficacy in high-risk occupational populations.

The role of environmental pollutants as risk factors for Alzheimer's disease (AD) and related neurodegenerative pathologies necessitates mechanistic investigation. Evidence implicates brominated flame retardants (BFRs)-decabromodiphenyl ethane (DBDPE)-in AD pathogenesis, though their molecular mechanisms remain inadequately elucidated. To address this challenge, we combined multiple cross-disciplinary methods (network toxicology, machine learning [ML], molecular docking, molecular dynamics [MD] simulations, and Mendelian randomization [MR] analysis) to systematically delineate DBDPE-induced AD pathogenesis. Initial screening of the SwissTargetPrediction database and GSE132903 dataset identified 47 overlapping DBDPE-AD targets. Subsequent protein-protein interaction (PPI) network analysis refined these to 42 high-confidence targets. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed association of core targets with metabolic pathways and neuroactive ligand-receptor interactions. Three core targets were prioritized using ML framework. Molecular docking confirmed strong binding affinities between DBDPE and the core targets. Given PLAU's exceptional binding energy, we conducted MD simulations to validate complex stability and characterize binding-site interactions. Finally, MR analysis established causal links between PLAU and AD susceptibility. In summary, this study establishes a comprehensive theoretical framework for understanding the molecular mechanisms of DBDPE-induced AD and provides valuable insights for developing preventive and therapeutic strategies targeting AD associated with DBDPE exposure.

This study explores the pharmacological synergy between (turmeric) compounds and cisplatin in ovarian cancer treatment, focusing on overcoming drug resistance and minimizing toxicity. Using bibliometric analysis with tools like Publish or Perish and VOSviewer, the research identifies significant novelty in this field. Active compounds of were screened for drug-likeness and oral bioavailability through Molsoft and SwissADME, while potential therapeutic targets were predicted using databases such as SwissTargetPrediction, GeneCards, and DrugBank. Network pharmacology and PPI analysis via Cytoscape and STRING, along with GO and REACTOME enrichment via DAVID. In the pharmacological network, quercetin, cytosolic tRNA aminoacylation, and ALOX5 (arachidonate 5-lipoxygenase) are the substances, targets, and pathways with the highest degrees. The PPI target with the highest degree is TP53 (tumor protein p53). GO enrichment (BP, CC, MF) and REACTOME are cytosolic tRNA aminoacylation, tRNA aminoacylation, and mucopolysaccharidoses. Docking simulations showed strong binding between campesterol and CDK2 (-10.8 kcal/mol) as well as campesterol and TP53 (-9.7 kcal/mol). These results suggest that compounds could enhance cisplatin's anticancer activity, reduce toxicity, and help overcome drug resistance in ovarian cancer therapy. The findings highlight the potential for natural, polyphenol-rich agents to complement chemotherapy and improve treatment outcomes.

Paclitaxel (PTX) is an efficacious natural product-derived anticancer agent. It exerts a remarkable disruption of nanopore microtubule dynamics, thus inducing cytotoxic effects on cancer cells. However, its drawback is associated with non-targeted healthy organ damage, including nephrotoxicity. Therefore, we explored the mechanistic protective effect of tert-butylhydroquinone (TBHQ) against PTX-induced nephrotoxicity in male Wistar rats. For this purpose, rats were divided into four (n = 5) groups: normal control, TBHQ control (50 mg/kg body weight, administered from day 1 to day 14), PTX control (2 mg/kg body weight injected from day 1 to day 5) and TBHQ + PTX (with doses indicated above). PTX injection significantly impaired renal function leading to elevated serum urea, creatinine and uric acid levels and caused disruption of histological integrity. PTX markedly reduced the renal antioxidant enzyme mechanisms, Nrf2 and ferroptosis GPX-4 levels, whereas the levels of malondialdehyde MDA, caspase-3, and BAX were conspicuously elevated compared to the control. The renal NF-κB and cytokine (TNF-α, IL-1β and IL-6) expressions were significantly increased due to the PTX injection. TBHQ administration effectively reversed these alterations associated with oxidative inflammation, apoptosis and ferroptosis via restoring renal function, renal antioxidant enzyme activities and reducing MDA levels. TBHQ considerably improved renal Nrf2, GPX-4 and GSH followed by ameliorated histopathological changes. Taken together, our results suggest that TBHQ has protective effects against PTX-induced nephrotoxicity, and is a promising antioxidant agent with the potential to improve quality of life during PTX chemotherapy.

This study aimed to determine whether dietary bee pollen protects common carp () from deltamethrin (DM)-induced oxidative stress by modulating serum paraoxonase (PON) and arylesterase (ARE) activities. DM, a widely used pyrethroid insecticide, can impair antioxidant defenses in aquatic organisms. PON and ARE, two HDL-associated enzymes with antioxidant properties, were used as biomarkers to evaluate oxidative stress. Fish were exposed to two sublethal concentrations of DM (0.018 and 0.036 µg/L) for 14 days, with or without dietary supplementation of 2% chestnut-origin bee pollen. Results showed that while DM exposure significantly reduced serum PON and ARE activities, indicating oxidative stress and enzyme inhibition, bee pollen supplementation effectively counteracted these effects in a dose-dependent manner ( < 0.05). However, co-administration of the bee pollen partially restored both enzyme activities in a dose-dependent manner ( < 0.05). The improvement suggests that bee pollen, rich in flavonoids, phenolic compounds, and vitamins, exerts antioxidant effects that mitigate DM-induced toxicity. Bee pollen alone did not significantly alter PON or ARE activity compared to controls, confirming its safety and potential as a dietary supplement. Overall, this study provides evidence that bee pollen can serve as a natural antioxidant supplement to protect aquatic organisms against pesticide-induced oxidative damage, thereby contributing to the sustainable health management of aquaculture. These findings demonstrate that bee pollen can protect against pesticide-induced oxidative damage and may serve as a natural therapeutic agent in aquaculture.

polysaccharide (FLL-P) is a class of important bioactive macromolecules extracted from the traditional Chinese medicinal herb wine-steamed . As one of the key active components responsible for the pharmacological effects of this herb, its modern pharmacological value has garnered widespread attention. Research has demonstrated that FLL-P exhibits diverse and significant biological activities, with potential applications that far exceed the traditional scope of Chinese medicine. In recent years, chemical modification has been recognized as an effective strategy for enhancing the biological activity of polysaccharides. Consequently, structural modification of FLL-P is anticipated to further augment its activity and broaden its application prospects. However, current research on the chemical modification of FLL-P remains inadequate, particularly concerning the safety evaluation of modified products, which is still extremely limited. This research comprehensively explores the acetylation modifications of FLL-P, encompassing detailed characterization and toxicity assessments. The optimal product, identified as acetylated FLL-P 12.5 (FLL-PA12.5), was established through analyses of the degree of substitution (DS), FT-IR, and NMR. Toxicity tests, both acute and subacute, were conducted on male mice. The findings indicated that FLL-PA12.5 had a median lethal dose (LD) exceeding 2000 mg/kg and a no-observed adverse effect level (NOAEL) of 250 mg/kg. Administration of FLL-PA12.5 at doses between 250 and 2000 mg/kg resulted in alterations in various oxidative stress-related parameters in different organs of the mice. These findings indicate that FLL-PA12.5 is a promising therapeutic candidate with an acceptable safety profile, warranting further pharmacological exploration.

Mono-2-ethylhexyl phthalate (MEHP), a major metabolite of diethylhexyl phthalate, is increasingly recognized as an environmental contaminant with potential cardiovascular toxicity. However, the molecular mechanisms underlying MEHP-induced atherosclerosis (AS) remain poorly understood. This study aimed to investigate the toxicological targets and pathways through which MEHP contributes to AS development using network toxicology approaches. DEGs associated with AS were identified from the GSE100927 dataset. MEHP targets were predicted using multiple databases including SEA, SwissTargetPrediction, and TargetNet. Common toxicological targets were identified through intersection analysis. Functional enrichment analysis, GSVA, and ssGSEA were performed. Machine learning algorithms including LASSO regression, RF, and SVM were employed to identify key targets. A nomogram model was constructed for AS risk prediction, and molecular docking analysis was conducted to validate protein-ligand interactions. Analysis identified 13,905 DEGs in AS, with 172 potential MEHP targets yielding 92 common toxicological targets. Enrichment analysis revealed involvement in calcium signaling, PPAR signaling, inflammatory response, and immune pathways. Machine learning identified three key targets: PDPK1, HDAC10, and HRH1. The nomogram model based on HDAC10 and HRH1 demonstrated excellent predictive performance. ssGSEA analysis revealed significant associations between key targets and immune pathways. Molecular docking confirmed strong binding affinities, with HRH1-MEHP showing the highest affinity. MEHP may promote AS via coordinated effects on calcium handling, receptor-mediated and transcriptional signaling, oxidative stress, apoptosis, and immune activation. HRH1, HDAC10, and PDPK1 emerge as mechanistic mediators and potential biomarkers, with an HDAC10/HRH1 nomogram offering translational utility for AS risk stratification; docking results provide testable hypotheses for mechanistic validation.

This study developed and evaluated a ready-to-use quinestrol nanoparticle-based bait for contraception in female (lesser bandicoot rat). in three treatment groups: Control (plain bait), Q (bait with bulk quinestrol, 100 ppm), and QNP (bait with quinestrol nanoparticles, 10 ppm) were evaluated at 15, 45, and 75 days after a five-day treatment in a bi-choice setting. Results showed no significant difference between treated and plain bait consumptions, indicating good acceptability. Ovary weight decreased, and uterine weight increased significantly in the treated groups. Organ histology revealed significant contraceptive effects, including an increased number of atretic follicles, a reduced number of normal follicles in the ovaries, and increased uterine gland numbers and diameter. The 17β-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase activities were significantly increased. Treated females produced 65-85% fewer pups when bred with untreated males. Quinestrol did not affect body weight, weight of vital organs, the activity of alkaline and acid phosphatases, and aspartate and alanine aminotransferases, indicating its safety. The effects of Q lasted up to 45 days, whereas the effects of QNP persisted for 75 days, despite using 10 times less active ingredient. This research represents a potential advancement in sustainable rodent pest management with extended efficacy and reduced dosage requirements.

Methanol (CHOH) is one of the toxic alcohols that has high morbidity and mortality. It causes lipid peroxidation and oxidative stress. Antioxidants and neuroprotective agents could have therapeutic roles in case of methanol exposure. The aim of this research was to assess the therapeutic impact of royal jelly (RJ) versus oil (NS) on brain areas affected by acute methanol poisoning in rats. This research was performed on 60 adult male albino rats that were randomly assigned to four groups: the negative control group (I), the positive control group (II), the methanol-intoxicated group (III), and the methanol and adjuvant treatment treated group (IV) which were categorized into two subgroups: the methanol and RJ treated group (IV a) and the methanol and NS treated group (IV b). After two weeks, the blood samples were obtained to determine the total antioxidant capacity (TAC). The frontal cortex, cerebellum, and hippocampus were excised and subjected to histopathological and transmission electron microscopic examination. Acute methanol poisoning induced oxidative stress, indicated by a significant reduction of TAC and marked degenerative changes in nerve cells and nerve fibers. Moreover, the administration of RJ and NS six hours after induction of acute methanol poisoning showed an increase in TAC compared to group III and a non-significant reduction compared to group II, with marked improvement and restoration of the normal brain architecture. Therefore, RJ and NS are effective in reducing the oxidative stress induced by acute methanol poisoning.

L., a poisonous medicinal plant is used safely after in Ayurveda. It is listed in Schedule E1 of Drugs and Cosmetics Act, as a poisonous medicinal plant to be used with caution. Although known for its toxic effects and reduction of toxicity by . However, the toxicity mechanism, effect of and toxicity profile after repeated dosing are missing. and seeds were subjected to extraction using 70% ethanol and phytochemicals analyzed by LC-MS. Acute and 28-day repeated-dose toxicity studies were conducted as per OECD 423 and OECD 407. Network pharmacology, molecular docking, and dynamics were used to predict the potential multicomponent multitarget interactions and toxicity mechanisms. exhibited toxicity viz., neurotoxicity and hepatotoxicity, characterized by weight loss, altered organ weights, disrupted hematological, biochemical, behavioral and histological abnormalities. On the contrary, was found safe with NOAEL 100 mg/kg. Whereas it was found to be 25 mg/kg for . Atropine and Scopolamine are predicted to disrupt cholinergic function and cause inflammation mediated through NFK-β1 and MAPK-1, altering neurotrophin, cAMP, PI3K-AKT, NOD-like receptor, AGE-RAGE, and IL-17 pathways. Atropine and scopolamine major toxic chemicals of were predicted to disrupt cholinergic function and induce inflammation, potentially mediated through NFK-β1 and MAPK-1 pathways. The purification process was found to be effective in mitigating toxicity.

Carbon tetrachloride (CCl) induces hepatotoxicity through oxidative stress, inflammation, and apoptosis. Cirsimaritin, a natural flavonoid with antioxidant and anti-inflammatory activity, has not been extensively investigated for hepatoprotection.

Drug-induced hepatotoxicity is a significant public health issue that influences the development of novel pharmaceutical therapies and the retraction of numerous promising medications from the market. Therefore, the current study investigated the potential hepato-protective benefits of NEF against hepatotoxicity caused by paracetamol (APAP) in mice and assessed its underlying mechanisms. Mice were divided randomly into six groups; control (received normal saline), NEF control, APAP, N-acetylcysteine (NAC; served as a standard treatment) + APAP, NEF (10 mg/kg) + APAP, and NEF (20 mg/kg) + APAP. The serum and hepatic tissues were collected for different biochemical, genetic, and histological assessments. APAP induced profound hepatic damage that was evident through all biochemical, histological, and molecular assessments. NEF pretreatment opposed the elevation of liver injury biomarkers and attenuated hepatic histological disruption. At the molecular level, NEF increased the hepatic level and protein expression of SIRT-1. NEF increased the hepatic mRNA and protein expression of Nrf2 and HO-1. NEF also decreased hepatic level of oxidative stress biomarker, MDA and increased the hepatic levels of antioxidants: GSH, GR, GST, TAC, and SOD, NEF also counteracted the activation of NF-κB and inhibited the upregulation of different inflammatory cytokines as TNF-α and interleukins- (IL-1β and IL-6). Furthermore, NEF pretreatment decreased the hepatic level and mRNA expression of COX-II and iNOS. NEF ameliorated APAP-induced liver injury in mice where the higher dose of NEF (20 mg/kg) was more effective than the lower (10 mg/kg) compared to NAC. This effect is association with upregulation of SIRT-1/Nrf2/HO-1 and interruption of NF-κB/cytokines/iNOS/COX-II signaling cascades.

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.

Potassium bromate (KBrO), a widely used food-additive and a major water disinfection by-product, causes severe toxicity in humans and experimental animals. Bromate is considered a probable human carcinogen and a complete carcinogen in animals. We have investigated the potential role of vitamin C in mitigating KBrO-induced nephrotoxcity. Animals were given KBrO alone or after pretreatment with vitamin C and then sacrificed. Blood and kidneys were collected and were used for the analysis of several biochemical parameters. Administration of single oral dose of KBrO alone caused nephrotoxicity as evident by elevated serum creatinine (+3-fold) and urea levels (+2.5-fold). Renal lipid peroxidation (+1.5-fold) and protein carbonyls (+2.5 fold) were increased while total sulfhydryl groups (-2.3-fold) and reduced glutathione levels (-1-fold) were decreased suggesting the induction of oxidative stress. The enzymes of renal brush border membrane were inhibited and those of carbohydrate metabolism were altered. There was increase in DNA damage and DNA-protein cross-linking. Treatment with vitamin C, prior to administration of KBrO, resulted in significant attenuation in all these parameters but the administration of vitamin C alone had no effect. Histological studies supported these biochemical results showing extensive renal damage in KBrO alone treated animals and greatly reduced tissue injury in the vitamin C + KBrO group. These results show that vitamin C is an effective chemoprotectant against bromate-induced renal damage and could prove to be useful in attenuating the toxicity of this and other related compounds.

Per- and polyfluoroalkyl substances (PFAS) are widely used in various industries but pose significant ecological and human health risks, particularly to the nervous system. However, the underlying neurotoxic mechanisms remain poorly understood. This study combines network toxicology and machine learning to explore these mechanisms. Using ADMETLAB 3.0, we assessed the environmental toxicity of six common PFAS and identified their potential targets using online tools. A compound-target interaction network was built, followed by protein-protein interaction (PPI) and KEGG pathway analyses to investigate toxicological pathways. Core targets were selected through machine learning, and differential gene expression was analyzed using transcriptomic data. Molecular docking simulations predicted binding affinities between PFAS and their core targets, while molecular dynamics simulations on key complexes were performed using Gromacs 2023.2 and the Charmm36 force field. PFDS showed the highest bioconcentration factors (BCF), while PFOA demonstrated the greatest toxicity. We identified 62 intersecting targets, with PTGS2, MMP9, and ESR1 being central in the PPI network. Transcriptomic analysis revealed 1,077 differentially expressed genes (DEGs), highlighting associated biological processes and pathways. The random forest model identified 20 core genes, with 9 significantly differentially expressed in the PFAS-treated group. Molecular docking suggested potential interactions between the compounds and core targets, and molecular dynamics simulations further supported the stability of the complexes under physiological conditions. This study provides valuable insights into the neurotoxic mechanisms of PFAS, enhancing our understanding of their impact on the nervous system.

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 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 and 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 and i.e., 250 mg/kg bw each, demonstrated the hepatoprotective effect against DEN-induced liver damage in the rat model.

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 ( = 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 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, 25 mg kg, and 50 mg kg in healthy Wistar rats, following Organization for Economic Co-operation and Development guidelines. A single oral dose of the compound mixture (10 mg kg, 25 mg kg, and 50 mg kg) 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, 25 mg kg, and 50 mg kg 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.

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/cm. The lethal dose 50 (LD) for film-forming topical dermal spray of meloxicam may be considered to be >2000 mg.kg. 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 in experimental animals. The IC 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 and applications. In conclusion, the moderate dose of film-forming dermal spray of meloxicam was found to be safe for topical use.

The present study is aimed to evaluate the hepatoprotective role of -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.