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Methotrexate (MTX), a potent chemotherapeutic and immunosuppressive agent, is widely used for cancer and autoimmune diseases. MTX-induced hepatotoxicity is a well-recognized adverse response, even at relatively low doses. This study investigates the possible protective effects of procyanidin B2 (PCB2) on MTX-induced hepatotoxicity. Rats were orally treated with PCB2 (40 mg/kg) for 10 days, followed by a single intraperitoneal MTX injection (20 mg/kg) on day 8. The study also included a positive control group treated with quercetin (20 mg/kg), a known antioxidant, alongside MTX. The results revealed that MTX-induced hepatic injury was evidenced by elevation in serum transaminases. This elevation was accompanied by hepatic oxidative stress due to an imbalance in oxidative/antioxidant markers, specifically elevated malondialdehyde (MDA) and decreased glutathione (GSH) levels and superoxide dismutase (SOD) activity. The inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), were markedly upregulated in the liver of MTX-intoxicated rats. Additionally, the expressions of nuclear factor kappa B (NF-κB), toll-like receptor 4 (TLR4), caspase-3 and gasdermin E (GSDME) were significantly increased in MTX rats. The use of PCB2 significantly ameliorated the deleterious effect of MTX on previous parameters by restoring oxidant/antioxidant balance, decreasing the inflammatory markers, and normalizing the expression of NF-κB, TLR4, caspase-3 and GSDME. In conclusion, this study uncovered the potential role of PCB2 on MTX-induced hepatotoxicity, confirming its antioxidant, anti-inflammatory, and anti-pyroptosis effects yet, further studies are needed to support its use as a protective therapy against such toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: Purpose: Valproate (VPA) is an antiepileptic drug widely used to treat various psychiatric and neurological disorders. Although its use is generally considered safe, chronic administration may lead to kidney injury. The mechanisms underlying VPA kidney toxicity are not entirely explored. This has prompted our investigation into a novel molecular signaling pathway involved in VPA-induced kidney injury and the exploration of strategies to ameliorate this toxicity using indole-3-acetic acid (IAA) and chenodeoxycholic acid (CDCA)., Methods: Rats were divided as follows: group I (control); group II (VPA group), where rats were administered VPA (500 mg/kg, i.p.) daily to induce kidney injury for 3 weeks; and groups III and IV, where rats were orally treated with either IAA (40 mg/kg) or CDCA (90 mg/kg), respectively, 1h post-VPA dose, for 3 weeks. The effects of these compounds on kidney tissues were evaluated with a focus on their antioxidant and anti-inflammatory properties using biochemical, histopathological, and immunohistochemical analyses., Results: VPA caused a significant reduction in renal glutathione (GSH) and heme oxygenase-1 (HO-1) levels, and superoxide dismutase (SOD) activity, along with a significant elevation in malondialdehyde (MDA) levels. Similarly, tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6) levels were significantly increased. Immunohistochemical analysis demonstrated a significant decline in the immunoreactivity of nuclear factor erythroid 2-related factor (Nrf2) and cytoglobin antigens in renal cells. However, administration of either IAA or CDCA significantly ameliorated these altered parameters, including Nrf2/HO-1 and cytoglobin levels., Conclusion: IAA and CDCA alleviated the kidney injury induced by VPA via downregulating the inflammatory response and upregulating the antioxidant capacity in renal tissue., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Isoproterenol (ISO), a chemically synthesized catecholamine, belongs to β-adrenoceptor agonist used to treat bradycardia. The β-adrenergic agonist is an essential regulator of myocardial metabolism and contractility; however, excessive exposure to ISO can initiate oxidative stress and inflammation. This study aims to investigate the molecular mechanisms underlying ISO-induced cardiac remodeling, the protective efficacy of resveratrol (RSVR), and its liposomal formulation (L-RSVR) against such cardiac change. Wistar albino rats were evenly divided into 4 groups. Control group, ISO group received ISO (50 mg/kg, s.c.) twice a week for 2 weeks, and RSVR- and L-RSVR-treated groups in which rats received either RSVR or L-RSVR (20 mg/kg/day, p.o.) along with ISO for 2 weeks. ISO caused a significant elevation of the expression levels of BAX and MEF2 mRNA, S100A1 and cytochrome C proteins, as well as DNA fragmentation in cardiac tissue compared to the control group. Treatment with either RSVR or L-RSVR for 14 days significantly ameliorated the damage induced by ISO, as evidenced by the improvement of all measured parameters. The present study shows that L-RSVR provides better cardio-protection against ISO-induced cardiac injury in rats, most likely through modulation of cardiac S100A1 protein expression and inhibition of inflammation and apoptosis., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Diabetic nephropathy is one of the complications of diabetes that affects the kidney and can result in renal failure. The cholesterol-lowering drug simvastatin (SIM) has shown promising effects against diabetic nephropathy (DN). This study evaluated the protective role of SIM on DN, pointing to the involvement of farnesoid X receptor (FXR) and Nrf2/HO-1 signaling in attenuating inflammatory response, oxidative injury, and tissue damage in streptozotocin-induced diabetic rats. SIM was supplemented orally for 8 weeks, and samples were collected for analysis. SIM effectively ameliorated hyperglycemia, kidney hypertrophy, body weight loss, and tissue injury and fibrosis in diabetic animals. SIM mitigated oxidative stress (OS), inflammatory response, and cell death, as evidenced by the suppressed malondialdehyde, nitric oxide, myeloperoxidase, NF-kB, TNF-α, IL-1β, CD68, Bax, and caspase-3 in the diabetic kidney. These effects were linked to suppressed Keap1, upregulated FXR, Nrf2, and HO-1, and enhanced antioxidant defenses and Bcl-2. The in silico findings revealed the binding affinity of SIM with NF-kB, caspase-3, Keap1, HO-1, and FXR. In conclusion, SIM protects against DN by attenuating hyperglycemia, kidney injury, fibrosis, inflammation, and OS, and upregulating antioxidants, FXR, and Nrf2/HO-1 signaling., Competing Interests: Declaration of competing interest All authors declare no conflict of interests in relation to the manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objective: Isoproterenol (ISO) is a non-selective β-adrenergic receptor agonist. It can be used to treat bradycardia and cardiogenic shock. Despite its usefulness, the overstimulation of β-receptors by ISO can cause "cardiorenal syndrome," a term used to describe heart and kidney damage. Resveratrol (RES), a natural polyphenol, has marked anti-inflammatory and antioxidant activities. The present work was designed to study the protective efficacy of liposomal resveratrol (L-RES) against ISO-induced kidney injury., Materials and Methods: The kidney injury was induced in rats by administering ISO (50 mg/kg, s.c.) twice a week for 2 weeks. RES and L-RES were administered at a dose (20 mg/kg/ day, p.o.) along with ISO for 2 weeks. Inflammatory and apoptotic biomarkers were analyzed, which were validated using histochemical analysis., Results: ISO caused renal dysfunction, which manifested as elevated urea, creatinine and uric acid, besides cystatin c and MAPK protein overexpression. In addition, ISO induced gene expression of Fas and lipocalin-2 and provoked genomic DNA fragmentation in renal tissues as compared with the control group. Histological examination confirmed morphological alterations of the kidney tissues obtained from the ISO group. Concurrent treatment of either RES or L-RES with ISO significantly ameliorated kidney damage as demonstrated by the improvement of all measured parameters with the best results for L-RES. The histopathological findings were correlated with the above biochemical parameters., Conclusion: L-RES could be a promising approach for the prevention of kidney injury induced by ISO, most likely via the downregulation of MAPK, cystatin c, Fas, and lipocalin-2., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Diabetes is a ubiquitous disease that causes several complications. It is associated with insulin resistance, which affects the metabolism of proteins, carbohydrates, and fats and triggers liver diseases such as fatty liver disease, steatohepatitis, fibrosis, and cirrhosis. Despite the effectiveness of Sitagliptin (ST) as an antidiabetic drug, its role in diabetes-induced liver injury is yet to be fully investigated. Therefore, this study aims to investigate the effect of ST on hepatic oxidative injury, inflammation, apoptosis, and the mTOR/NF-κB/NLRP3 signaling pathway in streptozotocin (STZ)-induced liver injury. Rats were allocated into four groups: two nondiabetic groups, control rats and ST rats (100 mg/kg), and two diabetic groups induced by STZ, and they received either normal saline or ST for 90 days. Diabetic rats showed significant hyperglycemia, hyperlipidemia, and elevation in liver enzymes. After STZ induction, the results revealed remarkable increases in hepatic oxidative stress, inflammation, and hepatocyte degeneration. In addition, STZ upregulated the immunoreactivity of NF-κB/p65, NLRP3, and mTOR but downregulated IKB-α in liver tissue. The use of ST mitigated metabolic and hepatic changes induced by STZ; it also reduced oxidative stress, inflammation, and hepatocyte degeneration. The normal expression of NF-κB/p65, NLRP3, mTOR, and IKB-α were restored with ST treatment. Based on that, our study revealed for the first time the hepatoprotective effect of ST that is mediated by controlling inflammation, oxidative stress, and mTOR/NF-κB/NLRP3 signaling.

Aim: Valproic acid (VPA) belongs to the first-generation antiepileptic drugs, yet its prolonged use can cause life-threatening liver damage. The importance of our study is to investigate the protective effect of indole-3-acetic acid (IAA), chenodeoxycholic acid (CDCA) and their combination on VPA-induced liver injury focusing on lipopolysaccharides (LPS)/toll-like receptor 4 (TLR4) pathway and farnesoid X receptor (FXR)., Methods: Thirty rats were randomly assigned into five groups, normal control group, VPA group received 500 mg/kg of VPA intraperitoneally. The remaining groups were orally treated with either 40 mg/kg of IAA, 90 mg/kg of CDCA, or a combination of both, along with VPA. All treatments were administered one hour after the administration of VPA for three weeks., Key Findings: VPA group showed significant elevations in the liver weight/body weight ratio, serum aminotransferases, triglyceride, and total cholesterol levels. Hepatic glutathione (GSH) level and superoxide dismutase (SOD) activity were significantly decreased, while malondialdehyde (MDA) level, tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), lipopolysaccharide (LPS) and caspase 3 were significantly increased. Likewise, immunohistochemical analysis revealed that TLR4 expression was elevated, whereas FXR expression was downregulated in hepatocytes. IAA substantially ameliorated all previously altered parameters, whereas CDCA treatment showed a partial improvement compared to IAA. Surprisingly, combination therapy of IAA with CDCA showed an additive effect only in the hepatic expression of TLR4 and FXR proteins., Significance: IAA could be a promising protective agent against VPA-induced liver injury., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Acetaminophen (APAP)-induced nephrotoxicity is detrimental consequence for which there has not been a standardized therapeutic regimen. Although, N-acetylcysteine (NAC) is a well-known antidote used in APAP-induced hepatotoxicity, its benefit in nephrotoxicity caused by APAP is almost lacking. This study aimed to compare the possible protective effect of thymoquinone (TQ), curcumin (CR), and α-lipoic acid (α-LA), either in solo or in combination regimens with that of NAC against APAP-induced renal injury., Design and Method: Rats were divided into nine groups; control group, APAP intoxicated group (1000 mg/kg; orally), and the remaining seven groups received, in addition to APAP, oral doses of NAC, TQ, CR, α-LA, CR plus TQ, TQ plus α-LA, or CR plus α-LA. The first dose of the aforementioned antioxidants was given 24 h before APAP, and then the second dose was given 2 h after APAP, whereas the last dose was given 10 h after administration of APAP., Results: Treatment with APAP elevated kidney markers like serum uric acid, urea, and creatinine. In addition, it increased the serum level of tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β) and thiobarbituric acid reactive species (TBARS). Also, the protein expression of renal janus kinase (JAK) and cyclooxygenase (COX)-2 were all upregulated by APAP. In contrast, the expression of Nrf2 and the renal levels of superoxide dismutase and glutathione were downregulated. Treatment with the indicated natural antioxidants resulted in amelioration of the aberrated parameters through exhibiting anti-inflammatory, antioxidant and free radical-scavenging effects with a variable degree., Conclusion: The combined administration of CR and TQ exerted the most potent protection against APAP-induced nephrotoxicity through its anti-inflammatory and free radical-scavenging effects (antioxidant) which were comparable to that of NAC-treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Copper (Cu) is an essential trace element for maintaining normal homeostasis in living organisms. Yet, an elevated level of Cu beyond homeostatic capacity may lead to oxidative damage of cellular components in several organs, including the lungs. This work investigated the effects of curcumin (Curc) and nano-curcumin (nCurc) against Cu-induced lung injury, accenting the roles of oxidative stress, inflammation, and the nuclear factor erythroid 2-related factor/heme oxygenase-1 Nrf2/HO-1 pathway. Rats were challenged with 100 mg/kg of copper sulfate (CuSO 4 ) while being treated with Curc or nCurc for 7 days. Cu-triggered lung oxidative stress detected as dysregulation of oxidative/antioxidant markers, a downregulation of Nrf-2/HO-1 signaling, and an increase in the inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and intracellular adhesion molecule-1 (ICAM-1). Additionally, it decreased the expression of lung-specific proteins, surfactant protein-C (SP-C), and mucin-1 (MUC-1), induced apoptosis, and caused changes in lung histology. Curc and nCurc alleviated CuSO 4 -induced lung injury by suppressing oxidative damage and inflammation and activating Nrf-2/HO-1. They also prevented apoptosis and restored the normal expression of SP-C and MUC-1. We concluded that nCurc exhibited superior efficacy compared with Curc in mitigating CuSO 4 -induced lung injury. This was associated with reduced oxidative stress, inflammation, and apoptotic responses and increased Nrf2/HO-1 signaling and expression of SP-C and MUC-1.

Background: Traditional modifiable cardiovascular risk factors, such as high blood pressure, have long been positively correlated with high carotid intima-media thickness (cIMT). However, traditional cardiovascular risk factors made a minor contribution to cIMT variance, meaning that other markers may be regarded as independent markers for increasing cIMT., Aims: To investigate the simple demographic patterns of carotid intima-media thickness (cIMT) in the UK Biobank and to identify which upstream cardiovascular disease (CVD) risk factors are independently associated with cIMT., Methods and Results: A cross-sectional-based study of healthy middle-aged people recruited in the UK between 2006 and 2010 ( n = 42,726)., Results: This study showed that the cardiovascular risk profile generally worsened across the cIMT quantiles from lowest to highest. The lowest cIMT quartile was defined as having a mean cIMT < 588 µm, while the highest cIMT quartile was defined as having a mean cIMT > 748 µm. Specifically, the highest cIMT quantile group had a worse CVD risk factors profile compared to the lowest cIMT quantile group. It was found that, for every one SD increase in age and systolic blood pressure, the mean cIMT increased by 0.357 SD and 0.115 SD, respectively., Conclusion: Systolic blood pressure and age were the strongest independent risk factors for a high cIMT value compared to other risk factors.

Propionic acid (PRA) is a metabolic end-product of enteric bacteria in the gut, and it is commonly used as a food preservative. Despite the necessity of PRA for immunity in the body, excessive exposure to this product may result in disruptive effects. The purpose of this study is to examine the hepatoprotective effects of acetyl-L-carnitine (A-CAR) and liposomal-coenzyme Q 10 (L-CoQ 10 ) against PRA-induced injury. Liver injury in rats was induced by oral administration of PRA, and A-CAR and L-CoQ 10 were administered concurrently with PRA for 5 days. Oxidative stress, inflammatory, apoptotic, and fibrotic biomarkers were analyzed; the histology of liver tissue was assessed as well to further explore any pathological alterations. PRA caused significant increases in the levels of serum liver enzymes and hepatic oxidative stress, inflammatory, and apoptotic biomarker levels, along with histopathological alterations. Concurrent treatment with A-CAR and/or L-CoQ 10 with PRA prevented tissue injury and decreased the levels of oxidative stress, proinflammatory cytokines, and apoptotic markers. Additionally, A-CAR and/or L-CoQ 10 modulated the expression of high-mobility group box-1, cytokeratin-18, transforming growth factor-beta1, and SMAD3 in liver tissue. In conclusion, A-CAR and/or L-CoQ 10 showed hepatoprotective efficacy by reducing oxidative stress, the inflammatory response, apoptosis, and fibrosis in liver tissue.

Autophagy and apoptosis are two important regulatory mechanisms for how the body can respond to diseases. This study was designed to investigate the protective actions of vitamin E (Vit-E) and lactobacillus plantarum (Lac-B) against mercuric chloride (HgCl 2 )-induced kidney injury. Thirty albino rats were divided into five groups: group 1 served as the normal group; rats in group 2 received high doses of HgCl 2 ; rats in groups 3, 4 and 5 were given Vit-E, Lac-B and the combination of Vit-E and Lac-B, respectively along with HgCl 2 for two weeks. HgCl 2 provoked renal injury, manifested by elevation in serum urea, urea nitrogen and creatinine. Kidney levels of oxidative stress and inflammation were markedly increased post HgCl 2 administration. Moreover, HgCl 2 significantly elevated the gene expression levels of VCAM-1 and cystatin C , while podocin was downregulated. Additionally, it markedly decreased the protein expression of Beclin-1 and Bcl-2. Histopathological examination revealed massive degeneration with congested blood vessels following HgCl 2 administration. Treatment with Vit-E or/and Lac-B restored the normal levels of the previously mentioned parameters, as well as improved the morphology of kidney tissues. Both Vit-E and Lac-B provided a protective effect against HgCl 2 -induced kidney damage by regulating autophagy and apoptosis.

Copper is essential for several cellular processes and is an important catalytic factor for many proteins. However, excess copper can provoke oxidative stress and reproductive toxicity. This study evaluated the effect of liposomal nano-curcumin (N-CUR) and CUR on testicular oxidative injury, inflammation, and apoptosis, and altered steroidogenesis and Nrf2/HO-1 signaling induced by copper sulfate (CuSO4). Rats received CuSO4 and N-CUR or CUR via oral gavage for 7 days. CuSO4 induced histopathological changes and altered pituitary-gonadal axis manifested by decreased serum gonadotropins and testosterone. Testicular steroidogenesis genes (StAR, 3β-HSD, CYP17A1, and 17β-HSD) and androgen receptor (AR) were downregulated in rats that received CuSO4. N-CUR and CUR prevented testicular tissue injury, increased circulating FSH, LH, and testosterone, and upregulated testicular steroidogenesis genes and AR. Additionally, N-CUR and CUR decreased testicular MDA, NO, NF-κB, iNOS, TNF-α, Bax, and caspase-3 while enhanced Bcl-2, Nrf2, and the antioxidants GSH, HO-1, SOD, and catalase. In conclusion, N-CUR and CUR prevented CuSO4-induced reproductive toxicity in male rats by suppressing oxidative injury and inflammatory response and boosting steroidogenesis, sex hormones, and Nrf2/HO-1 signaling. N-CUR was more effective in ameliorating tissue injury, oxidative stress, inflammation, and apoptosis and enhancing steroidogenesis and Nrf2/HO-1 than the native form.

Liver fibrosis is a common chronic hepatic disease. This study was done to examine the effect of pyridoxamine against thioacetamide-induced hepatic fibrosis. Animals were divided into four groups (1) control group; (2) Thioacetamide group (200 mg/kg, i.p.) twice a week for eight weeks; (3) Pyridoxamine-treated group treated with pyridoxamine (100 mg/kg/day, i.p.) for eight weeks; (4) Thioacetamide and pyridoxamine group, in which pyridoxamine was given (100 mg/kg/day, i.p.) during thioacetamide injections. Thioacetamide treatment resulted in hepatic dysfunction manifested by increased serum levels of bilirubin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Oxidative stress was noted by increased hepatic lipid peroxidation and decreased glutathione (GSH). Increased concentrations of total nitrite/nitrate, advanced glycation end products (AGEs), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), matrix metalloproteinases (MMP-2&9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were noticed in hepatic tissues. Immunostaining sections also revealed overexpression of MMP-2, MMP-9 and collagen IV. Liver fibrosis was confirmed by severe histopathological changes. Pyridoxamine improved the assessed parameters. Moreover, histopathological and immunohistological studies supported the ability of pyridoxamine to reduce liver fibrosis. The findings of the present study provide evidence that pyridoxamine is a novel target for the treatment of liver fibrosis., (Copyright © 2022. Published by Elsevier B.V.)

The purpose of this research was to evaluate the efficacy of carsil (CAR) either alone or in combination with α-tocopherol (α-TOCO) and/or turmeric (TUMR) against tetrachloromethane (TCM)-induced cardiomyocyte injury in rats. Administration of CAR either alone or in combination with α-TOCO and/or TUMR post-TCM injection, significantly mitigated the increases in serum troponin T, creatine kinase-MB (CK-MB) as well as interleukin-6 (IL-6), interferon γ (IFN-γ), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP). They also decline the elevation of caspase-3, vascular endothelial growth factor (VEGF) protein expression as well as DNA damage in cardiac tissues induced by TCM. The biochemical results were confirmed by histopathological investigation. Conclusion: The combination of the three antioxidants showed greater cardioprotective potential, compared to individual drugs. Therefore, this combination may be recommended as a complementary therapy to antagonize cardiac injury induced by different insults.

The current study aimed to develop and evaluate a sustained-release transdermal Glipizide (GLP) film to overcome its oral administration problems. Chitosan (CS)-coated deformable liposomes (DLs) were utilized to enhance the drug transdermal delivery. The formulations were characterized in terms of particle size, zeta potential, entrapment efficiency (EE%), vesicle deformability, morphology, stability, and in vitro release. Transdermal films of chosen formulations were prepared by the solvent casting technique, and an ex vivo study throughout rat skin was also performed. Moreover, a pharmacokinetics (PK) study was carried out and blood glucose levels were estimated. All the liposomes were in the nanometer range and a high EE% was obtained from DLs compared to conventional liposomes (CL). The prepared formulations showed a high stability and the DLs exhibited a high deformability compared to CL. The in vitro release study confirmed the sustained release of GLP from both CL and DL and a more pronounced sustained release of GLP was detected after coating with CS. Moreover, GLP was shown to efficiently permeate through the rat skin from transdermal films by an ex vivo permeation test. The transdermal films showed a promising PK profile in the rat as compared with oral GLP. Most importantly, GLP-CS-DL1 demonstrated a higher hypoglycemic effect, confirming the possibility of systemic action by the local topical delivery of GLP.

Background: Although doxorubicin (DXR) is one of the most used anticancer drugs, it can cause life-threatening renal damage. There has been no effective treatment for DXR-induced renal damage until now. Aim: This work aims at examining the potential impact of nano-resveratrol (N-Resv), native resveratrol (Resv), and their combination with carvedilol (Card) against DXR-induced renal toxicity in rats and to investigate the mechanisms through which these antioxidants act to ameliorate DXR nephrotoxicity. Method: DXR was administered to rats (2 mg/kg, i.p.) twice weekly over 5 weeks. The antioxidants in question were taken 1 week before the DXR dose for 6 weeks. Results: DXR exhibited an elevation in serum urea, creatinine, renal lipid peroxide levels, endoglin expression, kidney injury molecule-1 (KIM-1), and beclin-1. On the other hand, renal podocin and mTOR expression and GSH levels were declined. In addition, DNA fragmentation was markedly increased in the DXR-administered group. Treatment with either Resv or N-Resv alone or in combination with Card ameliorated the previously measured parameters. Conclusion: N-Resv showed superior effectiveness relative to Resv in most of the measured parameters. Histopathological examination revealed amelioration of renal structural and cellular changes after DXR by Card and N-Resv, thus validating the previous biochemical and molecular results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alhusaini, Fadda, Alanazi, Sarawi, Alomar, Ali, Hasan and Ali.)

Lead acetate (lead ac.) is a widespread ecological toxicant that can cause marked neurotoxicity and decline in brain functions. This study aimed to evaluate the possible neuroprotective role of L-ascorbic acid (ASCR) and curcumin (CRCM) alone or together against lead ac.-induced neurotoxicity. Rats were injected with lead ac. then treated orally with ASCR and CRCM alone or in combination for 7 days. Lead ac. caused elevation in brain tumor necrosis factor-α, interleukin-6, caspase-3, and malondialdehyde levels, while superoxide dismutase, reduced glutathione as well as the expression of brain-derived neurotrophic factor, cAMP response element-binding, and Beclin1 were downregulated. Expressions of C/EBP homologous protein and mammalian Target of rapamycin kinase were upregulated in brain tissues matched with the control group. Histopathological examination supported the previously mentioned parameters, the administration of the antioxidants in question modulated all the altered previous parameters. The combination regimen achieved the superlative results in the antagonizing lead ac.-induced neurotoxicity via its antioxidant and antiapoptotic activities., (© 2021 S. Karger AG, Basel.)

Copper (Cu) is essential for multiple biochemical processes, and copper sulphate (CuSO 4 ) is a pesticide used for repelling pests. Accidental or intentional intoxication can induce multiorgan toxicity and could be fatal. Curcumin (CUR) is a potent antioxidant, but its poor systemic bioavailability is the main drawback in its therapeutic uses. This study investigated the protective effect of CUR and N-CUR on CuSO 4 -induced cerebral oxidative stress, inflammation, and apoptosis in rats, pointing to the possible involvement of Akt/GSK-3β. Rats received 100 mg/kg CuSO 4 and were concurrently treated with CUR or N-CUR for 7 days. Cu-administered rats exhibited a remarkable increase in cerebral malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 associated with decreased GSH, SOD, and catalase. Cu provoked DNA fragmentation, upregulated BAX, caspase-3, and p53, and decreased BCL-2 in the brain of rats. N-CUR and CUR ameliorated MDA, NF-κB p65, and pro-inflammatory cytokines, downregulated pro-apoptotic genes, upregulated BCL-2, and enhanced antioxidants and DNA integrity. In addition, both N-CUR and CUR increased AKT Ser473 and GSK-3β Ser9 phosphorylation in the brain of Cu-administered rats. In conclusion, N-CUR and CUR prevent Cu neurotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis and upregulating AKT/GSK-3β signaling. The neuroprotective effect of N-CUR was more potent than CUR.

Copper (Cu) is essential for a plethora of biological processes; however, its high redox reactivity renders it potentially toxic. This study investigated the protective effect of curcumin (CUR) and nano-CUR (N-CUR) against Cu cardiotoxicity, emphasizing the role of oxidative stress, TLR4/NF-κB and mitogen-activated protein kinase (MAPK) signaling and cell death in rats. Rats received 100 mg/kg copper sulfate (CuSO 4 ), a pesticide used for repelling pests, and were concurrently treated with CUR or N-CUR for 7 days. Cu caused cardiac injury manifested by elevated serum cardiac troponin I (cTnI), creatine kinase (CK)-MB, and lactate dehydrogenase (LDH), as well as histopathological alterations. Cardiac malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 were increased, and reduced glutathione (GSH), superoxide dismutase (SOD) and catalase were decreased in Cu-treated rats. CUR and N-CUR prevented cardiac tissue injury, decreased serum cTnI, CK-MB, and LDH, and cardiac MDA, NF-κB p65, TNF-α, and IL-6, and enhanced cellular antioxidants. CUR and N-CUR downregulated TLR4 and AP-1, and decreased the phosphorylation levels of p38 MAPK, JNK, and ERK1/2. In addition, CUR and N-CUR increased cardiac Bcl-2 and BAG-1, decreased Bax and caspase-3, and prevented DNA fragmentation. In conclusion, N-CUR prevents Cu cardiotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis, and modulating TLR4/NF-κB and MAPK signaling. The cardioprotective effect of N-CUR was more potent than the native form.

Aim: Tamoxifen (TAMO) is a chemotherapeutic drug used for the treatment of breast cancer. Nevertheless, there is a lack of information available in regarding its nephrotoxicity. The purpose of this work was to investigate the impact of cyanocobalamin (COB) and/or calcitriol (CAL) injections on TAMO-induced nephrotoxicity., Main Methods: Animals were allocated into five groups as follows: normal control group; TAMO (45 mg/kg) administered group; TAMO+COB (6mg/kg, i.p) treated group; TAMO+CAL (0.3 μg/kg, i.p) treated group; TAMO+COB+CAL combination groups., Key Findings: Renal injury induced by TAMO was confirmed by the alteration in renal function parameters in the serum (urea and creatinine), as well as in the urine (creatinine clearance, total protein and albumin). These results were supported by histopathological examination. Upregulation of renal inflammatory parameters; tumor necrosis factor (TNF)-α, interleukin (IL)-6, C-reactive protein (CRP); and transforming growth factor (TGF)-β1 as well as in protein expression of nuclear factor-kappa B (NF-κB) and cleaved caspase-3 were observed to a greater extent in the TAMO-treated rats compared with the control. Renal fibrosis was also evidenced by a elevation in renal L-hydroxyproline level as well as by histomorphological collagen deposition in TAMO-treated groups compared to the control group. Administration of COB and/or CAL concurrently with TAMO significantly ameliorated the deviation in the above-studied parameters and improved the histopathological renal picture., Significance: Inhibition of NF-κβ-mediated inflammation and caspase-3-induced apoptosis are possible renoprotective mechanisms of COB and/or CAL against TAMO nephrotoxicity, which was more noticeable in the TAMO group treated with the combination of the two vitamins in question., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The current article was designed to assess the role of chitosan nanoparticles (CNPs) in the management of hepatic injury induced by the hepatocarcinogen 2-nitropropane (2-NP). Rats were divided into three groups. The first group served as a control, the second group was injected with 2-NP, while the third group was treated with CNPs 1 h before 2-NP injection every other day for 4 weeks. The 2-NP injection upregulated serum AST and ALT activities, as well as hepatic TNF- α, IL-6, and MDA levels and the expression of vascular endothelial growth factor (VEGF) and caspase-3, whereas GSH contents and SOD activity were decreased. Immunohistochemistry investigations revealed that the hepatic protein expression of collagen I, inducible nitric oxide synthetase, proliferating cell nuclear antigen, cluster of differentiation, and p53 were upregulated. hematoxylin and eosin (H&E) and Masson's trichrome stains supported the previous parameters, and CNPs ameliorated most of the previous biochemical parameters. CNPs achieved promising results in the limitation of 2-NP hepatotoxicity.

Hypoxia may lead to inflammatory responses by numerous signaling pathways. This investigation intended to inspect the defensive role of Quercetin (Quer) and/ or Melatonin (Mel) against reno toxicity induced by Sodium nitrite (Sod ntr). Sod ntr injection significantly decreased blood hemoglobin concentration (Hb) with a concurrent increase in serum tumor necrosis factor- α, interleukin-6, C-reactive protein, creatinine, and urea levels. Over protein-expression of vascular endothelial growth factor and heat shock, protein-70 and mRNA of HIF-1α were also observed. Pretreatment of the Sod ntr- injected rats with the aforementioned antioxidants; either alone or together significantly improved such parameters. Histopathological examination reinforced the previous results. It was concluded that the combined administration of Quer and Mel may be useful as a potential therapy against renal injury induced by Sod ntr. HIF-1α and HSP-70 are implicated in the induction of hypoxia and its treatment., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

The present work was aimed to evaluate the protective effects of alpha-tocopherol (α-toco) and/or Lactobacillus plantarum (LCB) against testicular atrophy induced by mercuric chloride (MCH). Rats were injected with 5 mg/kg MCH for 5 days consecutively, then treated with 100 mg/kg α-toco and 6 × 10 10 CFU 1.8701/kg LCB alone or together for 3 weeks. The MCH elevated serum TNF-α, IL- 6, caspase-3, and testicular malondialdehyde. However, serum testosterone, dehydroepiandrosterone, testicular messenger RNA of a steroidogenic acute regulatory protein, 17-β-hydroxysteroid dehydrogenase, 3β-hydroxysteroid dehydrogenase, glutathione level, and superoxide dismutase activity were decreased. Protein expression of Nrf2 was downregulated whereas that of Bax and DNA fragmentation was upregulated in the testicular tissues. Treatment with α-toco and LCB ameliorated the deviated biochemical parameters and improved tissue injury. It was concluded that the combination of LCB and α-toco achieved promising results in the amelioration of MCH-induced testicular atrophy. Nrf2, Bax expressions, and DNA fragmentation are involved in the testicular atrophy induced by MCH., (© 2020 Wiley Periodicals, Inc.)

Background: Lead is a dangerous systemic toxicant and can provoke life-threatening renal injury. The plan of this study was to evaluate the potential impact of curcumin (CRMN) and L-ascorbic acid (L-ascb) alone or together to counteract lead acetate (Pb-acetate)-induced renal damage in rats and to find out the underlying mechanisms of action of these nutraceuticals., Methods: Pb-acetate (100 mg/kg/day, i.p.) was injected in male rats along with L-ascb (250 mg/kg/day) and/or CRMN (200 mg/kg/day) orally for 7 days., Results: Pb-acetate administration increased serum urea, creatinine and uric acid. Renal tissue showed a marked depletion in reduced glutathione level and superoxide dismutase activity and elevation in nitric oxide and malondialdehyde levels. Serum C-reactive protein and IL-1β levels were elevated. Up-regulation of the expression of kidney injury molecule, vascular adhesion molecule-1 and Cystatin C were noticed after Pb-acetate administration. DNA fragmentation was also increased in renal tissues. Histopathological examination revealed a destructed partial layer of Bowman's capsule, proximal and distal convoluted tubules. Treatment with the aforementioned antioxidants ameliorated most of the altered measured biomarker levels., Conclusion: Interestingly, the combination of L-ascb and CRMN showed the superlative protective effect against Pb-acetate-induced nephrotoxicity.

Background: Lead is a common environmental and occupational pollutant which induced multiorgans dysfunction. The present study was designed to investigate the hepatoprotective effects of turmeric (TUR) and/or vitamin C (Vit-C) alone or together against lead acetate toxicity and to explore novel molecular pathways., Method: Acute hepatotoxicity was induced by lead acetate (100 mg/kg/day, i.p.) in male rats, and the effect of TUR (200 mg/kg/day, orally) and/or Vit-C (250 mg/kg/day, orally) along with lead acetate for 7 days was studied., Results: Lead acetate increased serum alanine transaminase, aspartate transaminase, lactate dehydrogenase, hepatic lipid peroxidation and nitric oxide; while, hepatic superoxide dismutase and glutathione activities were downregulated. Hepatic Bcl-2-associated X (Bax) and B-cell lymphoma-2 (Bcl-2) proteins expressions were altered and hepatic DNA damaged was increased as well. Liver/body weight ratio was decreased. Hematoxylin and eosin demonstrated that lead acetate induced focal areas of massive hepatic degeneration of the hepatocytes. Treatment with both antioxidants ameliorated all the altered parameters and induced marked improvement of liver architecture., Conclusion: The combination of TUR and Vit-C has shown the most protective effects against lead acetate-induced hepatotoxicity., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

The aim of the current study is to assess the effectiveness of milk thistle seeds (Mth) in combination with Taraxacum officinale ( Tof ) and/or Camellia sinensis ( Csin ) against tetrachloromethane (Tcm) renotoxicity in rats. Tetrachloromethane was injected in a single dose, followed by 1-month treatments with Mth, Tof , and Csin alone or in combination. Serum urea, uric acid, and creatinine levels were significantly increased matched with the control group. Masson trichrome stain revealed increase in the deposition of fibrous tissue in the interstitium between the tubules and the renal corpuscles. Immunohistochemical analysis of kidney tissues revealed that Tcm induced an increase in the immune response of tumor growth factor β (TGF-β) and Janus kinase (JAK) protein expressions and cysteine-aspartic acid protease 3 (caspase 3), while B-cell lymphoma 2 (Bcl2) was downregulated. Treatment with the antioxidants in question either alone or in combination ameliorated all kidney function parameters and showed mild immune reactivity toward TGF-β and JAK protein expressions in blood vessels and glomeruli in the kidney tissues and downregulated caspase 3 and activated Bcl2 protein expression. The combination regimen of the 3 antioxidants showed the most significant renoprotective effect. This was also confirmed histopathologically. It was concluded that the antioxidant mixture is considered as a promising candidate toward renal dysfunction and immune reactivity induced by Tcm and other toxicants., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The aim of the present work is to find the effects of N-acetylcysteine (NAC) and/or thymoquinone (THQ) in the protection against acute renal injury induced by sodium fluoride (NaF)., Method: Rats were distributed into five groups: G1 was normal (control), G2 was intoxicated with 10mg/kg NaF i.p., G3 was treated with 10mg THQ /kg, G4 was treated with 20mg NAC /kg, and G5 was treated with a combination of THQ and NAC. The previous treatments were given daily along with NaF for four weeks orally., Result: Rats intoxicated with NaF showed a significant increase in serum urea, creatinine, uric acid, renal lipid peroxidation, nitric oxide, and TNF- α levels, whereas the activity of superoxide dismutase (SOD) and glutathione (GSH) level was reduced. The expressions of Toll-like receptor-4 (TLR4), Lipocalin, vascular adhesion molecule-1(VCAM-1), and BAX proteins were upregulated, whereas Bcl-2 and NF-E2-related factor 2 (Nrf2) proteins expressions were downregulated. DNA fragmentation was also amplified. Histological analysis revealed that NaF caused a destructive renal cortex in the form of the glomerular corpuscle, the obliterated proximal and distal convoluted tubules, vacuolization in tubular cells focal necrosis, and cell infiltration. THQ and NAC supplementation counteracted NaF-induced nephrotoxicity as reflected by the increase in renal GSH and SOD. THQ and NAC ameliorated all the altered proteins expressions, improved renal architecture, and declined DNA fragmentation., Conclusion: The role of oxidative stress in the enhancement of NaF toxicity suggested the renoprotective effects of NAC and THQ against the toxicity of fluoride via multiple mechanisms.