Nephroprotective Potential of 1,3,4-Oxadiazole Derivative Against Methotrexate-Induced Nephrotoxicity in Rats by Upregulating Nrf2 and Downregulating NF-κB and TNF-α Signaling Pathways.

Nephrotoxicity is a prominent complication of methotrexate (MTX) therapy that limits clinicians in its extensive use. MTX triggers oxidative burden and inflammation, so the nephroprotective potential of the synthetic derivative of 1,3,4-oxadiazole (5b) was explored in this research. Male Wistar rats were divided into four groups i.e., control group, MTX group, 5b (5 mg/kg) + MTX group and 5b (10 mg/kg) + MTX group, respectively. All treatments were given, intraperitoneally (i.p.) during 12 days of the animal model. The MTX-induced nephrotoxicity was evaluated by renal function markers i.e., serum creatinine (Cret), blood urea nitrogen (BUN), and albumin (Alb). Furthermore, antioxidant markers, catalase (CAT), glutathione-S-transferase (GST), and reduced glutathione (GSH), and oxidative stress, markers lipid peroxidase (LPO) and nitric oxide (NO), were analyzed. Pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were also calculated. DNA damage was assessed by the comet assay. Histopathological staining (Hematoxylin and eosin, Masson's trichrome) was done and immunohistochemistry was performed against Caspase-3, Nrf2, HO-1, TLR-4, TNF-α, and NF-κB. A significant improvement in the serum Cret, BUN, and Alb was observed in (5b) treated groups. Antioxidant markers were elevated, oxidative stress markers and pro-inflammatory cytokines were reduced, moreover, histopathological analysis revealed less tissue damage in (5b) administered groups. Immunohistochemistry showed increased immune expression of Nrf2 and HO-1 and decreased expression of TLR-4, TNF-α, Caspase-3, and NF-κB in 5b (5 mg/kg) + MTX group and 5b (10 mg/kg) + MTX group as compared to the MTX group. Hence, the results of this study favor the use of (5b) against MTX-induced nephrotoxicity.

Rafique Z ，Aabid M ，Nadeem H ，Rehman A ，Khan JZ ，Waqas M ，Irshad N ... -  《-》

Urolithin B as a renoprotective agent against 5-fluorouracil-induced nephrotoxicity: Role of Nrf2/Keap1/HO-1, SIRT1/FOXO3, and NF-кB/TNF-α signaling pathways.

The clinical use of 5-fluorouracil (5-FU) in cancer patients has been associated with nephrotoxicity, which is greatly curbing its therapeutic application. The pathogenesis of 5-FU-induced nephrotoxicity is complex; however, oxidative stress-mediated inflammation is considered a central pathogenic factor. Urolithin B (UB), a product of ellagitannins, has recently been assigned diverse pharmacological activities due to its potent antioxidant and anti-inflammatory properties. Therefore, the current study explored the potential renoprotective effect of UB on 5-FU-induced nephrotoxicity in mice and illuminated its potential mechanistic pathways. In this study, administration of UB (50 and 100 mg/kg) mitigated 5-FU-induced elevated levels of kidney injury indices, including renal somatic index, serum creatinine, blood urea nitrogen, and serum cystatin C, that were concurrent with histopathological improvement. UB maintained renal oxidant/antioxidant balance and enhanced the nuclear factor-erythroid-2-related factor-2 (Nrf2)/heme oxygenase 1 (HO-1) as well as the silent information regulator factor 2-related enzyme 1 (SIRT1)/forkhead box O 3 (FOXO3) antioxidant protective responses. On the other hand, 5-FU-driven activation of the NF-кB/TNF-α inflammatory signaling was opposed by UB administration. Conclusively, UB protected against 5-FU-induced nephrotoxicity through dose-dependent antioxidant and anti-inflammatory effects. These effects are mediated mainly through upregulating Nrf2/HO-1 and SIRT-1/FOXO3 antioxidant responses with subsequent suppression of NF-κB inflammatory signaling.

Al-Rabia MW ，Asfour HZ ，Mansouri RA ，Abdulaal WH ，Choudhry H ，El-Agamy DS ，Alhakamy NA ，Alrabea RN ，Mosaoa RM ，Mohamed GA ，Ibrahim SRM ，Elshal M ... -  《-》

The power of trans-sodium crocetinate: exploring its renoprotective effects in a rat model of colistin-induced nephrotoxicity.

Colistin, a multidrug-resistant gram-negative bacterial infection medication, has been associated with renal impairment and failure. Trans-sodium crocetinate (TSC), a saffron-derived chemical recognized for its antioxidant and nephroprotective properties, was studied in this study to determine its potential to alleviate the nephrotoxic effects of colistin. Forty-two male Wistar rats were randomly classified into seven groups (n = 6): (1) control (normal saline, 12 days, i.p.), (2) colistin (22 mg/kg, 7 days, i.p.), (3-5) colistin + TSC (25, 50, and 100 mg/kg, 12 days, i.p., starting from 5 days before colistin), (6) TSC (100 mg/kg, 12 days, i.p.), (7) colistin + vitamin E (100 IU/kg, 12 days, i.p). On day 13, the rats were euthanized and the serum content of creatinine, BUN, Na+, and K+, as well as oxidative stress (GSH, MDA, SOD, CAT), inflammatory (IL-1β), apoptotic (Bax, Bcl-2, caspase-3, 8, 9), and autophagy (Beclin-1, LC3) markers, NGAL, and histopathological changes in the kidney were measured. Colistin significantly increased serum creatinine, BUN, MDA, IL-1β, caspase-3,8,9, Bax, Beclin-1, LC3, and NGAL levels in kidney tissue. It also caused inflammation, focal necrosis of tubular epithelial cells, protein cast, and acute tubular necrosis. Furthermore, colistin decreased SOD, CAT, GSH, and Bcl-2 levels. TSC and vitamin E administration along with colistin restored most of the alterations induced by colistin. Overall, it could be concluded that colistin induces oxidative stress, inflammation, autophagy, and apoptosis, which can cause kidney injury. However, TSC can also be used as a therapeutic agent to reduce injuries caused by colistin.

Naraki K ，Ghasemzadeh Rahbardar M ，Razavi BM ，Aminifar T ，Khajavi Rad A ，Amoueian S ，Hosseinzadeh H ... -  《-》

Linalool may have a therapeutic effect on cadmium-induced nephrotoxicity by regulating NF-κB/TNF and GRP78/CHOP signaling pathways.

Cadmium (Cd) is an environmental pollutant heavy metal with nephrotoxic effect. One of the primary constituents of essential oils is Linalool (Lin), a monoterpene having a variety of pharmacological properties including antimicrobial, anti-inflammatory, and antioxidant effects. The purpose of this study was to ascertain how Lin affected endoplasmic reticulum stress (ERS) and pro-inflammatory mediators in Cd-induced nephrotoxicity. In the experiment, 28 male rats were randomly divided into four equal groups as control (no application), Cd (Cd at a dose of 3 mg/kg for the first 7 days), Cd+Lin (Cd at a dose of 3 mg/kg for the first 7 days and 100 mg/kg/day Lin) and Lin (100 mg/kg/day Lin) (n=7). The experiment was completed on the 15th day after all treatments were performed. Blood serum and kidney tissue samples were used for analyses. Cd-induced histopathological changes, inflammation, oxidative stress, and apoptosis were determined to increase in kidney tissue. However, it was observed that Cd-induced adverse effects in kidney tissue were mainly eliminated by Lin treatment. In conclusion, Lin demonstrated anti-inflammatory, anti-oxidant and anti-apoptotic effects in Cd-induced nephrotoxicity. Therefore, we believe that Lin may represent a high potential therapeutic strategy against renal tissue damage.

Kaya S ，Yalçın T 《-》

The administration of Glycyrrhiza polysaccharides mitigates liver injury in mice caused by mancozeb via the Keap1-Nrf2/NF-κB pathway.

The extensive utilization of mancozeb (MCZ) poses environmental pollution risks, threatens human health, particularly hepatotoxicity. Glycyrrhiza polysaccharides (GP) exhibit antioxidant, anti-inflammatory and other biological activities. The aim of this study is to explore the mechanism of liver injury in mice exposed to MCZ and the protective effect of GP on alleviating MCZ induced liver injury. Initially, 70 female mice were divided into 7 groups, and the optimal dose of MCZ induced liver injury in mice was screened by oral administration different doses of MCZ (0, 50, 100, 150, 200, 250 and 300 mg/kg MCZ). The results demonstrated that, compared to the blank control group, as the concentration of MCZ increased, several physiological and biochemical parameters were significantly affected. Specifically, body weight and liver index significantly decreased, while the activities of SOD and CAT also decreased. Additionally, the content of ROS increased, the levels of Keap1 and Nrf2 proteins increased, the mRNA levels of Gpx2 and HO-1decreased, and the mRNA levels of Gstt2, GcLc and NQO1 were upregulated. Based on the test data, select 100 mg/kg MCZ as the optimal modeling dose for experimental animals. Sixty female mice were divided into six groups and orally administered: control group A (0.2 mL deionized water), model group B (100 mg/kg MCZ), positive control group F (100 mg/kg MCZ+100 mg/kg VC), the high-dose GP group C (100mg/kgMCZ+200mg/kgGP), the medium-dose GP group D (100 mg/kg MCZ+150mg/kgGP) and the low-dose GP group E (100 mg/kg MCZ+100mg/kgGP). The results showed that compared to the model group, adding GP alleviated the effects of MCZ on body weight, liver index, CAT and SOD activity, MDA content, HO-1, TNF-α, and IL-1β. Additionally, the addition of GP decreased the expression of Keap1, Nrf2, NF-kB, and NQO1, GcLc, and Gstt2 mRNA. GP ameliorated liver vacuolar degeneration, steatosis and nuclear pyknosis ameliorate by MCZ. The results show that MCZ triggers hepatotoxicity via the activation of the Keap1/Nrf2 signaling pathway, whereas GP has the potential to mitigate liver damage caused by MCZ exposure by inhibiting this pathway.

Gao N ，Li Y ，Zhang L ，Zhang Y ，Wang X ... -  《-》