Achillea millefolium ameliorates doxorubicin-induced renal injury via inhibition of oxidative stress and inflammation in rats.

Doxorubicin (Dox) is a potent anticancer medication. However, due to nephrotoxicity, its clinical application is restricted. Achillea millefolium (AM) is a plant used in traditional medicine to treat several conditions, including kidney disorders. The aim of this work was to investigate the preventative properties of AM extract (AME) and their mechanisms against nephrotoxicity caused by Dox in rats. The rats were assigned randomly to six groups, including a control group, Dox group (5 mg/kg/week via i.p. for 4 weeks), two groups receiving AME (100 or 200 mg/kg, orally for 28 days), and the last two groups receiving Dox + AME (100 or 200 mg/kg, orally for 4 weeks). After the treatment period concluded, samples of blood and renal tissue were collected for analysis. Serum creatinine, urea, and uric acid levels were used to determine nephrotoxicity biochemically. In renal tissue samples, superoxide dismutase (SOD), catalase, glutathione (GSH), glutathione peroxidase (GPx), total antioxidant capacity (TAC), nitric oxide (NOx), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and nuclear factor kappa B (NF-κB) were measured. Histopathological analysis of the kidneys was also performed. Dox caused a considerable increase in kidney function parameters and the occurrence of histological changes, which were significantly reversed by AME treatment. Mechanistically, Dox caused renal oxidative stress by raising malondialdehyde and NOx levels while lowering SOD, GSH, GPx, and TAC. It also caused inflammation via the stimulation of proinflammatory cytokines in renal tissues. Conversely, the treatment of AME mitigated Dox-evoked abnormalities in the above-mentioned tests. AME could protect against nephrotoxicity caused by Dox by reducing oxidative stress, stimulating antioxidant mechanisms, and suppressing proinflammatory cytokines, suggesting that AME may be useful as an adjuvant therapy for Dox-induced nephrotoxicity.

Shaiea M ，Dong Y ，Alomaisi S ，Al-Mahbashi H ，Zhang G ，Wang C ... -  《-》

Irvingia gabonensis Seed Extract: An Effective Attenuator of Doxorubicin-Mediated Cardiotoxicity in Wistar Rats.

Cardiotoxicity as an off-target effect of doxorubicin therapy is a major limiting factor for its clinical use as a choice cytotoxic agent. Seeds of Irvingia gabonensis have been reported to possess both nutritional and medicinal values which include antidiabetic, weight losing, antihyperlipidemic, and antioxidative effects. Protective effects of Irvingia gabonensis ethanol seed extract (IGESE) was investigated in doxorubicin (DOX)-mediated cardiotoxicity induced with single intraperitoneal injection of 15 mg/kg of DOX following the oral pretreatments of Wistar rats with 100-400 mg/kg/day of IGESE for 10 days, using serum cardiac enzyme markers (cardiac troponin I (cTI) and lactate dehydrogenase (LDH)), cardiac tissue oxidative stress markers (catalase (CAT), malonyldialdehyde (MDA), superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px), and reduced glutathione (GSH)), and cardiac histopathology endpoints. In addition, both qualitative and quantitative analyses to determine IGESE's secondary metabolites profile and its in vitro antioxidant activities were also conducted. Results revealed that serum cTnI and LDH were significantly elevated by the DOX treatment. Similarly, activities of tissue SOD, CAT, GST, and GSH levels were profoundly reduced, while GPx activity and MDA levels were profoundly increased by DOX treatment. These biochemical changes were associated with microthrombi formation in the DOX-treated cardiac tissues on histological examination. However, oral pretreatments with 100-400 mg/kg/day of IGESE dissolved in 5% DMSO in distilled water significantly attenuated increases in the serum cTnI and LDH, prevented significant alterations in the serum lipid profile and the tissue activities and levels of oxidative stress markers while improving cardiovascular disease risk indices and DOX-induced histopathological lesions. The in vitro antioxidant studies showed IGESE to have good antioxidant profile and contained 56 major secondary metabolites prominent among which are γ-sitosterol, Phytol, neophytadiene, stigmasterol, vitamin E, hexadecanoic acid and its ethyl ester, Phytyl palmitate, campesterol, lupeol, and squalene. Overall, both the in vitro and in vivo findings indicate that IGESE may be a promising prophylactic cardioprotective agent against DOX-induced cardiotoxicity, at least in part mediated via IGESE's antioxidant and free radical scavenging and antithrombotic mechanisms.

Olorundare O ，Adeneye A ，Akinsola A ，Kolo P ，Agede O ，Soyemi S ，Mgbehoma A ，Okoye I ，Albrecht R ，Mukhtar H ... -  《-》

Betaine alleviates doxorubicin-related cardiotoxicity via suppressing oxidative stress and inflammation via the NLRP3/SIRT1 pathway.

Cardiotoxicity is one of the side effects of the anti-cancer drug doxorubicin (DOX) that limits its clinical application. Betaine (BT) is a natural agent with promising useful effects against inflammation and oxidative stress (OS). We assessed the effects of BT on DOX-induced cardiotoxicity in mice. Forty-two male NMRI mice were assigned to six groups: I: control; II: BT (200 mg/kg; orally, alone); III: DOX (2.5 mg/kg; six injections (ip)) for two weeks; IV, V, VI: BT (50 mg/kg, 100 mg/kg, and 200 mg/kg; orally, once a day for two weeks, respectively) plus DOX administration. The cardiac enzymes like cardiac troponin-I (cTn-I), lactate dehydrogenase (LDH), and creatine kinase-MB (CK-MB) were assessed in serum. Oxidative/inflammatory markers like nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reduced glutathione level (GSH), and glutathione peroxidase (GPx) activities were determined in cardiac tissue. The expressions of NOD-like receptor protein 3 (NLRP3), caspase-1, interleukin (IL)-1β, and silent information regulator 1 (SIRT1) proteins were also evaluated in cardiac tissue. The results indicated that DOX significantly increased LDH, CK-MB, cTn-I, MDA, and NO levels and also the caspase-1, NLRP3, and IL-1β expression. Furthermore, DOX caused a significant reduction in the GSH levels and SOD, CAT, GPX activities, and the expression of SIRT1 protein in heart tissue. However, BT significantly improved all studied parameters. The findings were confirmed by histopathological assessments of the heart. BT can protect against DOX-induced cardiotoxicity by suppressing the activation of NLRP3 and OS by stimulating the SIRT1 pathway.

Mohammadpour YH ，Khodayar MJ ，Khorsandi L ，Kalantar H ... -  《-》

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 ... -  《-》

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 ... -  《-》