Amelioration of cyclosporine‐induced testicular toxicity by carvedilol and/or alpha‐lipoic acid: Role of TGF‐β1, the proinflammatory cytokines, Nrf2/HO‐1 pathway and apoptosis

Kabel, Ahmed M.; Salama, Samir A.; Alghorabi, Amal A.; Estfanous, Remon S.

doi:10.1111/1440-1681.13281

Cited by 16 publications

(20 citation statements)

References 33 publications

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“…[54,55] F I G U R E 8 Graphical representation of the possible cascades or pathways involved in the hepatoprotective effect of nilotinib against cyclosporine-A-induced liver injury. ALT, alanine aminotransferase; AST, aspartate aminotransferase; Bax, Bcl2-associated X; GSH, reduced glutathione; HO-1, hemoxygenase-1; IL-2, interleukin-2; MDA, malondialdehyde; NF-κB, nuclear factor-κB; Nrf2, nuclear factor erythroid-2 like-2; ROS, reactive oxygen species; TAC, total antioxidant capacity; γ-GT, Y-glutamyl transferase To elucidate the possible ameliorative effect of nilotinib treatment in CsA-injected rats, Nrf2 and OH-1 were addressed in the present study as CsA-treated group presented a significant reduction in nrf2 protein level and a marked decrease in mRNA expression and immunoreactivity against HO-1 in the hepatic tissue of rats and this was consistent with the previous studies which showed that CsA markedly decreased the nuclear expression of Nrf2 in rat kidneys [56][57][58] decreased Nrf2/HO-1 content in rat testicular tissue, [59] and decreased the ratio of nuclear/ total Nrf2 and HO-1 expression in rat kidney. [57,58] In the present study, nilotinib administration seems to increase Nrf2 levels in comparison to CsA-treated rats and it is considered as an Nrf2 activator.…”

Section: Effects Of Nilotinib On Histopathological Examinationsupporting

confidence: 89%

Hepatoprotective effect of the tyrosine kinase inhibitor nilotinib against cyclosporine‐A induced liver injury in rats through blocking the Bax/Cytochrome C/caspase‐3 apoptotic signaling pathway

Serrya

Nader

Abdelmageed

2021

J Biochem & Molecular Tox

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Cyclosporine-A (CsA) is a powerful immunosuppressive agent and hepatotoxicity results from CsA treatment. This study aimed to elucidate the effectiveness of tyrosine kinase inhibitor nilotinib against CsA-induced hepatotoxicity and the underlying molecular mechanisms. Male Sprague-Dawley rats were allocated into four groups and received drugs for 28 days as follows: Control group: received vehicle, Nilotinib group: received nilotinib (20 mg/kg orally), CsA group: received CsA by subcutaneous injection (20 mg/kg daily), CsA-nilotinib: received nilotinib and CsA. Serum lactate dehydrogenase (LDH), liver function biomarkers, hepatic levels of oxidative stress biomarkers, nuclear factor erythroid-2 like-2 (Nrf2), total antioxidant capacity (TAC), interleukin-2 (IL-2), IL-1β, IL-6, and cytochrome-C were assessed. Additionally, the protein levels and mRNA expression of Bcl2 associated X protein (Bax), caspase-3, nuclear factor-κB (NF-κB), hemoxygenase-1 (HO-1) were measured. Moreover, liver tissues were assessed histopathologically using hematoxylin-eosin and Masson trichrome stain. Nilotinib treatment decreased serum LDH, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase (γ-GT), hepatic malondialdehyde, and cytochrome-C. It also increased superoxide dismutase, reduced glutathione, glutathione reductase, glutathione peroxidase, glutathione-S-transferase (GST), TAC, and Nrf2 compared to CsA-injected rats.In addition, nilotinib decreased NF-κB, IL-1β, IL-6, Bax, and caspase-3, while elevated IL-2 and immunoexpression of HO-1. Additionally, mRNA expression of Bax and caspase-3 was elevated and that of HO-1 and inhibitory protein κB-α was reduced in the nilotinib-treated group. Moreover, nilotinib significantly attenuated CsA-induced histopathological alterations. Nilotinib may have a promising role as a hepato-protective through its antiapoptotic, antioxidant, and anti-inflammatory effects.

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Section: Effects Of Nilotinib On Histopathological Examinationsupporting

confidence: 89%

Hepatoprotective effect of the tyrosine kinase inhibitor nilotinib against cyclosporine‐A induced liver injury in rats through blocking the Bax/Cytochrome C/caspase‐3 apoptotic signaling pathway

Serrya

Nader

Abdelmageed

2021

J Biochem & Molecular Tox

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“…In addition to its antioxidant efficacy, ALA has been widely studied for its anti-inflammatory and anti-apoptotic impacts in various disease models [13,[52][53][54]. In this context, ALA demonstrated protective efficacy against CsA-induced renal [55], pancreatic [56], testicular [57], and neurological toxicity [58]. Similarly, ALA in the present study protected against CsA-induced liver injury through modulation of oxidative stress, inflammation, and apoptosis.…”

Section: Discussionsupporting

confidence: 67%

α-Lipoic Acid Protects against Cyclosporine A-Induced Hepatic Toxicity in Rats: Effect on Oxidative Stress, Inflammation, and Apoptosis

El-Mancy

Elsherbini

Al-Serwi

et al. 2022

Toxics

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The clinical application of cyclosporine A (CsA) as an immunosuppressive agent is limited by its organ toxicity. We aimed to evaluate the effectiveness of α-lipoic acid against CsA-induced hepatotoxicity and to delineate the underlying molecular mechanisms. Male Wistar rats (n = 24, 8 per each group) received the vehicle, CsA (25 mg/kg) and/or ALA (100 mg/kg, p.o.) for 3 weeks. Biochemical markers of liver function (serum ALT, AST, ALP < GGT), oxidative stress (MDA, TAC, SOD, GSH, Nrf2/HO-1), inflammation (NF-κB, CD68, iNOS, NO, COX-2), and apoptosis (caspase-3) were assessed in serum and tissue. Liver histological analysis using H&E and Sirius red was performed. The development of liver injury in CsA-treated animals was indicated by elevated levels of liver enzymes, oxidants/antioxidants imbalance, inflammatory cells infiltration, up-regulated expression of inflammatory mediators, and apoptosis. These changes were associated with altered architecture of hepatic cells and fibrous connective tissue. ALA co-administration protected against CsA-induced liver damage and ameliorated biochemical changes and cellular injury. In conclusion, ALA demonstrated hepatoprotective potential against CsA-induced liver injury through combating oxidative stress, inflammation, and apoptosis, highlighting ALA as a valuable adjunct to CsA therapy.

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“…Combined therapy with clopidogrel and irbesartan was found to inhibit nephritis by abolishing macrophage infiltration and thus to reduce early kidney damage caused by nephrectomy [136]. There are also some contradictory observations regarding the irbesartan ability to influence the concentration of CRP, TGF-β, TNF-alfa, IL-6, and the expression of NF-κB, ICAM-1, VCAM-1, and MCP-1 [137][138][139][140][141].…”

Section: Candesartan Irbesartanmentioning

confidence: 99%

Immunomodulatory Activity of the Most Commonly Used Antihypertensive Drugs—Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

Bryniarski

Nazimek

Marcinkiewicz

2022

IJMS

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This review article is focused on antihypertensive drugs, namely angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), and their immunomodulatory properties reported in hypertensive patients as well as in experimental settings involving studies on animal models and cell lines. The immune regulatory action of ACEI and ARB is mainly connected with the inhibition of proinflammatory cytokine secretion, diminished expression of adhesion molecules, and normalization of CRP concentration in the blood plasma. The topic has significant importance in future medical practice in the therapy of patients with comorbidities with underlying chronic inflammatory responses. Thus, this additional effect of immune regulatory action of ACEI and ARB may also benefit the treatment of patients with metabolic syndrome, allergies, or autoimmune disorders.

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Amelioration of cyclosporine‐induced testicular toxicity by carvedilol and/or alpha‐lipoic acid: Role of TGF‐β1, the proinflammatory cytokines, Nrf2/HO‐1 pathway and apoptosis

Cited by 16 publications

References 33 publications

Hepatoprotective effect of the tyrosine kinase inhibitor nilotinib against cyclosporine‐A induced liver injury in rats through blocking the Bax/Cytochrome C/caspase‐3 apoptotic signaling pathway

Hepatoprotective effect of the tyrosine kinase inhibitor nilotinib against cyclosporine‐A induced liver injury in rats through blocking the Bax/Cytochrome C/caspase‐3 apoptotic signaling pathway

α-Lipoic Acid Protects against Cyclosporine A-Induced Hepatic Toxicity in Rats: Effect on Oxidative Stress, Inflammation, and Apoptosis

Immunomodulatory Activity of the Most Commonly Used Antihypertensive Drugs—Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

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