Activation of autophagy by sitagliptin attenuates cadmium-induced testicular impairment in rats: Targeting AMPK/mTOR and Nrf2/HO-1 pathways

Arab, Hany H.; Gad, Amany M.; Reda, Enji; Yahia, Rania; Eid, Ahmed M.

doi:10.1016/j.lfs.2021.119031

Cited by 42 publications

(39 citation statements)

References 52 publications

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“…The sections were examined under a light microscope complemented with a full-HD microscopic imaging system (Leica Microsystems, Wetzlar, GmbH, Germany). The digital pictures were analyzed for positive protein staining using Image J software (Bethesda, MD, USA) to quantify the target protein expression [ 26 ]. Quantification of target protein was performed by detecting the optical density of the brown immunostaining.…”

Section: Methodsmentioning

confidence: 99%

Camel Milk Mitigates Cyclosporine-Induced Renal Damage in Rats: Targeting p38/ERK/JNK MAPKs, NF-κB, and Matrix Metalloproteinases

Arab

Ashour

Alqarni

et al. 2021

Biology

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Renal damage is a devastating adverse effect for cyclosporine; a widely used immunosuppressant drug. The present work examined the potential of camel milk, a natural agent with marked anti-inflammatory/antioxidant properties, to attenuate cyclosporine-induced renal injury. The kidney tissue was examined with the aid of Western blotting, immunohistochemistry, biochemical assays, including colorimetric and ELISA kits. The present findings revealed that camel milk (10 mL/kg/day; for 3 weeks by gavage) significantly lowered serum creatinine, BUN, and KIM-1 renal dysfunction markers. Mechanistically, camel milk inhibited renal inflammation, as seen by significant decrease of the pro-inflammatory cytokines (MCP-1, TNF-α, IL-1β, and IL-18) and extracellular degradation signals (MMP-2 and MMP-9) and enhanced the generation of the anti-inflammatory IL-10. Moreover, it inhibited the upstream pro-inflammatory p38/ERK/JNK MAPK pathway by lowering the phosphorylation of the 3 subfamilies of MAPKs (p38 MAPK, JNK1/2, and ERK1/2). Furthermore, camel milk curbed the NF-κB pathway activation by downregulating the protein expression of activated NF-κBp65, p-NF-κBp65, and p-IκBα proteins. Additionally, camel milk inhibited renal oxidative stress by lowering the MPO activity and augmenting the reduced/oxidized glutathione ratio and total antioxidant capacity. These findings propose that camel milk may be a promising agent that inhibits cyclosporine-triggered renal inflammation via curtailing the p38/ERK/JNK MAPK and NF-κB pathways, matrix metalloproteinases, and pro-inflammatory cytokines.

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Section: Methodsmentioning

confidence: 99%

Camel Milk Mitigates Cyclosporine-Induced Renal Damage in Rats: Targeting p38/ERK/JNK MAPKs, NF-κB, and Matrix Metalloproteinases

Arab

Ashour

Alqarni

et al. 2021

Biology

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“…Four‐micrometer sections were used for the immunohistochemical labeling of target proteins. Blocking of the sections was performed with 5% BSA for 2 hr, as reported (Arab et al., 2021; Fikry et al., 2019). Primary antibody incubation was carried out overnight at 4°C in a moist chamber using anti‐PCNA and anti‐Bax antibodies (Thermo Scientific).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of oxidative stress and apoptosis by camel milk mitigates cyclosporine‐induced nephrotoxicity: Targeting Nrf2/HO‐1 and AKT/eNOS/NO pathways

Arab

Eid

Gad

et al. 2021

Food Science & Nutrition

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Cyclosporine (CsA) is a widely used immunosuppressive agent that incurs marked nephrotoxicity in the clinical setting. Thus, there is a need for finding safe/effective agents that can attenuate CsA‐induced kidney injury. Meanwhile, the underlying mechanisms for CsA‐associated nephrotoxicity are inadequately investigated, in particular, the AKT/eNOS/NO pathway. Here, the present work aimed to explore the potential of camel milk, a natural product with distinguished antioxidant/anti‐inflammatory actions, to ameliorate CsA‐induced nephrotoxicity in rats. The molecular mechanisms related to renal oxidative aberrations and apoptosis were studied, including Nrf2/HO‐1 and AKT/eNOS/NO pathways. The kidney tissues were inspected using histopathology, ELISA, Western blotting, and immunohistochemistry. The present findings demonstrated that camel milk (10 ml/kg) significantly lowered creatine, BUN, and NGAL nephrotoxicity markers and the aberrant histopathology, with similar efficacy to the reference quercetin. Moreover, camel milk suppressed the renal oxidative stress, as evidenced by significantly lowering NOX‐1 and lipid peroxides and significantly augmenting the renal antioxidant moieties (GSH, GPx, and SOD), thereby, driving the restoration of Nrf2/HO‐1 pathway. Meanwhile, camel milk counteracted the pro‐apoptotic reactions by significantly lowering Bax protein expression, caspase‐3 activity/cleavage, and PARP cleavage, alongside significantly increasing the expression of the proliferation signal PCNA. Regarding the anti‐apoptotic AKT/eNOS/NO pathway, camel milk activated its signaling by significantly increasing the protein expression of PI3Kp110, p‐AKT(Ser473)/total AKT, and p‐eNOS (Ser1177)/total eNOS besides significantly boosting the renoprotective NO levels. In conclusion, these findings reveal that camel milk may be a promising candidate for the alleviation of CsA‐induced nephrotoxicity.

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“…Concurrently, cadmium exposure triggered Beclin 1 upregulation, a critical regulator of autophagosome sequestration [ 14 ] in testes of rats. In cadmium intoxication models, impaired autophagy flux [ 17 , 18 ], as well as overactive autophagy [ 15 , 16 ] have been characterized, pointing to the need for supplemental studies for determining the exact role of autophagy in the pathology of testicular dysfunction provoked by cadmium. In line with the present findings of impaired testicular autophagy, the literature has revealed that defective autophagy impacts the later stages of spermatogenesis, resulting in defective acrosome biogenesis, spermatogenesis suppression, and rodent infertility [ 17 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…In cadmium intoxication models, impaired autophagy flux [ 17 , 18 ], as well as overactive autophagy [ 15 , 16 ] have been characterized, pointing to the need for supplemental studies for determining the exact role of autophagy in the pathology of testicular dysfunction provoked by cadmium. In line with the present findings of impaired testicular autophagy, the literature has revealed that defective autophagy impacts the later stages of spermatogenesis, resulting in defective acrosome biogenesis, spermatogenesis suppression, and rodent infertility [ 17 , 18 ]. In the same regard, excessive germ cell apoptosis, spermatogenic failure, and accumulation of damaged mitochondria have been characterized by defective testicular autophagy in rodents [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, evidence also exists that excessive autophagy is envisioned as a cell-death pathway, advocating the notion that autophagy may be a double-edged sword under testicular pathological conditions [ 14 ]. Coinciding with these studies, overactive autophagy [ 15 , 16 ], as well as disrupted autophagy flux [ 17 , 18 ], have been elucidated in animal models of cadmium-induced testicular injury. Therefore, supplementary studies are required for exploration of the exact role of autophagy in mediating cadmium toxicity in vivo in rats.…”

Section: Introductionmentioning

confidence: 99%

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Repositioning Linagliptin for the Mitigation of Cadmium-Induced Testicular Dysfunction in Rats: Targeting HMGB1/TLR4/NLRP3 Axis and Autophagy

et al. 2022

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Cadmium, a ubiquitous environmental toxicant, disrupts testicular function and fertility. The dipeptidyl peptidase-4 inhibitor linagliptin has shown pronounced anti-inflammatory and anti-apoptotic features; however, its effects against cadmium-evoked testicular impairment have not been examined. Herein, the present study investigated targeting inflammation, apoptosis, and autophagy by linagliptin for potential modulation of cadmium-induced testicular dysfunction in rats. After 60 days of cadmium chloride administration (5 mg/kg/day, by gavage), testes, epididymis, and blood were collected for analysis. The present findings revealed that linagliptin improved the histopathological lesions, including spermatogenesis impairment and germ cell loss. Moreover, it improved sperm count/motility and serum testosterone. The favorable effects of linagliptin were mediated by curbing testicular inflammation seen by dampening of HMGB1/TLR4 pathway and associated lowering of nuclear NF-κBp65. In tandem, linagliptin suppressed the activation of NLRP3 inflammasome/caspase 1 axis with consequent lowering of the pro-inflammatory IL-1β and IL-18. Jointly, linagliptin attenuated testicular apoptotic responses seen by Bax downregulation, Bcl-2 upregulation, and suppressed caspase 3 activity. With respect to autophagy, linagliptin enhanced the testicular autophagy flux seen by lowered accumulation of p62 SQSTM1 alongside upregulation of Beclin 1. The observed autophagy stimulation was associated with elevated AMPK (Ser487) phosphorylation and lowered mTOR (Ser2448) phosphorylation, indicating AMPK/mTOR pathway activation. In conclusion, inhibition of testicular HMGB1/TLR4/NLRP3 pro-inflammatory axis and apoptosis alongside stimulation of autophagy were implicated in the favorable actions of linagliptin against cadmium-triggered testicular impairment.

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Activation of autophagy by sitagliptin attenuates cadmium-induced testicular impairment in rats: Targeting AMPK/mTOR and Nrf2/HO-1 pathways

Cited by 42 publications

References 52 publications

Camel Milk Mitigates Cyclosporine-Induced Renal Damage in Rats: Targeting p38/ERK/JNK MAPKs, NF-κB, and Matrix Metalloproteinases

Camel Milk Mitigates Cyclosporine-Induced Renal Damage in Rats: Targeting p38/ERK/JNK MAPKs, NF-κB, and Matrix Metalloproteinases

Inhibition of oxidative stress and apoptosis by camel milk mitigates cyclosporine‐induced nephrotoxicity: Targeting Nrf2/HO‐1 and AKT/eNOS/NO pathways

Repositioning Linagliptin for the Mitigation of Cadmium-Induced Testicular Dysfunction in Rats: Targeting HMGB1/TLR4/NLRP3 Axis and Autophagy

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