Blunting p38 MAPKα and ERK1/2 activities by empagliflozin enhances the antifibrotic effect of metformin and augments its AMPK-induced NF-κB inactivation in mice intoxicated with carbon tetrachloride

Abdelhamid, A. M.; Youssef, Mahmoud E.; El-Fattah, Eslam E. Abd; Gobba, Naglaa A.; Gaafar, Ahmed Gaafar Ahmed; Girgis, Samuel; Shata, Ahmed; Abdel-Moneim, Abdel-Moneim Hafez; El‐Ahwany, Eman; Amin, Noha A.; Shahien, Mohamed Awad; Abdel-Dayem, Marwa A.; Abou-Elrous, Magdy; Saber, Sameh

doi:10.1016/j.lfs.2021.120070

Cited by 30 publications

(20 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These inflammatory mediators stimulate the nociceptive neurons developing pain hypersensitivity (Ji and Suter 2007 ). Herein, EMPA ameliorated the deleterious effect of such inflammatory mediators through suppressing p-p38 MAPK/p-ERK1/2/p-NF-κB p65 expression, and this coincides with earlier studies displaying the potential impact of EMPA to treat inflammatory kidney diseases as well as hepatic inflammation and fibrosis via inhibition of this axis (Das et al 2020 ; Abdelhamid et al 2021 ).…”

Section: Discussionsupporting

confidence: 89%

Empagliflozin mitigates type 2 diabetes-associated peripheral neuropathy: a glucose-independent effect through AMPK signaling

et al. 2022

View full text Add to dashboard Cite

Diabetic peripheral neuropathy (DPN) represents a severe microvascular condition that dramatically affects diabetic patients despite adequate glycemic control, resulting in high morbidity. Thus, recently, anti-diabetic drugs that possess glucose-independent mechanisms attracted attention. This work aims to explore the potentiality of the selective sodium-glucose cotransporter-2 inhibitor, empagliflozin (EMPA), to ameliorate streptozotocin-induced DPN in rats with insight into its precise signaling mechanism. Rats were allocated into four groups, where control animals received vehicle daily for 2 weeks. In the remaining groups, DPN was elicited by single intraperitoneal injections of freshly prepared streptozotocin and nicotinamide (52.5 and 50 mg/kg, respectively). Then EMPA (3 mg/kg/p.o.) was given to two groups either alone or accompanied with the AMPK inhibitor dorsomorphin (0.2 mg/kg/i.p.). Despite the non-significant anti-hyperglycemic effect, EMPA improved sciatic nerve histopathological alterations, scoring, myelination, nerve fibers’ count, and nerve conduction velocity. Moreover, EMPA alleviated responses to different nociceptive stimuli along with improved motor coordination. EMPA modulated ATP/AMP ratio, upregulated p-AMPK while reducing p-p38 MAPK expression, p-ERK1/2 and consequently p-NF-κB p65 as well as its downstream mediators (TNF-α and IL-1β), besides enhancing SOD activity and lowering MDA content. Moreover, EMPA downregulated mTOR and stimulated ULK1 as well as beclin-1. Likewise, EMPA reduced miR-21 that enhanced RECK, reducing MMP-2 and -9 contents. EMPA’s beneficial effects were almost abolished by dorsomorphin administration. In conclusion, EMPA displayed a protective effect against DPN independently from its anti-hyperglycemic effect, probably via modulating the AMPK pathway to modulate oxidative and inflammatory burden, extracellular matrix remodeling, and autophagy.

show abstract

Section: Discussionsupporting

confidence: 89%

Empagliflozin mitigates type 2 diabetes-associated peripheral neuropathy: a glucose-independent effect through AMPK signaling

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Inflammation is another pathogenic scenario implicated in AA-induced colitis ( Saber et al, 2021c ; Bahrami et al, 2022 ). There is a close relationship between inflammation and oxidative stress ( Abdelhamid et al, 2021a ; Abdelhamid et al, 2021b ), where oxidative stress is connected to UC exacerbation by stimulating the overexpression of proinflammatory proteins, hence increasing inflammatory responses ( Bahrami et al, 2022 ). The NFκB signaling pathway has been reported to be activated by AA-administration ( Viennois et al, 2012 ; Rezayat et al, 2018 ; Rashidian et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…All protocols were performed in accordance with the manufacturer’s guidelines. An assay kit obtained from abcam was used for the assessment of nuclear translocation of p65 subunit in nuclear extracts in which a specific double stranded DNA sequence containing the NF-κB p65 consensus binding site (5′–GGGACTTTCC–3′) binds to the active NF-κB p65 which is detected by a primary antibody that recognizes an epitope of NF-κB p65 accessible only when the protein is activated and bound to its target DNA ( Abdelhamid et al, 2021b ). The NF-κB p65 activity was determined in duplicate.…”

Section: Methodsmentioning

confidence: 99%

Carbocisteine as a Modulator of Nrf2/HO-1 and NFκB Interplay in Rats: New Inspiration for the Revival of an Old Drug for Treating Ulcerative Colitis

et al. 2022

View full text Add to dashboard Cite

Ulcerative colitis (UC), an inflammatory bowel disease, is a chronic condition of a multifaceted pathophysiology. The incidence of UC is increasing internationally. The current therapies for UC lack relative effectiveness and are associated with adverse effects. Therefore, novel therapeutic options should be developed. It has been well documented that modulating the Nrf2/NFκB is a promising therapeutic target in inflammation. Carbocisteine is a mucoregulatory medication and its efficacy in COPD was found to be more closely related to its antioxidant and anti-inflammatory properties. Carbocisteine has not yet been examined for the management of UC. Hence, our approach was to investigate the potential coloprotective role of carbocisteine in acetic acid-induced colitis in rats. Our results revealed that carbocisteine improved colon histology and macroscopic features and subdued the disease activity as well. Additionally, carbocisteine attenuated colon shortening and augmented colon antioxidant defense mechanisms via upregulating catalase and HO-1 enzymes. The myeloperoxidase activity was suppressed indicating inhibition of the neutrophil infiltration and activation. Consistent with these findings, carbocisteine boosted Nrf2 expression along with NFκB inactivation. Consequently, carbocisteine downregulated the proinflammatory cytokines IL-6 and TNF-α and upregulated the anti-inflammatory cytokine IL-10. Concomitant to these protective roles, carbocisteine displayed anti-apoptotic properties as revealed by the reduction in the Bax: BCL-2 ratio. In conclusion, carbocisteine inhibited oxidative stress, inflammatory response, and apoptosis in acetic acid-induced UC by modulating the Nrf2/HO-1 and NFκB interplay in rats. Therefore, the current study provides a potential basis for repurposing a safe and a commonly used mucoregulator for the treatment of UC.

show abstract

“…In HCC, TGF-β is linked to immune cell exhaustion (Eslam E. Abd El-Fattah & Zakaria, 2022; Saber et al, 2021). TGF-β regulates immune cells in the liver, balancing immunological tolerance and activation (Youssef et al, 2021). TGF-β is a growth factor that controls immune cells (Fig.…”

Section: Transforming Growth Factor-beta (Tgf-β)mentioning

confidence: 99%

Immunomodulatory effect of ADO on liver tumor microenvironment

El-Fattah¹,

Goda²

2022

Delta University Scientific Journal

View full text Add to dashboard Cite

Liver cancer is affected by adenosine expression and metabolic byproducts. Cancer patients treated with different adenosine antagonists had their pathological alterations rectified by influencing proliferation, apoptosis, and angiogenesis. Our review focuses on new carcinogenic mechanisms driving adenosine activity, especially changes in immunological mediators and immune archetypes. In this study, we look at how adenosine affects the reprogramming of tumor immune cells like dendritic cells, T cells, Tregs, and neutrophils. This study covers current knowledge of the molecular mechanisms underlying adenosine's unique carcinogenic mechanisms via modification of the expression pattern of immune mediators in the tumor immune microenvironment, such as PD-1, CTLA-4, TGF-β, and IL-12, IL-23, and FOXP3. Adenosine reprograms tumor immunological architecture and mediators, making it a viable therapeutic target for tumor eradication through its multiple mechanisms of carcinogenicity.

show abstract

Blunting p38 MAPKα and ERK1/2 activities by empagliflozin enhances the antifibrotic effect of metformin and augments its AMPK-induced NF-κB inactivation in mice intoxicated with carbon tetrachloride

Cited by 30 publications

References 53 publications

Empagliflozin mitigates type 2 diabetes-associated peripheral neuropathy: a glucose-independent effect through AMPK signaling

Empagliflozin mitigates type 2 diabetes-associated peripheral neuropathy: a glucose-independent effect through AMPK signaling

Carbocisteine as a Modulator of Nrf2/HO-1 and NFκB Interplay in Rats: New Inspiration for the Revival of an Old Drug for Treating Ulcerative Colitis

Immunomodulatory effect of ADO on liver tumor microenvironment

Contact Info

Product

Resources

About