Inhibition of the JAK/STAT pathway by ruxolitinib ameliorates thioacetamide-induced hepatotoxicity

Shaker, Mohamed E.; Hazem, Sara H.; Ashamallah, Sylvia A.

doi:10.1016/j.fct.2016.08.018

Cited by 21 publications

(15 citation statements)

References 25 publications

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“…17,62,64,65 It has been shown that this alkaloid ameliorated inflammatory cells infiltration as well as prostaglandins and cytokines release. 17,64 Hepatic inflammation plays an essential role in the pathogenesis of liver injury in the thioacetamide model, 66 or other types of xenobiotics-induced hepatotoxicity. 27,67 In the current study we found that inflammatory cells infiltration was significantly lower in boldine-treated groups (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Boldine Supplementation Regulates Mitochondrial Function and Oxidative Stress in a Rat Model of Hepatotoxicity

et al. 2019

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Background: The xenobiotics-induced liver injury is a clinical complication. Hence, finding new hepatoprotective strategies has clinical value. Oxidative stress and its subsequent complications are major mechanisms involved in xenobiotics-induced hepatotoxicity. Boldine is one of the most potent antioxidant molecules widely investigated for its protective properties in different experimental models. In the current study, the hepatoprotective properties of boldine and its potential mechanisms of hepatoprotection have been investigated. Methods: Rats received thioacetamide (TAA; 200 mg/kg, i.p) as a model of acute liver injury. Boldine (5, 10, 1nd 20 mg/kg; 24 hours intervals; oral) was administered as the hepatoprotective agent. Results: Liver injury was evident in TAA-treated animals (48 hours after TAA exposure) as a severe increase in serum level of liver injury biomarkers and histopathological alterations. Moreover, markers of oxidative stress were increased in liver tissue of TAA-treated rats. Assessment of mitochondrial indices of functionality revealed a significant decrease in mitochondrial dehydrogenases activity, the collapse of mitochondrial membrane potential, mitochondrial swelling and depletion of ATP content. It was found that boldine supplementation mitigated liver tissue markers of oxidative stress and improved mitochondrial indices of functionality in TAA-treated animals. Conclusion: The hepatoprotective properties of boldine might primarily rely on antioxidant and mitochondria protecting effects of this alkaloid.

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Section: Discussionmentioning

confidence: 99%

Boldine Supplementation Regulates Mitochondrial Function and Oxidative Stress in a Rat Model of Hepatotoxicity

et al. 2019

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“…Consistent with this, preclinical experiments have shown that treatment with ruxolitinib, a JAK1/2 inhibitor, prevented liver toxicity in mice treated with known hepatotoxic agents. 28,29 Although the possibility that JAK inhibition exerts a hepatoprotective effect is interesting, this finding may instead reflect divergent populations or other factors related to prior treatment or histology.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Phillips

Forero‐Torres

Sher

et al. 2018

Blood

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Because both phosphatidylinositol 3-kinase δ (PI3Kδ) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose-escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3Kδ inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas. Final results are reported. Overall, 114 patients were treated (monotherapy, n = 49; combination therapy, n = 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily + itacitinib 300 mg once daily (combination) were the recommended phase 2 doses. One dose-limiting toxicity (gastrointestinal bleed secondary to gastric diffuse large B-cell lymphoma [DLBCL] regression) occurred with monotherapy. The most common serious adverse events with monotherapy were pneumonia (n = 5) and pyrexia (n = 4), and with combination pneumonia (n = 5), pneumonia (unrelated to; n = 5), and pyrexia (n = 4). Grade 3 or higher transaminase elevations were less common with combination. INCB040093 was active across the B-cell lymphomas; 63% of patients (5/8) with follicular lymphoma responded to monotherapy. Adding itacitinib provided promising activity in select subtypes, with responses of 67% (14/21) in classic Hodgkin lymphoma (vs 29% [5/17] with monotherapy) and 31% (4/13) in nongerminal center B-cell-like DLBCL. INCB040093 with/without itacitinib was tolerated and active in this study, and is a promising treatment strategy for patients with select R/R B-cell lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT01905813.

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“…Agents such as rosiglitazone and rapamycin demonstrated the potential to interfere with the fibrogenic pathways by reducing the expression of TGF-β ( 195 , 208 ). Others such as the ruxolitinib have also shown the potential to inhibit the hepatotoxicity and fibrogenesis, after initial injury by multiple agents, by inhibiting the JAK/STAT pathway ( 207 , 209 , 210 ).…”

Section: Mechanisms and Pathways Linking The Th17/il-17 Axis To Fibromentioning

confidence: 99%

Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis

Paquissi

2017

Front. Immunol.

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Cirrhosis is a common final pathway for most chronic liver diseases; representing an increasing burden worldwide and is associated with increased morbidity and mortality. Current evidence has shown that, after an initial injury, the immune response has a significant participation in the ongoing damage, and progression from chronic viral hepatitis (CVH) to cirrhosis, driving the activation and maintenance of main fibrogenic pathways. Among immune deregulations, those related to the subtype 17 of T helper lymphocytes (Th17)/interleukin-17 (IL-17) axis have been recognized as key immunopathological and prognostic elements in patients with CVH. The Th17/IL-17 axis has been found involved in several points of fibrogenesis chain from the activation of stellate cells, increased expression of profibrotic factors as TGF-β, promotion of the myofibroblastic or epithelial–mesenchymal transition, stimulation of the synthesis of collagen, and induction of imbalance between matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). It also promotes the recruitment of inflammatory cells and increases the expression of proinflammatory cytokines such as IL-6 and IL-23. So, the Th17/IL-17 axis is simultaneously the fuel and the flame of a sustained proinflammatory and profibrotic environment. This work aims to present the immunopathologic and prognostic role of the Th17/IL-17 axis and related pathways in fibrogenesis and progression to cirrhosis in patients with liver disease due to hepatitis B virus (HBV) and hepatitis C virus (HCV).

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Inhibition of the JAK/STAT pathway by ruxolitinib ameliorates thioacetamide-induced hepatotoxicity

Cited by 21 publications

References 25 publications

Boldine Supplementation Regulates Mitochondrial Function and Oxidative Stress in a Rat Model of Hepatotoxicity

Boldine Supplementation Regulates Mitochondrial Function and Oxidative Stress in a Rat Model of Hepatotoxicity

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis

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