scholarly journals The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jinrui Dong ◽  
Sivakumar Viswanathan ◽  
Eleonora Adami ◽  
Sebastian Schafer ◽  
Fathima F Kuthubudeen ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Competitive Inhibition ◽  
Hepatic Regeneration ◽  
Drug Induced ◽  
Erk Activation ◽  
Drug Induced Liver Injury ◽  
Beneficial Effects ◽  
Stat3 Signaling ◽  
Mouse Hepatocytes ◽  
Target Effects

It is generally accepted that IL6-mediated STAT3 signaling in hepatocytes, mediated via glycoprotein 130 (gp130; IL6ST), is beneficial and that the synthetic IL6:IL6ST fusion protein (HyperIL6) promotes liver regeneration. Recently, autocrine IL11 activity that also acts via IL6ST but uses ERK rather than STAT3 to signal, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11-dependent IL6ST signaling. In human and mouse hepatocytes, HyperIL6 reduced N-acetyl-p-aminophenol (APAP)-induced cell death independent of STAT3 activation and instead, dose-dependently, inhibited IL11-related signaling and toxicities. In mice, expression of HyperIl6 reduced ERK activation and promoted STAT3-independent hepatic regeneration (PCNA, Cyclin D1, Ki67) following administration of either IL11 or APAP. Inhibition of putative intrinsic IL6 trans-signaling had no effect on liver regeneration in mice. Following APAP, mice deleted for Il11 exhibited spontaneous liver repair but HyperIl6, despite robustly activating STAT3, had no effect on liver regeneration in this strain. These data show that synthetic IL6ST binding proteins such as HyperIL6 can have unexpected, on-target effects and suggest IL11, not IL6, as important for liver regeneration.

scholarly journals Overturning the paradigm that IL6 signaling drives liver regrowth while shining light on a new therapeutic target for regenerative medicine

2021 ◽  
Author(s):  
Jinrui Dong ◽  
Sivakumar Viswanathan ◽  
Eleonora Adami ◽  
Sebastian Schafer ◽  
Fathima Farzana Kuthubudeen ◽  
...  
Keyword(s):  
Cell Death ◽  
Regenerative Medicine ◽  
Beneficial Effect ◽  
Liver Regeneration ◽  
Competitive Inhibition ◽  
Hepatic Regeneration ◽  
Independent Manner ◽  
Beneficial Effects ◽  
Stat3 Phosphorylation ◽  
Spontaneous Regeneration

It is accepted that IL6 signaling in hepatocytes, mediated via glycoprotein 130 (gp130), is beneficial and that HyperIL6 promotes liver regeneration by activating STAT3. Recently, autocrine IL11 activity, which also signals via gp130 and ERK, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11 signaling. In hepatocytes, HyperIL6 inhibited N-acetyl-p-aminophenol (APAP)-induced cell death that mimicked inhibition of IL11 signaling and was unrelated to STAT3 phosphorylation. In mice, expression of HyperIL6 reduced liver damage due to IL11 dosing or APAP and promoted hepatic regeneration in a STAT3-independent manner. Following APAP, mice deleted for Il11 were protected from liver failure and exhibited spontaneous regeneration. Despite robustly activating STAT3, HyperIL6 had no beneficial effect in Il11 null mice. These data overturn the premise that IL6 promotes liver regeneration, show STAT3 activation to be redundant and suggest IL11 as a focus for regenerative medicine.

scholarly journals Impact of pharmacological agents on mitochondrial function: a growing opportunity?

2019 ◽  
Vol 47 (6) ◽  
pp. 1757-1772 ◽  
Author(s):  
Megan L. Stoker ◽  
Emma Newport ◽  
James C. Hulit ◽  
A. Phillip West ◽  
Karl J. Morten
Keyword(s):  
Side Effects ◽  
Mitochondrial Function ◽  
Immune Modulation ◽  
Antiviral Agents ◽  
Aging Population ◽  
Drug Induced ◽  
Pharmacological Agents ◽  
Beneficial Effects ◽  
Drug Classes ◽  
Target Effects

Present-day drug therapies provide clear beneficial effects as many diseases can be driven into remission and the symptoms of others can be efficiently managed; however, the success of many drugs is limited due to both patient non-compliance and adverse off-target or toxicity-induced effects. There is emerging evidence that many of these side effects are caused by drug-induced impairment of mitochondrial function and eventual mitochondrial dysfunction. It is imperative to understand how and why drug-induced side effects occur and how mitochondrial function is affected. In an aging population, age-associated drug toxicity is another key area of focus as the majority of patients on medication are older. Therefore, with an aging population possessing subtle or even more dramatic individual differences in mitochondrial function, there is a growing necessity to identify and understand early on potentially significant drug-associated off-target effects and toxicity issues. This will not only reduce the number of unwanted side effects linked to mitochondrial toxicity but also identify useful mitochondrial-modulating agents. Mechanistically, many successful drug classes including diabetic treatments, antibiotics, chemotherapies and antiviral agents have been linked to mitochondrial targeted effects. This is a growing area, with research to repurpose current medications affecting mitochondrial function being assessed in cancer, the immune system and neurodegenerative disorders including Parkinson's disease. Here, we review the effects that pharmacological agents have on mitochondrial function and explore the opportunities from these effects as potential disease treatments. Our focus will be on cancer treatment and immune modulation.

scholarly journals N-Acetyl Cysteine as an Adjunct in the Treatment of Tuberculosis

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Dawit A. Ejigu ◽  
Solomon M. Abay
Keyword(s):  
Oxidative Stress ◽  
Hearing Loss ◽  
Multidrug Resistant ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Beneficial Effects ◽  
Tb Treatment ◽  
Mdr Tb ◽  
Acetyl Cysteine ◽  
Karnofsky Performance Index

Oxidative stress is a common feature of tuberculosis (TB), and persons with reduced antioxidants are at more risk of TB. TB patients with relatively severe oxidative stress had also more advanced disease as measured by the Karnofsky performance index. Since adverse effects from anti-TB drugs are also mediated by free radicals, TB patients are prone to side effects, such as hearing loss. In previous articles, researchers appealed for clinical trials aiming at evaluating N-acetyl cysteine (NAC) in attenuating the dreaded hearing loss during multidrug-resistant TB (MDR-TB) treatment. However, before embarking on such trials, considerations of NAC’s overall impact on TB treatment are crucial. Unfortunately, such a comprehensive report on NAC is missing in the literature and this manuscript reviews the broader effect of NAC on TB treatment. This paper discusses NAC’s effect on mycobacterial clearance, hearing loss, drug-induced liver injury, and its interaction with anti-TB drugs. Based on the evidence accrued to date, NAC appears to have various beneficial effects on TB treatment. However, despite the favorable interaction between NAC and first-line anti-TB drugs, the interaction between the antioxidant and some of the second-line anti-TB drugs needs further investigations.

scholarly journals Liver Regeneration after Hepatectomy and Partial Liver Transplantation

2020 ◽  
Vol 21 (21) ◽  
pp. 8414
Author(s):  
Shintaro Yagi ◽  
Masaaki Hirata ◽  
Yosuke Miyachi ◽  
Shinji Uemoto
Keyword(s):  
Liver Transplantation ◽  
Liver Injury ◽  
Liver Regeneration ◽  
Drug Induced ◽  
Venous Flow ◽  
Tissue Ischemia ◽  
Drug Induced Liver Injury ◽  
Partial Liver Transplantation ◽  
Clinical Conditions ◽  
Distinct Features

The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration after a viral- or drug-induced liver injury, that of post-PHx or -PLTx has several distinct features, such as hemodynamic changes in portal venous flow or pressure, tissue ischemia/hypoxia, and hemostasis/platelet activation. Although some of these changes also occur during liver regeneration after a viral- or drug-induced liver injury, they are more abrupt and drastic following PHx or PLTx, and can thus be the main trigger and driving force of liver regeneration. In this review, we first provide an overview of the molecular biology of liver regeneration post-PHx and -PLTx. Subsequently, we summarize some clinical conditions that negatively, or sometimes positively, interfere with liver regeneration after PHx or PLTx, such as marginal livers including aged or fatty liver and the influence of immunosuppression.

scholarly journals Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models

2014 ◽  
Vol 5 (3) ◽  
pp. 76 ◽  
Author(s):  
Cheau Tan ◽  
Ruenn Lai ◽  
Winnie Wong ◽  
Yock Dan ◽  
Sai-Kiang Lim ◽  
...  
Keyword(s):  
Stem Cell ◽  
Liver Injury ◽  
Mesenchymal Stem Cell ◽  
Hepatic Regeneration ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Injury Models

scholarly journals Beneficial effects of α-lipoic acid in diabetes- and drug- induced liver injury

2018 ◽  
Vol 70 (4) ◽  
pp. 621-628
Author(s):  
Aleksandra Uskokovic ◽  
Svetlana Dinic ◽  
Nevena Grdovic ◽  
Jelena Arambasic-Jovanovic ◽  
Melita Vidakovic ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Damage ◽  
Lipoic Acid ◽  
Drug Toxicity ◽  
Tissue Injury ◽  
Redox Homeostasis ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Beneficial Effects ◽  
Slowing Down

This review summarizes the effects of ?-lipoic acid (LA) on liver damage and complications in diabetes and drug toxicity. LA is a naturally occurring dithiol compound that plays an essential role in mitochondrial metabolism in its protein-bound form. In contrast, free LA in supplements has diverse biological actions, and its antioxidant effect is its most studied and important activity. Due to its strong antioxidant potential, LA could have a promising role in the treatment of pathologies resulting from an imbalance in redox homeostasis. This includes diabetes, which produces deleterious effects on many organs, including the liver. In diabetes specifically, LA prevents ?-cell destruction, enhances glucose uptake, and its antioxidant effects may be particularly useful in slowing down the development of diabetic complications. Diabetesrelated liver damage is a serious complication in which oxidative stress is the main contributor to tissue injury. Oxidative stress is regarded as one of the main pathological mechanisms underlying liver pathologies provoked by other insults, such as drug toxicity, where LA could also be a useful agent in therapeutic intervention. However, before wider application of LA in a clinical setting, experimental and clinical research needs to be extended.

Leberschaden unter oraler Antikoagulation, Statin- und ACE-Hemmertherapie

Praxis ◽  
2010 ◽  
Vol 99 (21) ◽  
pp. 1259-1265 ◽  
Author(s):  
Bruggisser ◽  
Terraciano ◽  
Rätz Bravo ◽  
Haschke
Keyword(s):  
Liver Injury ◽  
Wird Eine ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Ein 71-jähriger Patient stellt sich mit Epistaxis und ikterischen Skleren auf der Notfallstation vor. Der Patient steht unter einer Therapie mit Phenprocoumon, Atorvastatin und Perindopril. Anamnestisch besteht ein langjähriger Alkoholabusus. Laborchemisch werden massiv erhöhte Leberwerte (ALAT, Bilirubin) gesehen. Der INR ist unter oraler Antikoagulation und bei akuter Leberinsuffizienz >12. Die weiterführenden Abklärungen schliessen eine Virushepatitis und eine Autoimmunhepatitis aus. Nachdem eine Leberbiopsie durchgeführt werden kann, wird eine medikamentös-toxische Hepatitis, ausgelöst durch die Komedikation von Atorvastatin, Phenprocoumon und Perindopril bei durch Alkohol bereits vorgeschädigter Leber diagnostiziert. Epidemiologie, Pathophysiologie und Klink der medikamentös induzierten Leberschäden (drug induced liver injury, DILI), speziell von Coumarinen, Statinen und ACE-Hemmern werden im Anschluss an den Fallbericht diskutiert.

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