Pentoxifylline inhibits liver fibrosis via hedgehog signaling pathway

Li, Hui; Hua, Juan; Guo, Chunmei; Wang, Weixian; Wang, Baoju; Yang, Dongliang; Wei, Ping; Lu, Yinping

doi:10.1007/s11596-016-1594-7

Cited by 12 publications

(8 citation statements)

References 29 publications

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“…The effect of PDE inhibitor, pentoxifylline, on HSC activation and trans-differentiation and the development of fibrosis was also demonstrated in In vitro and in vivo studies, supporting the role of PDE inhibition as a protective mechanism in liver fibrosis [174–178]. More recently, a study demonstrated that pentoxifylline suppressed TGF-β1 expression in activated LX-2 hepatic stellate cells by inhibiting the pro-fibrogenic hedgehog signaling pathway [179]. In addition, pentoxifylline has also been reported to improve complications such as bacterial infection and renal dysfunction in patients with advanced cirrhosis [180].…”

Section: Therapeutic Interventions Via Camp Signalingmentioning

confidence: 89%

Role of cAMP and phosphodiesterase signaling in liver health and disease

Wahlang

McClain

Barve

et al. 2018

Cellular Signalling

108

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Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.

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Section: Therapeutic Interventions Via Camp Signalingmentioning

confidence: 89%

Role of cAMP and phosphodiesterase signaling in liver health and disease

Wahlang

McClain

Barve

et al. 2018

Cellular Signalling

108

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“…3 D). As previously proposed for in vivo experiments 61 , 62 , we evaluated the effect of the immunomodulatory agent Pentoxifylline combined with Bz treatment. The concentrations of 0.125 mg/mL and 0.250 mg/mL did not affect cell viability (Fig.…”

Section: Resultsmentioning

confidence: 99%

Modulation of miR-145-5p and miR-146b-5p levels is linked to reduced parasite load in H9C2 Trypanosoma cruzi infected cardiomyoblasts

Farani

Ferreira

Gibaldi

et al. 2022

Sci Rep

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In the heart tissue of acutely Trypanosoma cruzi-infected mice miR-145-5p and miR-146b-5p are, respectively, downregulated and upregulated. Here, we used the H9C2 rat cardiomyoblast cell line infected with the Colombian T. cruzi strain to investigate the parasite-host cell interplay, focusing on the regulation of miR-145-5p and miR-146b-5p expression. Next, we explored the effects of interventions with the trypanosomicidal drug Benznidazole (Bz) alone or combined with Pentoxifylline (PTX), a methylxanthine derivative shown to modulate immunological and cardiac abnormalities in a model of chronic chagasic cardiomyopathy, on parasite load and expression of miR-145-5p and miR-146b-5p. The infection of H9C2 cells with trypomastigote forms allowed parasite cycle with intracellular forms multiplication and trypomastigote release. After 48 and 144 h of infection, upregulation of miR-145-5p (24 h: 2.38 ± 0.26; 48 h: 3.15 ± 0.9-fold change) and miR-146b-5b (24 h: 2.60 ± 0.46; 48 h: 2.97 ± 0.23-fold change) was detected. The peak of both miRNA levels paralleled with release of trypomastigote forms. Addition of 3 µM and 10 µM of Bz 48 h after infection reduced parasite load but did not interfere with miR-145-5p and miR-146b-5p levels. Addition of PTX did not interfere with Bz-induced parasite control efficacy. Conversely, combined Bz + PTX treatment decreased the levels of both microRNAs, resembling the expression levels detected in non-infected H9C2 cells. Moreover, the use of miR-145-5p and miR-146b-5p mimic/inhibitor systems before infection of H9C2 cells decreased parasite load, 72 h postinfection. When H9C2 cells were treated with miR-145-5p and miR-146b-5p mimic/inhibitor 48 h after infection, all the used systems, except the miR-146b-5p inhibitor, reduced parasite load. Altogether, our data indicate that these microRNAs putatively control signaling pathways crucial for parasite–host cell interaction. Thus, miR-145-5p and miR-146b-5p deserve to be further investigated as biomarkers of parasite control and tools to identify therapeutic adjuvants to etiological treatment in Chagas disease.

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“…In addition, it exerts an anti-inflammatory regulation by affecting TGF-β- and tissue inhibitor metalloproteinase-1 (TIMP-1) expressions. Beneficial effects in humans with advanced liver disease have been described ( 68 ), and regulating effects of the hepatic stellate cell activity, is suggested to be related to the Hedgehog signalling pathway ( 86 ).…”

Section: Resultsmentioning

confidence: 99%

Novel Anti-inflammatory Treatments in Cirrhosis. A Literature-Based Study

et al. 2021

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Liver cirrhosis is a disease characterised by multiple complications and a poor prognosis. The prevalence is increasing worldwide. Chronic inflammation is ongoing in liver cirrhosis. No cure for the inflammation is available, and the current treatment of liver cirrhosis is only symptomatic. However, several different medical agents have been suggested as potential healing drugs. The majority are tested in rodents, but few human trials are effectuated. This review focuses on medical agents described in the literature with supposed alleviating and curing effects on liver cirrhosis. Twelve anti-inflammatory, five antioxidative, and three drugs with effects on gut microflora and the LPS pathway were found. Two drugs not categorised by the three former categories were found in addition. In total, 42 rodent studies and seven human trials were found. Promising effects of celecoxib, aspirin, curcumin, kahweol, pentoxifylline, diosmin, statins, emricasan, and silymarin were found in cirrhotic rodent models. Few indices of effects of etanercept, glycyrrhizin arginine salt, and mitoquinone were found. Faecal microbiota transplantation is in increasing searchlight with a supposed potential to alleviate cirrhosis. However, human trials are in demand to verify the findings in this review.

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Pentoxifylline inhibits liver fibrosis via hedgehog signaling pathway

Cited by 12 publications

References 29 publications

Role of cAMP and phosphodiesterase signaling in liver health and disease

Role of cAMP and phosphodiesterase signaling in liver health and disease

Modulation of miR-145-5p and miR-146b-5p levels is linked to reduced parasite load in H9C2 Trypanosoma cruzi infected cardiomyoblasts

Novel Anti-inflammatory Treatments in Cirrhosis. A Literature-Based Study

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