LP340, a novel histone deacetylase inhibitor, decreases liver injury and fibrosis in mice: role of oxidative stress and microRNA-23a DOI Creative Commons

Devadoss J. Samuvel,

John J. Lemasters, C. James Chou

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: May 17, 2024

Effective therapy for liver fibrosis is lacking. Here, we examined whether LP340, the lead candidate of a new-generation hydrazide-based HDAC1,2,3 inhibitors (HDACi), decreases fibrosis. Liver was induced by CCl 4 treatment and bile duct ligation (BDL) in mice. At 6 weeks after , serum alanine aminotransferase increased, necrotic cell death leukocyte infiltration occurred liver. Tumor necrosis factor-α myeloperoxidase markedly indicating inflammation. After weeks, α-smooth muscle actin (αSMA) collagen-1 expression increased 80% 575%, respectively, hepatic stellate (HSC) activation fibrogenesis. Fibrosis detected trichrome Sirius-red staining primarily pericentral regions with some bridging sections. 4-Hydroxynonenal adducts (indicator oxidative stress), profibrotic cytokine transforming growth factor-β (TGFβ), TGFβ downstream signaling molecules phospho-Smad2/3 also increased. LP340 attenuated indices injury, inflammation, markedly. Moreover, Ski-related novel protein-N (SnoN), an endogenous inhibitor signaling, decreased, whereas SnoN suppressor microRNA-23a (miR23a) (0.05 mg/kg, ig., daily during last 2 treatment) decreased 4-hydroxynonenal miR23a production, blunted decreases, inhibited TGFβ/Smad signaling. By contrast, had no effect on matrix metalloproteinase-9 expression. histone-3 acetylation but not tubulin acetylation, that Class-I Class-II HDAC vivo . BDL, focal necrosis, ductular reactions, portal at αSMA 256% 560%, respectively. prevented BDL. In vitro immortal human cells (hTERT-HSC) culture (αSMA expression) as well demonstrating its direct inhibitory effects HSC. conclusions, promising both fibrosis, it works inhibiting stress decreasing miR23a.

Language: Английский

Emerging advanced approaches for diagnosis and inhibition of liver fibrogenesis DOI Creative Commons

Tamer A. Addissouky,

Majeed M. A. Ali, Ibrahim El Tantawy El Sayed

et al.

The Egyptian Journal of Internal Medicine, Journal Year: 2024, Volume and Issue: 36(1)

Published: Feb. 12, 2024

Abstract Background Liver fibrosis results from chronic liver injury and is characterized by excessive deposition of extracellular matrix proteins including collagen. It can progress to cirrhosis failure. Main body the abstract Multiple cellular signaling pathways drive hepatic stellate cell activation fibrogenesis. Advances in biomarkers, imaging modalities, omics platforms enable noninvasive diagnosis staging fibrosis. Emerging antifibrotic approaches include medications like pirfenidone, obeticholic acid, monoclonal antibodies targeting pro-fibrotic mediators. Cell therapies using mesenchymal stem cells demonstrate potential through paracrine immunosuppression. Tissue-engineered grafts biomaterial carriers for localized drug delivery are promising technologies. Microfluidic liver-on-a-chip with patient-derived provide unprecedented models study human test candidates. Short conclusion Significant has elucidated mechanisms underlying fibrogenesis uncovered novel therapeutic targets. Ongoing challenges translating preclinical findings, improving efficacy, enabling personalized precision medicine approaches. Further research into combinatorial therapies, tissue engineering technologies will advance treatment all causes.

Language: Английский

Citations

9
NAFLD Fibrosis Progression and Type 2 Diabetes: The Hepatic–Metabolic Interplay DOI Creative Commons
Simona Cernea

Life, Journal Year: 2024, Volume and Issue: 14(2), P. 272 - 272

Published: Feb. 18, 2024

The bidirectional relationship between type 2 diabetes and (non-alcoholic fatty liver disease) NAFLD is indicated by the higher prevalence worse disease course of one condition in presence other, but also apparent beneficial effects observed one, when other improved. This partly explained their belonging to a multisystemic that includes components metabolic syndrome shared pathogenetic mechanisms. Throughout progression more advanced stages, complex systemic local derangements are involved. During fibrogenesis, significant reprogramming occurs hepatic stellate cells, hepatocytes, immune engaging carbohydrate lipid pathways support high-energy-requiring processes. natural history evolves variable dynamic manner, probably due interaction number modifiable (diet, physical exercise, microbiota composition, etc.) non-modifiable (genetics, age, ethnicity, risk factors may intervene concomitantly, or subsequently/intermittently time. influence (and rate) fibrosis progression/regression. recognition control determine rapid (or its regression) critical, as stages associated with liver-related all-cause mortality.

Language: Английский

Citations

8
Advances in liver organoids: replicating hepatic complexity for toxicity assessment and disease modeling DOI Creative Commons
Weidong Shao, Hui Xu,

Kanghua Zeng

et al.

Stem Cell Research & Therapy, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 26, 2025

The lack of in vivo accurate human liver models hinders the investigation liver-related diseases, injuries, and drug-related toxicity, posing challenges for both basic research clinical applications. Traditional cellular animal models, while widely used, have significant limitations replicating liver's complex responses to various stressors. Liver organoids derived from pluripotent stem cells, adult cells primary or tissues can mimic diverse cell types, major physiological functions, architectural features. Recent advancements field shown that some sufficient accuracy replicate specific aspects complexity. This review highlights recent progress organoid research, with a particular emphasis on their potential toxicity assessment disease modeling. intrinsic advantages include higher sensitivity suitability long-term studies, which enhance predictive value drug nanomaterial testing. integration microfluidic devices enables simulation microenvironment facilitates high-throughput screening. also serve as ideal platforms studying diseases such hepatitis, fibrosis, viral monogenic diseases. Additionally, this discusses along avenues future research.

Language: Английский

Citations

1
Fibrosis: cross-organ biology and pathways to development of innovative drugs DOI
Florian Rieder, Laura E. Nagy, Toby M. Maher

et al.

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Language: Английский

Citations

1
Preclinical Promise and Clinical Challenges for Innovative Therapies Targeting Liver Fibrogenesis DOI Creative Commons

Tamer A. Addissouky,

Majeed M. A. Ali, Ibrahim El Tantawy El Sayed

et al.

Archives of Gastroenterology Research, Journal Year: 2023, Volume and Issue: 4(1), P. 14 - 23

Published: Nov. 14, 2023

Liver fibrosis resulting from chronic liver injury can progress to cirrhosis and failure. Current treatments are limited, creating an urgent need for novel antifibrotic therapies. Multiple emerging approaches have shown preclinical promise in inhibiting fibrogenesis or stimulating regeneration, including artificial support, stem cell therapy, cell/gene nanomedicines, immunotherapy, herbal medicines. Artificial support provides detoxification but has inconsistent transplant bridging benefits. Stem transplantation demonstrates paracrine effects differentiation potential. Cell therapy with hepatocytes modulatory immune cells, as well genetic engineering approaches, aims replace damaged cells suppress inflammation. Nanoparticles enable targeted delivery of drugs genes. Immunotherapy using checkpoint inhibitors, vaccines, engineered attenuate fibrogenesis-related Some traditional Chinese formulas compounds exhibit antifibrotic, anti-inflammatory, regenerative mechanisms. Despite encouraging data, most therapies yet achieve clinical translation, limited by challenges safety, delivery, efficacy. Combination treatment regimens may provide maximal therapeutic impact. Ongoing optimization rigorous evaluation needed develop effective new patients disease.

Language: Английский

Citations

21
Interleukins in liver disease treatment DOI Open Access
Ming Yang, Chunye Zhang

World Journal of Hepatology, Journal Year: 2024, Volume and Issue: 16(2), P. 140 - 145

Published: Feb. 27, 2024

Cytokines play pleiotropic roles in human health and disease by regulating both innate adaptive immune responses. Interleukins (ILs), a large group of cytokines, can be divided into seven families, including IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, IL-17 families. Here, we review the functions ILs pathogenesis resolution liver diseases, such as inflammation (e.g. , IL-35), alcohol-related IL-11), non-alcoholic steatohepatitis IL-22), fibrosis Il-17a), cancer IL-8). Overall, IL-1 family members are implicated induced different etiologies, alcohol consumption, high-fat diet, hepatitis viruses. IL-2 mainly regulate T lymphocyte NK cell proliferation activation, differentiation cells. IL-6 cytokines important acute phase response infection, regeneration, metabolic regulation, well activation. also known CXCL8, is activated chronic which associated with accumulation neutrophils macrophages. IL-10 contribute key to tolerance immunosuppression disease. IL-12 influence T-cell an essential role autoimmune subfamilies infection defense, inflammation, Th17 differentiation. interact type I II cytokine receptors intracellular signaling pathways that mediate their functions. However, most clinical studies only performed evaluate IL-mediated therapies on virus infection-induced hepatitis. More pre-clinical required monotherapy synergistic therapies.

Language: Английский

Citations

7
Can Nutraceuticals Support the Treatment of MASLD/MASH, and thus Affect the Process of Liver Fibrosis? DOI Open Access
Aneta Sokal, Sara Jarmakiewicz-Czaja, Katarzyna Ferenc

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5238 - 5238

Published: May 11, 2024

Currently, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are considered to be the main causes of fibrosis. In turn, fibrosis may lead development hepatocellular carcinoma or advanced cirrhosis, i.e., potentially life-threatening conditions. It is likely that therapy aimed at reducing risk developing hepatic steatosis inflammation could helpful in minimizing threat/probability organ recent years, increasing attention has been paid influence nutraceuticals prevention treatment diseases. Therefore, aim this review was describe precise role selected ingredients such as vitamin C, beta-carotene, omega-3 fatty acids, curcumin. use these patients with MASLD/MASH, along behavioral pharmacological therapy, have a beneficial effect on combating inflammation, oxidative stress, thereby preventing damage.

Language: Английский

Citations

7
Adjuvant and neoadjuvant therapies for hepatocellular carcinoma DOI
Arndt Vogel, Robert C. Grant, Tim Meyer

et al.

Hepatology, Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 18, 2023

Immune-oncology–based regimens have shown efficacy in advanced HCC and been implemented as standard of care first-line therapy. Their efficacy, including high response rates, safety justify their evaluation earlier disease stages. Following negative results for adjuvant sorafenib the global STORM trial 2015, 4 phase 3 trials, featuring different immune checkpoint inhibitor combinations, entered parallel race setting. The IMbrave050 trial, comparing atezolizumab combination with bevacizumab to active surveillance following curative-intent resection or ablation, was first report, fast-tracking interim analysis demonstrating an improvement recurrence-free survival. has provoked a discussion on horizon expectations from treatment clinical relevance endpoints. Moreover, major pathological responses reported early 2 data neoadjuvant setting provide strong rationale these concepts trials. In this review, we summarize current evidence outline future directions systemic therapies early-stage HCC.

Language: Английский

Citations

14
Investigating the Antifibrotic Effects of β-Citronellol on a TGF-β1-Stimulated LX-2 Hepatic Stellate Cell Model DOI Creative Commons
Watunyoo Buakaew, Sucheewin Krobthong, Yodying Yingchutrakul

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(7), P. 800 - 800

Published: July 5, 2024

Liver fibrosis, a consequence of chronic liver damage or inflammation, is characterized by the excessive buildup extracellular matrix components. This progressive condition significantly raises risk severe diseases like cirrhosis and hepatocellular carcinoma. The lack approved therapeutics underscores urgent need for novel anti-fibrotic drugs. Hepatic stellate cells (HSCs), key players in fibrogenesis, are promising targets drug discovery. study investigated potential Citrus hystrix DC. (KL) its bioactive compound, β-citronellol (β-CIT), human HSC cell line (LX-2). Cells exposed to TGF-β1 induce fibrogenesis were co-treated with crude KL extract β-CIT. Gene expression was analyzed real-time qRT-PCR assess fibrosis-associated genes (ACTA2, COL1A1, TIMP1, SMAD2). release metalloproteinase 9 (MMP-9) measured ELISA. Proteomic analysis molecular docking identified signaling proteins modeled protein–ligand interactions. results showed that both β-CIT suppressed activation MMP-9 levels. MAPK pathway emerged as target demonstrates ability inhibit during TGF-β1-induced suggesting role anti-hepatic fibrosis therapies.

Language: Английский

Citations

5
Roles of transforming growth factor-β signaling in liver disease DOI Open Access
Xiaoling Wang, Meng Yang, Ying Wang

et al.

World Journal of Hepatology, Journal Year: 2024, Volume and Issue: 16(7), P. 973 - 979

Published: July 26, 2024

In this editorial we expand the discussion on article by Zhang

Language: Английский

Citations

5