Integrative approach to alcohol-related liver fibrosis: natural compounds modulating oxidative stress and ferroptosis.

Hepatic fibrosis (HF) is a critical marker of advanced‑stage chronic liver disease and involves pivotal contributions from hepatic stellate cells (HSCs). Currently, there are no effective treatments for HF. Umbelliferone (7‑hydroxycoumarin; UMB) is a natural compound with significant anti‑inflammatory, antioxidant and anti‑tumor activities. However, its potential efficacy in treating HF has not been studied. The present study explored the protective effects of UMB against HF, targeting the TGF‑β1‑Smad signaling pathway to explore the underlying mechanisms of UMB. Carbon tetrachloride (CCl4) was injected intraperitoneally to induce HF in rats and primary HSCs were treated in vitro with UMB to investigate the improvement effect of UMB on HF. The levels of fibrosis markers, inflammation, oxidative stress and TGF‑β1‑Smad signaling pathway in the rat liver tissue and HSCs were detected using hematoxylin and eosin staining, enzyme‑linked immunosorbent assay, reverse transcription‑quantitative PCR, Cell Counting Kit‑8 and western blotting. The improvement in liver histopathology, liver function indexes and fibrosis markers demonstrated that UMB markedly inhibited the CCl4‑induced HF and inflammation in the rats. Additionally, UMB prominently reduced the pro‑inflammatory factors and oxidative stress levels. In vitro, UMB markedly inhibited primary HSC activation and decreased alpha‑smooth muscle actin and collagen I expression. The mechanism experiment proved that UMB inhibited the TGF‑β1‑Smad signaling pathway and ameliorated HF. The present study was the first to demonstrate, to the best of the authors' knowledge, that UMB might be a promising natural active compound for treating HF. Its therapeutic effect is associated with its modulation of the TGF‑β1‑Smad signaling pathway.

Nonalcoholic Fatty Liver Disease in Children: Where Are We?

Hydroxy Safflower Yellow A: A Natural Compound from Carthamus tinctorius L. with Potent Activity Against Liver Fibrosis and Cancer.

The liver is the largest digestive organ in the human body. The increasing incidence of chronic liver fibrosis is one of the major health challenges in the world. Liver fibrosis is a wound-healing response to acute or chronic cellular damage of liver tissue. At present, despite a series of research progress on the pathophysiological mechanism of fibrosis that has been made, there is still a gap in identifying antifibrotic targets and converting them into effective treatments. Therefore, it is extremely important to seek a molecular target that can alleviate or reverse liver fibrosis, which has important scientific and clinical significance. In the current study, to evaluate the therapeutic effect of HBO1 as a molecular target on liver aging and fibrosis, naturally-aged mice and CCL4-induced liver fibrosis mice were used as animal models, and multiple experiments were performed. Experimental results showed that HBO1 knockdown could strongly mitigate the accumulation of hepatic collagen by Masson and Sirius Red staining. Further study showed that HBO1 knockdown reduced the expression of fibrosis-related marker molecules (α-SMA, collagen type I (ColI), and fibronectin). Further work showed that HBO1 knockdown could significantly alleviate HSC activation. On this basis, we analyzed the underlying mechanism by which HBO1 alleviates liver fibrosis. It was found that HBO1 knockdown may modulate liver fibrosis by regulating the processes of EMT, inflammation, and oxidative stress. We further studied the effect of HBO1 knockdown on liver aging and aging-related liver fibrosis, and the results showed that HBO1 knockdown could significantly reduce the level of aging-related liver fibrosis and relieve liver aging. In conclusion, we systematically investigated the potential of HBO1 as a therapeutic target to attenuate liver fibrosis and liver aging. The current study found a crucial target for liver fibrosis and liver-aging therapy, which has laid a solid foundation for the liver fibrosis-related research.

Vitamin A intake forms resistance to hypervitaminosis A and affects the functional activity of the liver

Nonalcoholic fatty liver disease (NAFLD), an increasingly prevalent paediatric disorder, is diagnosed and managed not only by both pediatric gastroenterologists/hepatologists but also frequently by the general pediatrician. This article updates recent advances in diagnostic and therapeutic approach, which may be applied to everyday practice. Diagnosis of NAFLD takes into account the risk factor profile and is a diagnosis of exclusion. Techniques such as transient elastography and specific biomarkers aimed at improving diagnosis and monitoring of NAFLD need further validation in the pediatric population. Defining the risk to develop cirrhosis seems to be of primary importance already in childhood and a combination of genetic, clinical, and environmental factors can help in monitoring and making decisions on therapy. Weight reduction therapy should be the aim of treatment approach, but the compliance is poor and pharmacological treatment would be helpful; docosahexaenoic acid, some probiotics, and vitamin E are to be considered, but evidence is not sufficient to recommend widespread use.

Abrogation of the Antifibrotic Effects of Natural Killer Cells/Interferon-γ Contributes to Alcohol Acceleration of Liver Fibrosis

Apigenin intervenes in liver fibrosis by regulating PKM2-HIF-1α mediated oxidative stress

Lactoferrin as a therapeutic agent for attenuating hepatic stellate cell activation in thioacetamide-induced liver fibrosis

Sirtuin 3 (SIRT3) is a deacetylase involved in the development of many inflammation-related diseases including liver fibrosis. Withaferin A (WFA) is a bioactive constituent derived from the Withania somnifera plant, which has extensive pharmacological activities; however, little is known about the regulatory role of SIRT3 in the WFA-induced antifibrogenic effect. The current study is aimed at investigating the role of SIRT3 in WFA-induced antioxidant effects in liver fibrosis. Our study verified that WFA attenuated platelet-derived growth factor BB- (PDGF-BB-) induced liver fibrosis and promoted PDGF-BB-induced SIRT3 activity and expression in JS1 cells. SIRT3 silencing attenuated the antifibrogenic and antioxidant effects of WFA in activated JS1 cells. Moreover, WFA inhibited carbon tetrachloride- (CCl4-) induced liver injury, collagen deposition, and fibrosis; increased the SIRT3 expression; and suppressed the CCl4-induced oxidative stress in fibrotic livers of C57/BL6 mice. Furthermore, the antifibrogenic and antioxidant effects of WFA could be available in CCl4-induced WT (129S1/SvImJ) mice but were unavailable in CCl4-induced SIRT3 knockout (KO) mice. Our study suggested that WFA inhibited liver fibrosis through the inhibition of oxidative stress in a SIRT3-dependent manner. WFA could be a potential compound for the treatment of liver fibrosis.

Liver fibrosis (LF) is a healing response to wounds resulting in liver injury that can cause liver failure or even cancer without functional prevention. Resveratrol (RSV) has been suggested to exert biological effects against various human diseases. MicroRNA-20a (miRNA/miR-20a) has been shown to promote disease progression. The present study aimed to assess the mechanisms through which RSV induces autophagy and activates the miR-20a-mediated phosphatase and tensin homolog (PTEN)/PI3K/AKT signaling pathway in LF. First, a rat model of carbon tetrachlo-ride (CCL4)-induced LF and a cell model of platelet-derived growth factor (PDGF)-BB-stimulated HSC-T6 cells were established for use in subsequent experiments. Subsequently, RSV at a range of concentrations was injected into the model rats with LF. Indicators related to liver injury, oxidative stress and fibrosis were determined in the rats with LF. The RSV-treated HSC-T6 cells were subjected to transfection with miR-20a mimic and PTEN overexpression plasmid to assess the levels of liver injury and LF. A dual-luciferase reporter gene assay was performed to verify the binding sites between PTEN and miR-20a. RSV was found to alleviate LF in rats, and autophagy was enhanced in the rats with LF following RSV treatment. Furthermore, the activation of the PTEN/PI3K/AKT axis attenuated LF, which was reversed by transfection with miR-20a mimic. RSV reversed the inhibitory effects of miR-20a on PTEN expression, reducing miR-20a expression and promoting PTEN, PI3K and p-AKT protein expression, thus attenuating LF. On the whole, the present study demonstrates that RSV induces autophagy and activates the miR-20a-mediated PTEN/PI3K/AKT signaling pathway to attenuate LF. These findings may lead to the development of potential therapeutic strategies for LF.

Background:Advanced glycation end products (AGEs) are formed as a result of non-enzymatic reactions between reducing sugars and proteins, lipids, and nucleic acids. Their excessive accumulation promotes oxidative stress, chronic inflammation, and the development of metabolic, neurodegenerative, and cardiovascular diseases. Natural bioactive compounds may limit the formation of AGEs and mitigate their harmful effects on the body. Aim:The aim of this study is to review current literature data on natural compounds that inhibit the formation of AGEs and their effects on oxidative stress and inflammatory processes. Material and Methods:A narrative literature review was conducted using the PubMed, Web of Science, and Google Scholar databases, including systematic reviews as well as experimental and clinical studies published between 2010 and 2026. The effects of polyphenols, anthocyanins, and vitamins C, E, and B1 were analyzed in the context of reducing glycation, oxidative stress, and inflammatory responses. Results:The analysis of the literature demonstrated that polyphenols, anthocyanins, and vitamins C, E, and B1 effectively reduce the formation of major glycation products (CML, CEL) both in vitro and in vivo. These compounds increase the activity of antioxidant enzymes, decrease the levels of reactive oxygen species and pro-inflammatory cytokines, and modulate the NF-κB and RAGE signaling pathways. The combination of several compounds, such as resveratrol and curcumin, shows a synergistic effect, further reducing AGE formation and oxidative stress. Conclusions:Natural bioactive compounds, including polyphenols, anthocyanins, and vitamins, demonstrate significant potential in reducing the formation of AGEs, oxidative stress, and chronic inflammation. Their use may support the protection of tissues susceptible to glycation and oxidative damage.

Osteoporosis, a systemic skeletal disease characterized by a decrease in bone mass and deterioration of bone structure leading to an increased risk of fragility fractures, represents one of the major health problems worldwide. Currently, there are numerous pharmacological products used for the treatment of osteoporosis. Anti-resorptive drugs include bisphosphonates, hormone therapy, selective estrogen-receptor modulators, calcitonin, denosumab, calcium and vitamin D supplementation. Anabolic drugs such as teriparatide, strontium ranelate, romosozumab have recently become available based on advanced clinical trials. In recent years, combination therapy of anabolic and anti-resorptive agents is expected to be ideal anti-osteoporosis option. The adverse side effects caused by the long-term administration of pharmacological drugs have prompted researchers to study natural therapeutic compounds to find an alternative and effective way for osteoporosis treatment. Natural compounds including phytoestrogens with estrogenic effects (e.g. genistein, daidzein, icariin, dioscin, Ginkgo biloba), antioxidant and anti-inflammatory agents (e.g. acteoside, curcumin, resveratrol, Camellia sinensis), treatments that exert their effects by multiple actions (e.g. kinsenoside, berberine, Olea europaea, Prunus domestica, Allium cepa) could provide a safer alternative to primary pharmacological strategies. In this review, both pharmacological agents and natural compounds as available treatments for osteoporosis are characterized. In addition, possible mechanisms of action of all aforementioned treatments associated with bone remodelling, osteoclastogenesis, osteoblastogenesis, bone cell activity, death, and oxidative stress are presented. Nevertheless, more high-quality clinical studies with natural compounds are needed to provide greater evidence of the beneficial and safer antiosteoporotic application for the candidate.

Effective therapy for liver fibrosis is lacking. Here, we examined whether LP340, the lead candidate of a new-generation of hydrazide-based HDAC1,2,3 inhibitors (HDACi), decreases liver fibrosis. Liver fibrosis was induced by CCl4 treatment and bile duct ligation (BDL) in mice. At 6 weeks after CCl4, serum alanine aminotransferase increased, and necrotic cell death and leukocyte infiltration occurred in the liver. Tumor necrosis factor-α and myeloperoxidase markedly increased, indicating inflammation. After 6 weeks, α-smooth muscle actin (αSMA) and collagen-1 expression increased by 80% and 575%, respectively, indicating hepatic stellate cell (HSC) activation and fibrogenesis. Fibrosis detected by trichrome and Sirius-red staining occurred primarily in pericentral regions with some bridging fibrosis in liver sections. 4-Hydroxynonenal adducts (indicator of oxidative stress), profibrotic cytokine transforming growth factor-β (TGFβ), and TGFβ downstream signaling molecules phospho-Smad2/3 also markedly increased. LP340 attenuated indices of liver injury, inflammation, and fibrosis markedly. Moreover, Ski-related novel protein-N (SnoN), an endogenous inhibitor of TGFβ signaling, decreased, whereas SnoN expression suppressor microRNA-23a (miR23a) increased markedly. LP340 (0.05mg/kg, ig., daily during the last 2weeks of CCl4 treatment) decreased 4-hydroxynonenal adducts and miR23a production, blunted SnoN decreases, and inhibited the TGFβ/Smad signaling. By contrast, LP340 had no effect on matrix metalloproteinase-9 expression. LP340 increased histone-3 acetylation but not tubulin acetylation, indicating that LP340 inhibited Class-I but not Class-II HDAC in vivo. After BDL, focal necrosis, inflammation, ductular reactions, and portal and bridging fibrosis occurred at 2 weeks, and αSMA and collagen-1 expression increased by 256% and 560%, respectively. LP340 attenuated liver injury, ductular reactions, inflammation, and liver fibrosis. LP340 also decreased 4-hydroxynonenal adducts and miR23a production, prevented SnoN decreases, and inhibited the TGFβ/Smad signaling after BDL. In vitro, LP340 inhibited immortal human hepatic stellate cells (hTERT-HSC) activation in culture (αSMA and collagen-1 expression) as well as miR23a production, demonstrating its direct inhibitory effects on HSC. In conclusions, LP340 is a promising therapy for both portal and pericentral liver fibrosis, and it works by inhibiting oxidative stress and decreasing miR23a.

Liver fibrosis, a complex process resulting from most chronic liver diseases, remains devoid of effective treatments. An increasing body of evidence links liver fibrosis to the "gut-liver axis", with disruptions in the gut microbiota-host balance emerging as a critical contributor to its progression. Cinnamaldehyde (Cin), a natural compound with antioxidant, anti-inflammatory, and anticytotoxic properties, has shown potential in counteracting hepatic stellate cell (HSC) activation. Additionally, Cin has been shown to promote probiotics in the intestine, thereby restoring a healthy microbial community. These characteristics position Cin as a promising candidate for liver fibrosis treatment through modulation of the gut-liver axis. In this study, a Vitamin A (Va)-formulated Cin Nanoemulsion (Va-Cin@NM) was developed to enhance the physicochemical stability of Cin while preserving intestinal homeostasis and facilitating targeted liver deposition. In bile duct ligation (BDL)-induced liver fibrosis in rats, Va-Cin@NM intervention significantly reduced bile duct-like structure proliferation and collagen deposition in the liver. These effects are likely attributed to the restoration of gut microbiota, increased short-chain fatty acid (SCFA) concentrations, and improved intestinal integrity. Moreover, Va-Cin@NM treatment suppressed harmful bacterial populations in the liver, thus mitigating immune injury and inflammatory cell recruitment. Consequently, oxidative stress and HSC activation were attenuated. Overall, Va-Cin@NM demonstrates significant potential as a nanotherapeutic approach for liver fibrosis by modulating the gut-liver axis.