Parkin-Mediated Mitophagy by TGF-ß Is Connected with Hepatic Stellate Cell Activation.

Hepatic stellate cells (HSCs) are the main contributors to the development and progression of liver fibrosis. Parkin is an E3 ligase involved in mitophagy mediated by lysosomes that maintains mitochondrial homeostasis. Unfortunately, there is little information regarding the regulation of parkin by transforming growth factor-ß (TGF-ß) and its association with HSC trans-differentiation. This study showed that parkin is upregulated in fibrotic conditions and elucidated the underlying mechanism. Parkin was observed in the cirrhotic region of the patient liver tissues and visualized using immunostaining and immunoblotting of mouse fibrotic liver samples and primary HSCs. The role of parkin-mediated mitophagy in hepatic fibrogenesis was examined using TGF-ß-treated LX-2 cells with mitophagy inhibitor, mitochondrial division inhibitor 1. Parkin overexpression and its colocalization with desmin in human tissues were found. Increased parkin in fibrotic liver homogenates of mice was observed. Parkin was expressed more abundantly in HSCs than in hepatocytes and was upregulated under TGF-ß. TGF-ß-induced parkin was due to Smad3. TGF-ß facilitated mitochondrial translocation, leading to mitophagy activation, reversed by mitophagy inhibitor. However, TGF-ß did not change mitochondrial function. Mitophagy inhibitor suppressed profibrotic genes and HSC migration mediated by TGF-ß. Collectively, parkin-involved mitophagy by TGF-ß facilitates HSC activation, suggesting mitophagy may utilize targets for liver fibrosis.

Integrative roles of sphingosine kinase in liver pathophysiology.

Bioactive sphingolipids and enzymes that metabolize sphingolipid-related substances have been considered as critical messengers in various signaling pathways. One such enzyme is the crucial lipid kinase, sphingosine kinase (SphK), which mediates the conversion of sphingosine to the potent signaling substance, sphingosine-1-phosphate. Several studies have demonstrated that SphK metabolism is strictly regulated to maintain the homeostatic balance of cells. Here, we summarize the role of SphK in the course of liver disease and illustrate its effects on both physiological and pathological conditions of the liver. SphK has been implicated in a variety of liver diseases, such as steatosis, liver fibrosis, hepatocellular carcinoma, and hepatic failure. This study may advance the understanding of the cellular and molecular foundations of liver disease and establish therapeutic approaches via SphK modulation.

Castanopsis sieboldii Extract Alleviates Acute Liver Injury by Antagonizing Inflammasome-Mediated Pyroptosis.

Castanopsis sieboldii (CS), a subtropical species, was reported to have antioxidant and antibacterial effects. However, the anti-inflammatory effects of CS have not been studied. This study aimed to investigate whether the 70% ethanol extract of the CS leaf (CSL3) inhibited lipopolysaccharide (LPS)-induced inflammatory responses and LPS and ATP-induced pyroptosis in macrophages. CSL3 treatment inhibited NO release and iNOS expression in LPS-stimulated cells. CSL3 antagonized NF-κB and AP-1 activation, which was due to MAPK (p38, ERK, and JNK) inhibition. CSL3 successfully decreased NLRP3 inflammasome activation and increased IL-1ß expression. CSL3 treatment diminished LPS and ATP-induced pore formation in GSDMD. The in vivo effect of CSL3 on acute liver injury was evaluated in a CCl4-treated mouse model. CCl4 treatment increased the activity of serum alanine aminotransferase and aspartate aminotransferase, which decreased by CSL3. In addition, CCl4-induced an increase in TNF-α, and IL-6 levels decreased by CSL3 treatment. Furthermore, we verified that the CCl4-induced inflammasome and pyroptosis-related gene expression in liver tissue and release of IL-1ß into serum were suppressed by CSL3 treatment. Our results suggest that CSL3 protects against acute liver injury by inhibiting inflammasome formation and pyroptosis.

Identification of Histone Lysine Acetoacetylation as a Dynamic Post-Translational Modification Regulated by HBO1.

Ketone bodies have long been known as a group of lipid-derived alternative energy sources during glucose shortages. Nevertheless, the molecular mechanisms underlying their non-metabolic functions remain largely elusive. This study identified acetoacetate as the precursor for lysine acetoacetylation (Kacac), a previously uncharacterized and evolutionarily conserved histone post-translational modification. This protein modification is comprehensively validated using chemical and biochemical approaches, including HPLC co-elution and MS/MS analysis using synthetic peptides, Western blot, and isotopic labeling. Histone Kacac can be dynamically regulated by acetoacetate concentration, possibly via acetoacetyl-CoA. Biochemical studies show that HBO1, traditionally known as an acetyltransferase, can also serve as an acetoacetyltransferase. In addition, 33 Kacac sites are identified on mammalian histones, depicting the landscape of histone Kacac marks across species and organs. In summary, this study thus discovers a physiologically relevant and enzymatically regulated histone mark that sheds light on the non-metabolic functions of ketone bodies.

Protective Effect of Castanopsis sieboldii Extract against UVB-Induced Photodamage in Keratinocytes.

Ultraviolet B (UVB) rays disrupt the skin by causing photodamage via processes such as reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, DNA damage, and/or collagen degradation. Castanopsis sieboldii is an evergreen tree native to the southern Korean peninsula. Although it is known to have antioxidant and anti-inflammatory effects, its protective effect against photodamage in keratinocytes has not been investigated. Thus, in the present study, we investigated the effect of 70% ethanol extract of C. sieboldii leaf (CSL3) on UVB-mediated skin injuries and elucidated the underlying molecular mechanisms. CSL3 treatment restored the cell viability decreased by UVB irradiation. Moreover, CSL3 significantly inhibited UVB- or tert-butyl hydroperoxide-mediated ROS generation in HaCaT cells. ER stress was inhibited, whereas autophagy was upregulated by CSL3 treatment against UVB irradiation. Additionally, CSL3 increased collagen accumulation and cell migration, which were decreased by UVB exposure. Notably, epigallocatechin gallate, the major component of CSL3, improved the cell viability decreased by UVB irradiation through regulation of ER stress and autophagy. Conclusively, CSL3 may represent a promising therapeutic candidate for the treatment of UVB-induced skin damage.

LDHA Desuccinylase Sirtuin 5 as A Novel Cancer Metastatic Stimulator in Aggressive Prostate Cancer.

Prostate cancer (PCa) is the most commonly diagnosed genital cancer in men worldwide. Around 80% of the patients who developed advanced PCa suffered from bone metastasis, with a sharp drop in the survival rate. Despite great efforts, the detailed mechanisms underlying castration-resistant PCa (CRPC) remain unclear. Sirtuin 5 (SIRT5), an NAD+-dependent desuccinylase, is hypothesized to be a key regulator of various cancers. However, compared to other SIRTs, the role of SIRT5 in cancer has not been extensively studied. Here, we revealed significantly decreased SIRT5 levels in aggressive PCa cells relative to the PCa stages. The correlation between the decrease in the SIRT5 level and the patient's reduced survival rate was also confirmed. Using quantitative global succinylome analysis, we characterized a significant increase in the succinylation at lysine 118 (K118su) of lactate dehydrogenase A (LDHA), which plays a role in increasing LDH activity. As a substrate of SIRT5, LDHA-K118su significantly increased the migration and invasion of PCa cells and LDH activity in PCa patients. This study reveals the reduction of SIRT5 protein expression and LDHA-K118su as a novel mechanism involved in PCa progression, which could serve as a new target to prevent CPRC progression for PCa treatment.

Ferroptosis contribute to hepatic stellate cell activation and liver fibrogenesis.

Ferroptosis is a widely known regulator of cell death in connection with the redox state as a consequence of the depletion of glutathione or accumulation of lipid peroxidation. Hepatic stellate cells (HSCs) play a pivotal role in the progression of hepatic fibrosis by increasing the production and secretion of the extracellular matrix. However, the role of ferroptosis in HSC activation and liver fibrogenesis has not been clearly elucidated. The ferroptosis inducer RAS-selective lethal 3 (RSL3) or erastin treatment in HSCs caused cell death. This effect was suppressed only after exposure to ferroptosis inhibitors. We observed induction of ferroptosis by RSL3 treatment in HSCs supported by decreased glutathione peroxidase 4, glutathione deficiency, reactive oxygen species generation, or lipid peroxidation. Interestingly, RSL3 treatment upregulated the expression of plasminogen activator inhibitor-1, a representative fibrogenic marker of HSCs. In addition, treatment with ferroptosis-inducing compounds increased c-JUN phosphorylation and activator protein 1 luciferase activity but did not alter Smad phosphorylation and Smad-binding element luciferase activity. Chronic administration of iron dextran to mice causes ferroptosis of liver in vivo. The expression of fibrosis markers, such as alpha-smooth muscle actin and plasminogen activator inhibitor-1, was increased in the livers of mice with iron accumulation. Hepatic injury accompanying liver fibrosis was observed based on the levels of alanine aminotransferase, aspartate aminotransferase, and hematoxylin and eosin staining. Furthermore, we found that both isolated primary hepatocyte and HSCs undergo ferroptosis. Consistently, cirrhotic liver tissue of patients indicated glutathione peroxidase 4 downregulation in fibrotic region. In conclusion, our results suggest that ferroptosis contribute to HSC activation and the progression of hepatic fibrosis.

Experience with and perceptions of non-prescription anthelmintics for cancer treatments among cancer patients in South Korea: A cross-sectional survey.

Although non-prescription anthelmintics are used by many patients as cancer treatment in South Korea, data regarding the experiences or perceptions of these drugs are lacking. This study aimed to investigate the repercussions of non-prescription anthelmintics for cancer treatment and evaluate their perceived effectiveness and adverse effects. This survey included 86 cancer patients, aged 19 years and older, who underwent anthelmintic therapy for cancer. They were recruited from two online communities in South Korea through a structured questionnaire that was provided online. Cancer patients under non-prescription anthelmintic therapy for cancer in South Korea were mostly in their advanced stages and had started the treatment in 2019. About half of the cancer patients had taken non-prescription anthelmintics during their chemotherapy, and 96.5% of them did not inform the clinicians. These participants had a positive perception (79.1%) toward the effectiveness of anthelmintics, as they felt it improved their physical condition. Data on the adverse effects of anthelmintics showed that more than two-third of the participants did not report experiencing any adverse effects. Communication between the clinicians and cancer patients regarding the use of non-prescription anthelmintics should be enhanced to prevent adverse effects.

Repurposing of Benzimidazole Anthelmintic Drugs as Cancer Therapeutics.

Benzimidazoles have shown significant promise for repurposing as a cancer therapy. The aims of this review are to investigate the possibilities and limitations of the anti-cancer effects of benzimidazole anthelmintics and to suggest ways to overcome these limitations. This review included studies on the anti-cancer effects of 11 benzimidazoles. Largely divided into three parts, i.e., preclinical anti-cancer effects, clinical anti-cancer effects, and pharmacokinetic properties, we examine the characteristics of each benzimidazole and attempt to elucidate its key properties. Although many studies have demonstrated the anti-cancer effects of benzimidazoles, there is limited evidence regarding their effects in clinical settings. This might be because the clinical trials conducted using benzimidazoles failed to restrict their participants with specific criteria including cancer entities, cancer stages, and genetic characteristics of the participants. In addition, these drugs have limitations including low bioavailability, which results in insufficient plasma concentration levels. Additional studies on whole anti-cancer pathways and development strategies, including formulations, could result significant enhancements of the anti-cancer effects of benzimidazoles in clinical situations.

Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure.

Sphingosine kinase (SK) enzyme, a central player of sphingolipid rheostat, catalyzes the phosphorylation of sphingosine to the bioactive lipid mediator sphingosine 1 phosphate (S1P), which regulates cancer cell proliferation, migration, differentiation, and angiogenesis through its extracellular five G protein-coupled S1P receptors (S1PR1-5). Recently, several research studies on SK inhibitors have taken place in order use them for the development of novel anticancer-targeted therapy. In this study, we designed and synthesized analog derivatives of known SK1 inhibitors, namely RB005 and PF-543, by introducing heteroatoms at their tail structure, as well as investigated their anticancer activities and pharmacokinetic parameters in vitro. Compounds 1-20 of RB005 and PF-543 derivatives containing an aliphatic chain or a tail structure of benzenesulfonyl were synthesized. All compounds of set 1 (1-10) effectively reduced cell viability in both HT29 and HCT116 cells, whereas set 2 derivatives (11-20) showed poor anticancer effect. Compound 10, having the highest cytotoxic effect (48 h, HT29 IC50 = 6.223 µM, HCT116 IC50 = 8.694 µM), induced HT29 and HCT116 cell death in a concentration-dependent manner through the mitochondrial apoptotic pathway, which was demonstrated by increased annexin V-FITC level, and increased apoptotic marker cleaved caspase-3 and cleaved PARP. Compound 10 inhibited SK1 by 20%, and, thus, the S1P level decreased by 42%. Unlike the apoptosis efficacy, the SK1 inhibitory effect and selectivity of the PF-543 derivative were superior to that of the RB005 analog. As a result, compounds with an aliphatic chain tail exhibited stronger apoptotic effects. However, this ability was not proportional to the degree of SK inhibition. Compound 10 increased the protein phosphatase 2A (PP2A) activity (1.73 fold) similar to FTY720 (1.65 fold) and RB005 (1.59 fold), whereas compounds 11 and 13 had no effect on PP2A activation. Since the PP2A activity increased in compounds with an aliphatic chain tail, it can be suggested that PP2A activation has an important effect on anticancer and SK inhibitory activities.

REDD1 attenuates hepatic stellate cell activation and liver fibrosis via inhibiting of TGF-ß/Smad signaling pathway.

Liver fibrosis is caused by repetitive hepatic injury. Regulated in development and DNA damage response 1 (REDD1) gene is induced by various stresses and has been studied in cell proliferation and survival. However, the role of REDD1 in hepatic stellate cell activation and hepatic fibrogenesis has not yet been investigated. In the current study, we examined the effect of REDD1 on hepatic fibrogenesis and the underlying molecular mechanism. REDD1 protein was upregulated in the activated primary hepatic stellate cells and transforming growth factor-ß (TGF-ß)-treated LX-2 cells. REDD1 mRNA levels were also elevated by TGF-ß treatment. TGF-ß signaling is primarily transduced via the activation of the Smad transcription factor. However, TGF-ß-mediated REDD1 induction was not Smad-dependent. Thus, we investigated the transcription factors that influence the REDD1 expression by TGF-ß. We found that c-JUN, a component of AP-1, upregulated the REDD1 expression that was specifically suppressed by p38 inhibitor. In silico analysis of the REDD1 promoter region showed putative AP-1-binding sites; additionally, its deletion mutants demonstrated that the AP-1-binding site between -716 and -587 bp within the REDD1 promoter is critical for TGF-ß-mediated REDD1 induction. Moreover, REDD1 overexpression markedly inhibited TGF-ß-induced plasminogen activator inhibitor-1 (PAI-1) expression and Smad phosphorylation. REDD1 adenovirus infection inhibited CCl4-induced hepatic injury in mice, which was demonstrated by reduced ALT/AST levels and collagen accumulation. In addition, we observed that REDD1 inhibited CCl4-induced fibrogenic gene induction and restored GSH and malondialdehyde levels. Our findings implied that REDD1 has the potential to inhibit HSC activation and protect against liver fibrosis.

Cystine and Methionine Deficiency Promotes Ferroptosis by Inducing B-Cell Translocation Gene 1.

Ferroptosis is a type of programmed necrosis triggered by iron-dependent lipid peroxidation. We investigated the role of B-cell translocation gene 1 (BTG1) in cystine and methionine deficiency (CST/Met (-))-mediated cell death. CST/Met (-) depleted reduced and oxidized glutathione in hepatocyte-derived cells, increased prostaglandin-endoperoxide synthase 2 expression, and promoted reactive oxygen species accumulation and lipid peroxidation, as well as necrotic cell death. CST/Met (-)-mediated cell death and lipid peroxidation was specifically inhibited by pretreatment with ferroptosis inhibitors. In parallel with cell death, CST/Met (-) blocked global protein translation and increased the expression of genes associated with the integrated stress response. Moreover, CST/Met (-) significantly induced BTG1 expression. Using a BTG1 promoter-harboring reporter gene and siRNA, activating transcription factor 4 (ATF4) was identified as an essential transcription factor for CST/Met (-)-mediated BTG1 induction. Although knockout of BTG1 in human HAP1 cells did not affect the accumulation of reactive oxygen species induced by CST/Met (-), BTG1 knockout significantly decreased the induction of genes associated with the integrated stress response, and reduced lipid peroxidation and cell death in response to CST/Met (-). The results demonstrate that CST/Met (-) induces ferroptosis by activating ATF4-dependent BTG1 induction.

Pharmacy services for the 2019 Fédération Internationale de Natation (FINA) World Masters Championships in Gwangju, South Korea.

BACKGROUND: The role of sports pharmacists is being emphasized in international athletic events. This study aimed to describe the pharmacy services for the 2019 Fédération Internationale de Natation (FINA) World Masters Championships in Gwangju, South Korea. METHOD: Research focused on athletes and coaching staff who received medications after visiting medical centers and pharmacies located in the athletes' village from July 5 to July 29, 2019. We collected daily results of pharmacy operation and prescription interventions. The data were analyzed using Microsoft Excel, and were expressed as frequency (%). RESULTS: Throughout the tournament, 633 patients received medication at the athletes' village pharmacy (gender: 338 men [53.4%], 295 women [46.6%]; nationality: 299 Korean [47.2%], 334 overseas players [52.8%]; patient type: 150 athletes [23.7%], 427 non-athletes [67.5%]). Therapy for musculoskeletal disorders was the most common (n = 29, 19.3%), and oral NSAIDs (n = 56, 22.0%) were the most frequently dispensed medication in athletes. Pharmacists intervened for 47 out of 491 prescriptions (9.6%), with dosage change (n = 21, 44.7%) being the most common intervention type. CONCLUSION: Sports pharmacists at FINA World Masters Championships played a pivotal role in ensuring the safe usage of medications by all participants, especially athletes. This study results will be a useful reference for pharmacy services at future international or domestic sports competitions.

Characterization of hyperglycemia due to sub-chronic administration of red ginseng extract via comparative global proteomic analysis.

Ginseng (Panax ginseng Meyer) is commonly used as an herbal remedy worldwide. Few studies have explored the possible physiological changes in the liver although patients often self-medicate with ginseng preparations, which may lead to exceeding the recommended dose for long-term administration. Here, we analyzed changes in the hepatic proteins of mouse livers using quantitative proteomics after sub-chronic administration of Korean red ginseng (KRG) extract (control group and 0.5, 1.0, and 2.0 g/kg KRG) using tandem mass tag (TMT) 6-plex technology. The 1.0 and 2.0 g/kg KRG groups exhibited signs of liver injury, including increased levels of aspartate transaminase (AST) and alanine aminotransferase (ALT) in the serum. Furthermore, serum glucose levels were significantly higher following KRG administration compared with the control group. Based on the upregulated proteins found in the proteomic analysis, we found that increased cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) levels promoted greater hydrogen sulfide (H2S) synthesis in the liver. This investigation provides novel evidence that sub-chronic administration of KRG can elevate H2S production by increasing protein expression of CBS and CSE in the liver.

Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3.

Hemistepta lyrata (Bunge) Bunge is a biennial medicinal plant possessing beneficial effects including anti-inflammation, and hemistepsin A (HsA) isolated from H. lyrata has been known as a hepatoprotective sesquiterpene lactone. In this report, we explored the cytotoxic effects of H. lyrata on hepatocellular carcinoma (HCC) cells and investigated the associated bioactive compounds and their relevant mechanisms. From the viability results of HCC cells treated with various H. lyrata extracts, HsA was identified as the major compound contributing to the H. lyrata-mediated cytotoxicity. HsA increased expression of cleaved PARP and cells with Sub-G1 phase, Annexin V binding, and TUNEL staining, which imply HsA induces apoptosis. In addition, HsA provoked oxidative stress by decreasing the reduced glutathione/oxidized glutathione ratio and accumulating reactive oxygen species and glutathione-protein adducts. Moreover, HsA inhibited the transactivation of signal transducer and activator of transcription 3 (STAT3) by its dephosphorylation at Y705 and glutathione conjugation. Stable expression of a constitutive active mutant of STAT3 prevented the reduction of cell viability by HsA. Finally, HsA enhanced the sensitivity of sorafenib-mediated cytotoxicity by exaggerating oxidative stress and Y705 dephosphorylation of STAT3. Therefore, HsA will be a promising candidate to induce apoptosis of HCC cells via downregulating STAT3 and sensitizing conventional chemotherapeutic agents.

Protective Effect of Cudrania tricuspidata Extract against High-Fat Diet Induced Nonalcoholic Fatty Liver Disease through Nrf-2/HO-1 Pathway.

Nonalcoholic fatty liver disease is the most common chronic disease affecting a wide range of the world's population and associated with obesity-induced metabolic syndrome. It is possibly emerging as a leading cause of life-threatening liver diseases for which a drug with a specific therapeutic target has not been developed yet. Previously, there have been reports on the benefits of Cudrania tricuspidata (CT) for treating obesity and diabetes via regulation of metabolic processes, such as lipogenesis, lipolysis, and inflammation. In this study, we investigated the ameliorative effect of orally administered 0.25% and 0.5% (w/w) CT mixed with high-fat diet (HFD) to C57BL/6J mice for 7 weeks. It was found that body weight, fat mass, hepatic mass, serum glucose level, and liver cholesterol levels were significantly reduced after CT treatment. In CT-treated HFD-fed mice, the mRNA expression levels of hepatic lipogenic and inflammatory cytokine-related genes were markedly reduced, whereas the expression level of epididymal lipogenic genes was increased. The mRNA expression level of beta-oxidation and Nrf-2/HO-1 genes significantly increased in CT-treated obese mice livers. We propose that CT alleviates hepatic steatosis by reducing oxidative stress and inflammation.

Neoagarooligosaccharide Protects against Hepatic Fibrosis via Inhibition of TGF-ß/Smad Signaling Pathway.

Hepatic fibrosis occurs when liver tissue becomes scarred from repetitive liver injury and inflammatory responses; it can progress to cirrhosis and eventually to hepatocellular carcinoma. Previously, we reported that neoagarooligosaccharides (NAOs), produced by the hydrolysis of agar by ß-agarases, have hepatoprotective effects against acetaminophen overdose-induced acute liver injury. However, the effect of NAOs on chronic liver injury, including hepatic fibrosis, has not yet been elucidated. Therefore, we examined whether NAOs protect against fibrogenesis in vitro and in vivo. NAOs ameliorated PAI-1, α-SMA, CTGF and fibronectin protein expression and decreased mRNA levels of fibrogenic genes in TGF-ß-treated LX-2 cells. Furthermore, downstream of TGF-ß, the Smad signaling pathway was inhibited by NAOs in LX-2 cells. Treatment with NAOs diminished the severity of hepatic injury, as evidenced by reduction in serum alanine aminotransferase and aspartate aminotransferase levels, in carbon tetrachloride (CCl4)-induced liver fibrosis mouse models. Moreover, NAOs markedly blocked histopathological changes and collagen accumulation, as shown by H&E and Sirius red staining, respectively. Finally, NAOs antagonized the CCl4-induced upregulation of the protein and mRNA levels of fibrogenic genes in the liver. In conclusion, our findings suggest that NAOs may be a promising candidate for the prevention and treatment of chronic liver injury via inhibition of the TGF-ß/Smad signaling pathway.

Hemistepsin A inhibits T0901317-induced lipogenesis in the liver.

Hemistepsin A (HsA) is a guaianolide sesquiterpene lactone that inhibits hepatitis and liver fibrosis. We evaluated the effects of HsA on liver X receptor (LXR)-mediated hepatic lipogenesis in vitro and in vivo. Up to 10 µM, HsA did not affect the viability of HepG2 and Huh7 cells. Pretreatment with 5-10 µM HsA significantly decreased the luciferase activity of the LXR response element, which was transactivated by T0901317, GW 3965, and LXRα/retinoid X receptor α overexpression. In addition, it significantly inhibited the mRNA expression of LXRα in HepG2 and Huh7 cells. It also suppressed the expression of sterol regulatory element-binding protein-1c and lipogenic genes and reduced the triglyceride accumulation triggered by T0901317. Intraperitoneal injection of HsA (5 and 10 mg/kg) in mice significantly alleviated the T0901317-mediated increases in hepatocyte diameter and the percentage of regions in hepatic parenchyma occupied by lipid droplets. Furthermore, HsA significantly attenuated hepatic triglyceride accumulation by restoring the impaired expression of LXRα-dependent lipogenic genes caused by T0901317. Therefore, based on its inhibition of the LXRα-dependent signaling pathway, HsA has prophylactic potential for steatosis. [BMB Reports 2021; 54(2): 106-111].

Transforming Growth Factor Beta-Induced Foxo3a Acts as a Profibrotic Mediator in Hepatic Stellate Cells.

Hepatic stellate cells (HSCs) are major contributors to hepatic fibrogenesis facilitating liver fibrosis. Forkhead box O 3a (FoxO3a) is a member of the forkhead transcription factor family, which mediates cell proliferation and differentiation. However, the expression and function of FoxO3a during HSC activation remain largely unknown. FoxO3a overexpression was related to fibrosis in patients, and its expression was colocalized with desmin or α-smooth muscle actin, representative HSC markers. We also observed upregulated FoxO3a levels in two animal hepatic fibrosis models, a carbon tetrachloride-injected model and a bile duct ligation model. In addition, transforming growth factor beta (TGF-ß) treatment in mouse primary HSCs or LX-2 cells elevated FoxO3a expression. When FoxO3a was upregulated by TGF-ß in LX-2 cells, both the cytosolic and nuclear levels of FoxO3a increased. In addition, we found that the induction of FoxO3a by TGF-ß was due to both transcriptional and proteasome-dependent mechanisms. Moreover, FoxO3a overexpression promoted TGF-ß-mediated Smad activation. Furthermore, FoxO3a increased fibrogenic gene expression, which was reversed by FoxO3a knockdown. TGF-ß-mediated FoxO3a overexpression in HSCs facilitated hepatic fibrogenesis, suggesting that FoxO3a may be a novel target for liver fibrosis prevention and treatment.

Emerging roles of ferroptosis in liver pathophysiology.

Ferroptosis is a widely recognized process of regulated cell death linking redox state, metabolism, and human health. It is considered a defense mechanism against extensive lipid peroxidation, a complex process that may disrupt the membrane integrity, eventually leading to toxic cellular injury. Ferroptosis is controlled by iron, reactive oxygen species, and polyunsaturated fatty acids. Accumulating evidence has addressed that ferroptosis plays an unneglectable role in regulating the development and progression of multiple pathologies of the liver, including hepatocellular carcinoma, liver fibrosis, nonalcoholic steatosis, hepatic ischemia-reperfusion injury, and liver failure. This review may increase our understating of the cellular and molecular mechanisms of liver disease progression and establish the foundation of strategies for pharmacological intervention.