Pterocarpus soyauxii (P. soyauxii) is a Fabaceae family traditionally used to treat menopausal disorders. This study aims to investigate the effect of P. soyauxii on menopause-related non-alcoholic fatty liver disease (NAFLD) and to determine its mechanisms of action and signaling pathways. The pharmacokinetic and dynamic properties and the toxicological profile of P. soyauxii compounds were assessed using the SwissADME and Protox III databases. A pharmacology network was constructed to identify active compound targets and corresponding genes. Compound target and protein-protein interaction networks were created using Cytoscape software. Molecular docking studies were conducted to assess the binding affinity of P. soyauxii compounds with specific proteins. In vitro experiments evaluated the antioxidant properties of P. soyauxii. In vivo studies using ovariectomized (Ovx) rat models underlined pathways and effects of P. soyauxii on biochemical and histological features linked with NAFLD. Findings suggest that P. soyauxii compounds are readily absorbed through the intestine and exhibit a relatively low level of toxicity. Protein-protein interaction, compound-target networks, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed several pathways and target proteins of P. soyauxii compounds. Indeed, they target specific proteins such as estrogen receptor alpha/beta ERα/β, nicotinamide adenine dinucleotide phosphate oxidase (NADPH-O), epidermal growth factor receptor (EGFR), MAPK1, peroxisome proliferator-activated receptors alpha/gamma (PPARα/G), and HMG-CoA reductase. Molecular docking revealed that P. soyauxii compounds demonstrate high binding affinity to various proteins. In vitro, P. soyauxii inhibits the oxidative power of OH, H2O2, and NO. In vivo, P. soyauxii significantly (p < 0.01, p < 0.001, and p < 0.01, respectively) reduces ALAT (25.14%), hepatic cholesterol (15.27%), and malondialdehyde (MDA) (26.78%) levels at 200 mg/kg and prevents steatosis in the liver. These findings suggest that P. soyauxii may have a protective role against menopause-related NAFLD.

Therapeutic efficacy and safety of adeno-associated virus (AAV) liver gene therapy depend on capsid choice. To predict AAV capsid performance under near-clinical conditions, we established side-by-side comparison at single-cell resolution in human livers maintained by normothermic machine perfusion. AAV-LK03 transduced hepatocytes much more efficiently and specifically than AAV5, AAV8 and AAV6, which are most commonly used clinically, and AAV-NP59, which is better at transducing human hepatocytes engrafted in immune-deficient mice. AAV-LK03 preferentially transduced periportal hepatocytes in normal liver, whereas AAV5 targeted pericentral hepatocytes in steatotic liver. AAV5 and AAV8 transduced liver sinusoidal endothelial cells as efficiently as hepatocytes. AAV capsid and steatosis influenced vector episome formation, which determines gene therapy durability, with AAV5 delaying concatemerization. Our findings inform capsid choice in clinical AAV liver gene therapy, including consideration of disease-relevant hepatocyte zonation and effects of steatosis, and facilitate the development of AAV capsids that transduce hepatocytes or other therapeutically relevant cell types in the human liver with maximum efficiency and specificity.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by lipid accumulation in the liver due to an excess in their supplies or an impairment in their management. While some patients remain stable for years, a proportion of them progress up to steatohepatitis (MASH). MASLD links with systemic pathways being associated with metabolic and non-metabolic diseases. Although liver lipid accumulation represents the first hit for MASLD, the pathophysiology of its development and progression to MASH remains not completely understood. Oxidative stress has received particular attention in recent years, as most of the oxidative process occurs in the liver, which is also the target of oxidative stress-induced damage. Growing evidence linked the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) to the increased liver production of reactive oxygen species up to liver damage and fibrosis. NOX acts both in hepatocytes and in non-parenchymal hepatic cells, contributing to hepatocyte lipotoxicity, impaired hepatic microcirculation, hepatic stellate, and mesenchymal stem cells activation and proliferation. This review aims to summarize the current knowledge on the involvement of oxidative stress in the MASLD-MASH transition, focusing on the role of NOX isoforms, and to suggest targeting NOX as a therapeutic approach in MASLD.

Calotropis gigantea (L.) Dryand. (C. gigantea) is a traditional medicinal plant, recognized for its effectiveness in managing diabetes, along with its notable antioxidant, anti-inflammatory, and anticancer properties. Type II diabetes mellitus (T2DM) is characterized by chronic metabolic disorders associated with an elevated risk of hepatocellular carcinoma (HCC) due to hyperglycemia and impaired insulin response. The scientific validation of C. gigantea's ethnopharmacological efficacy offers advantages in alleviating cancer progression in T2DM complications, enriching existing knowledge and potentially aiding future clinical cancer treatments.

This study aimed to investigate the preventive potential of the dichloromethane fraction of C. gigantea stem bark extract (CGDCM) against diethylnitrosamine (DEN)-induced HCC in T2DM rats, aiming to reduce cancer incidence associated with diabetes while validating C. gigantea's ethnopharmacological efficacy.

Spontaneously Diabetic Torii (SDT) rats were administered DEN to induce HCC (SDT-DEN-VEH), followed by treatment with CGDCM. Metformin was used as a positive control (SDT-DEN-MET). All the treatments were administered for 10 weeks after the initial DEN injection. Diabetes-related parameters, including serum levels of glucose, insulin, and glycosylated hemoglobin (HbA1c), as well as liver function enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase), were quantified. Serum inflammation biomarkers interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were evaluated. Liver tissue samples were analyzed for inflammation protein expression (IL-6, TNF-α, transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin (α-SMA)). Histopathological evaluation was performed to assess hepatic necrosis, inflammation, and fibrosis. Liver cell proliferation was determined using immunohistochemistry for Ki-67 expression.

Rats with SDT-DEN-induced HCC treated with CGDCM exhibited reduced serum glucose levels, elevated insulin levels, and decreased HbA1c levels. CGDCM treatment also reduced elevated hepatic IL-6, TNF-α, TGF-β1, and α-SMA levels in SDT-DEN-VEH rats. Additionally, CGDCM treatment prevented hepatocyte damage, fibrosis, and cell proliferation. No adverse effects on normal organs were observed with CGDCM treatment, suggesting its safety for the treatment of HCC complications associated with diabetes. Additionally, the absence of adverse effects in SD rats treated with CGDCM at 2.5 mg/kg further supports the notion of its safe usage.

These findings suggest that C. gigantea stem bark extract exerts preventive effects against the development of HCC complications in patients with T2DM, expanding the potential benefits of its ethnopharmacological advantages.

Nonalcoholic fatty liver disease (NAFLD) shares common pathogenic mechanisms of type 2 diabetes mellitus (T2DM) with upregulated advanced glycation end products (AGEs). Here, we aim to investigate the effect of FPS-ZM1, an inhibitor for receptor for AGEs (RAGE), on lipid deposition in the liver of mice.

KK-Ay mice were used as models of T2DM with NAFLD, while C57BL/6j mice were controls. Additionally, KK-Ay mice were treated with DMSO (with a concentration of 1%), with or without FPS-ZM1 (3 mg/kg/day, i.p). Lipid deposition in hepatocytes was observed using oil red O stain. Levels of AGEs and RAGE were measured. Sterol regulatory element-binding protein-1c (SREBP-1c), as well as nuclear factor κB p65 (p65 nfκb) and mitogen-activated protein kinase p38 (p38 MAPK), were also detected.

Lipid deposition is increased in the hepatocytes of KK-Ay mice compared to C57BL/6j mice. In addition, not only were the levels of AGEs elevated in plasma, but also the levels of RAGE in liver tissue. Although total SREBP-1c levels did not change in the liver of diabetic mice, mature SREBP-1c increased in KK-Ay mice with diabetes mellitus. Moreover, diabetic mice showed increased levels of phosphorylated-p65 nfκb (p-p65 nfκb) and phosphorylated-p38 MAPK (p-p38 MAPK). On the contrary, FPS-ZM1 decreased lipid deposition in liver cells, as well as mature SREBP-1c, p-p65 nfκb and p-p38 MAPK levels in liver tissue.

Generally, FPS-ZM1 may attenuate lipid deposition in hepatocytes of diabetic mice via SREBP-1c down-regulation. This may depend on the downregulation of p65 nfκb and p38 MAPK phosphorylation.

Gastric cancer (GC) is a common malignancy of the digestive system. According to global 2018 cancer data, GC has the fifth-highest incidence and the third-highest fatality rate among malignant tumors. More than 60% of GC are linked to infection with Helicobacter pylori (H. pylori), a gram-negative, active, microaerophilic, and helical bacterium. This parasite induces GC by producing toxic factors, such as cytotoxin-related gene A, vacuolar cytotoxin A, and outer membrane proteins. Ferroptosis, or iron-dependent programmed cell death, has been linked to GC, although there has been little research on the link between H. pylori infection-related GC and ferroptosis.

To identify coregulated differentially expressed genes among ferroptosis-related genes (FRGs) in GC patients and develop a ferroptosis-related prognostic model with discrimination ability.

Gene expression profiles of GC patients and those with H. pylori-associated GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases. The FRGs were acquired from the FerrDb database. A ferroptosis-related gene prognostic index (FRGPI) was created using least absolute shrinkage and selection operator-Cox regression. The predictive ability of the FRGPI was validated in the GEO cohort. Finally, we verified the expression of the hub genes and the activity of the ferroptosis inducer FIN56 in GC cell lines and tissues.

Four hub genes were identified (NOX4, MTCH1, GABARAPL2, and SLC2A3) and shown to accurately predict GC and H. pylori-associated GC. The FRGPI based on the hub genes could independently predict GC patient survival; GC patients in the high-risk group had considerably worse overall survival than did those in the low-risk group. The FRGPI was a significant predictor of GC prognosis and was strongly correlated with disease progression. Moreover, the gene expression levels of common immune checkpoint proteins dramatically increased in the high-risk subgroup of the FRGPI cohort. The hub genes were also confirmed to be highly overexpressed in GC cell lines and tissues and were found to be primarily localized at the cell membrane. The ferroptosis inducer FIN56 inhibited GC cell proliferation in a dose-dependent manner.

In this study, we developed a predictive model based on four FRGs that can accurately predict the prognosis of GC patients and the efficacy of immunotherapy in this population.

There is a complex interrelationship between the nervous system and the cardiovascular system. Comorbidities of cardiovascular diseases (CVD) with mental disorders, and vice versa, are prevalent. Adults with mental disorders such as anxiety and depression have a higher risk of developing CVD, and people with CVD have an increased risk of being diagnosed with mental disorders. Oxidative stress is one of the many pathways associated with the pathophysiology of brain and cardiovascular disease. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is one of the major generators of reactive oxygen species (ROS) in mammalian cells, as it is the enzyme that specifically produces superoxide. This review summarizes recent findings on the consequences of NOX activation in thrombosis and depression. It also discusses the therapeutic effects and pharmacological strategies of NOX inhibitors in CVD and brain disorders. A better comprehension of these processes could facilitate the development of new therapeutic approaches for the prevention and treatment of the comorbidity of thrombosis and depression.

The liver is the most important organ for biological transformation in the body and is crucial for maintaining the body's vital activities. Liver injury is a serious pathological condition that is commonly found in many liver diseases. It has a high incidence rate, is difficult to cure, and is prone to recurrence. Liver injury can cause serious harm to the body, ranging from mild to severe fatty liver disease. If the condition continues to worsen, it can lead to liver fibrosis and cirrhosis, ultimately resulting in liver failure or liver cancer, which can seriously endanger human life and health. Therefore, establishing an rodent model that mimics the pathogenesis and severity of clinical liver injury is of great significance for better understanding the pathogenesis of liver injury patients and developing more effective clinical treatment methods. The author of this article summarizes common chemical liver injury models, immune liver injury models, alcoholic liver injury models, drug-induced liver injury models, and systematically elaborates on the modeling methods, mechanisms of action, pathways of action, and advantages or disadvantages of each type of model. The aim of this study is to establish reliable rodent models for researchers to use in exploring anti-liver injury and hepatoprotective drugs. By creating more accurate theoretical frameworks, we hope to provide new insights into the treatment of clinical liver injury diseases.

This review provides an update on recent findings from basic, translational, and clinical studies on the molecular mechanisms of mitochondrial dysfunction and apoptosis of hepatocytes in multiple liver diseases, including but not limited to alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and drug-induced liver injury (DILI). While the ethanol-inducible cytochrome P450-2E1 (CYP2E1) is mainly responsible for oxidizing binge alcohol via the microsomal ethanol oxidizing system, it is also responsible for metabolizing many xenobiotics, including pollutants, chemicals, drugs, and specific diets abundant in n-6 fatty acids, into toxic metabolites in many organs, including the liver, causing pathological insults through organelles such as mitochondria and endoplasmic reticula. Oxidative imbalances (oxidative stress) in mitochondria promote the covalent modifications of lipids, proteins, and nucleic acids through enzymatic and non-enzymatic mechanisms. Excessive changes stimulate various post-translational modifications (PTMs) of mitochondrial proteins, transcription factors, and histones. Increased PTMs of mitochondrial proteins inactivate many enzymes involved in the reduction of oxidative species, fatty acid metabolism, and mitophagy pathways, leading to mitochondrial dysfunction, energy depletion, and apoptosis. Unique from other organelles, mitochondria control many signaling cascades involved in bioenergetics (fat metabolism), inflammation, and apoptosis/necrosis of hepatocytes. When mitochondrial homeostasis is shifted, these pathways become altered or shut down, likely contributing to the death of hepatocytes with activation of inflammation and hepatic stellate cells, causing liver fibrosis and cirrhosis. This review will encapsulate how mitochondrial dysfunction contributes to hepatocyte apoptosis in several types of liver diseases in order to provide recommendations for targeted therapeutics.

Nonalcoholic fatty liver disease (NAFLD) is a global public health problem that affects more than a quarter of the population. The development of this disease is correlated with metabolic dysfunctions that lead to lipid accumulation in the liver. Pesticides are one of etiologies that support NAFLD establishment. Therefore, the effects of the insecticide fipronil on the lipid metabolism of the human hepatic cell line, HepG2, was investigated, considering its widespread use in field crops and even to control domestic pests. To address the goals of the study, biochemical, cellular, and molecular analyses of different concentrations of fipronil in cell cultures were investigated, after 24 h of incubation. Relevant metabolites such as triglycerides, glucose levels, β-oxidation processes, and gene expression of relevant elements correlated with lipid and metabolism of xenobiotics were investigated. The results suggested that at 20 μM, the pesticide increased the accumulation of triglycerides and neutral lipids by reducing fatty acid oxidation and increasing de novo lipogenesis. In addition, changes were observed in genes that control oxidative stress and the xenobiotic metabolism. Together, the results suggest that the metabolic changes caused by the insecticide fipronil may be deleterious if persistent, favoring the establishment of hepatic steatosis.

This review offers an in-depth exploration of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) in metabolic health. It delves into how NADPH affects insulin secretion, influences insulin resistance, and plays a role in ferroptosis. NADPH, a critical cofactor in cellular antioxidant systems and lipid synthesis, plays a central role in maintaining metabolic homeostasis. In adipocytes and skeletal muscle, NADPH influences the pathophysiology of insulin resistance, a hallmark of metabolic disorders such as type 2 diabetes and obesity. The review explores the mechanisms by which NADPH contributes to or mitigates insulin resistance, including its role in lipid and reactive oxygen species (ROS) metabolism. Parallelly, the paper investigates the dual nature of NADPH in the context of pancreatic β-cell health, particularly in its relation to ferroptosis, an iron-dependent form of programmed cell death. While NADPH's antioxidative properties are crucial for preventing oxidative damage in β-cells, its involvement in lipid metabolism can potentiate ferroptotic pathways under certain pathological conditions. This complex relationship underscores the delicate balance of NADPH homeostasis in pancreatic health and diabetes pathogenesis. By integrating findings from recent studies, this review aims to illuminate the nuanced roles of NADPH in different tissues and its potential as a therapeutic target. Understanding these dynamics offers vital insights into the development of more effective strategies for managing insulin resistance and preserving pancreatic β-cell function, thereby advancing the treatment of metabolic diseases.

The objective of the study was to characterize adaptations of hepatic metabolism of dairy cows of two Holstein strains with varying proportions of grazing in the feeding strategy. Multiparous autumn calving Holstein cows of New Zealand (NZH) and North American (NAH) strains were assigned to a randomized complete block design with a 2 x 2 factorial arrangement with two feeding strategies that varied in the proportions of pasture and supplementation: maximum pasture and supplementation with a pelleted concentrate (MaxP) or fixed pasture and supplementation with a total mixed ration (FixP) from May through November of 2018. Hepatic biopsies were taken at - 45 ± 17, 21 ± 7, 100 ± 23 and 180 ± 23 days in milk (DIM), representing prepartum, early lactation, early mid-lactation and late mid-lactation. The effects of DIM, feeding strategy (FS), strain and their interactions were analyzed with mixed models using repeated measures. Cows of both strains had similar triglyceride levels, mitochondrial function and carnitine palmitoyltransferase activity in liver during lactation. However, there was an effect of DIM and FS as liver triglyceride was higher for the MaxP strategy at 21 DIM and both mitochondrial function and carnitine palmitoyltransferase activity in liver were lower for the MaxP strategy at 21 DIM. Hepatic mitochondrial function and acetylation levels were affected by the interaction between strain and feeding strategy as both variables were higher for NAH cows in the MaxP strategy. Mid-lactation hepatic gene expression of enzymes related to fatty acid metabolism and nuclear receptors was higher for NZH than NAH cows. This work confirms the association between liver triglyceride, decreased hepatic mitochondrial function and greater mitochondrial acetylation levels in cows with a higher inclusion of pasture and suggests differential adaptative mechanisms between NAH and NZH cows to strategies with varying proportions of grazing in the feeding strategy.

Introduction: The rising incidence of type 2 diabetes has seriously affected international public health. The search for more drugs that can effectively treat diabetes has become a cutting-edge trend in research. Coenzyme Q10 (CoQ10) has attracted much attention in the last decade due to its wide range of biological activities. Many researchers have explored the clinical effects of CoQ10 in patients with type 2 diabetes. However, CoQ10 has low bio-availability due to its high lipophilicity. Therefore, we have structurally optimized CoQ10 in an attempt to exploit the potential of its pharmacological activity. Methods: A novel coenzyme Q10 derivative (L-50) was designed and synthesized by introducing a group containing bromine atom and hydroxyl at the terminal of coenzyme Q10 (CoQ10), and the antidiabetic effect of L-50 was investigated by cellular assays and animal experiments. Results: Cytotoxicity results showed that L-50 was comparatively low toxicity to HepG2 cells. Hypoglycemic assays indicated that L-50 could increase glucose uptake in IR-HepG2 cells, with significantly enhanced hypoglycemic capacity compared to the CoQ10. In addition, L-50 improved cellular utilization of glucose through reduction of reactive oxygen species (ROS) accumulated in insulin-resistant HepG2 cells (IR-HepG2) and regulation of JNK/AKT/GSK3β signaling pathway, resulting in hypoglycemic effects. Furthermore, the animal experiments demonstrated that L-50 could restore the body weight of HFD/STZ mice. Notably, the findings suggested that L-50 could improve glycemic and lipid metabolism in HFD/STZ mice. Moreover, L-50 could increase fasting insulin levels (FINS) in HFD/STZ mice, leading to a decrease in fasting blood glucose (FBG) and hepatic glycogen. Furthermore, L-50 could recover triglycerides (TG), total cholesterol (T-CHO), lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) levels in HFD/STZ mice. Discussion: The addition of a bromine atom and a hydroxyl group to CoQ10 could enhance its anti-diabetic activity. It is anticipated that L-50 could be a promising new agent for T2DM.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease without pharmacological treatment yet. There is also a lack of specific dietary recommendations and strategies to treat the negative health impacts derived from NAFLD.

This scoping review aimed to compile dietary patterns, foods, and nutrients to ameliorate NAFLD.

A literature search was performed through MEDLINE, Scopus, Web of Science, and Google Scholar.

Several guidelines are available through the literature. Hypocaloric Mediterranean diet is the most accepted dietary pattern to tackle NAFLD. Coffee consumption (sugar free) may have a protective effect for NAFLD. Microbiota also plays a role in NAFLD; hence, fibre intake should be guaranteed.

A high-quality diet could improve liver steatosis. Weight loss through hypocaloric diet together with physical activity and limited sugar intake are good strategies for managing NAFLD. Specific dietary recommendations and a Mediterranean plate have been proposed to ameliorate NAFLD.

Obesity is a major risk factor for cardiovascular and metabolic diseases. Multiple experimental and clinical studies have shown increased oxidative stress and inflammation linked to obesity. NADPH oxidases are major sources of reactive oxygen species in the cardiovascular system and in metabolically active cells and organs. An impaired balance due to the increased formation of reactive oxygen species and a reduced antioxidative capacity contributes to the pathophysiology of cardiovascular and metabolic diseases and is linked to inflammation as a major pathomechanism in cardiometabolic diseases. Non-alcoholic fatty liver disease is particularly characterized by increased oxidative stress and inflammation. In recent years, COVID-19 infections have also increased oxidative stress and inflammation in infected cells and tissues. Increasing evidence supports the idea of an increased risk for severe clinical complications of cardiometabolic diseases after COVID-19. In this review, we discuss the role of oxidative stress and inflammation in experimental models and clinical studies of obesity, cardiovascular diseases, COVID-19 infections and potential therapeutic strategies.

Chronic liver disease (CLD) constitutes a growing global health issue, with no effective treatments currently available. Oxidative stress closely interacts with other cellular and molecular processes to trigger stress pathways in different hepatic cells and fuel the development of liver fibrosis. Therefore, inhibition of reactive oxygen species (ROS)-mediated effects and modulation of major antioxidant responses to counteract oxidative stress-induced damage have emerged as interesting targets to prevent or ameliorate liver injury. Although many preclinical studies have shown that dietary supplements with antioxidant properties can significantly prevent CLD progression in animal models, this strategy has not proved effective to significantly reduce fibrosis when translated into clinical trials. Novel and more specific therapeutic approaches are thus required to alleviate oxidative stress and reduce liver fibrosis. We have reviewed the relevant literature concerning the crucial role of alterations in redox homeostasis in different hepatic cell types during the progression of CLD and discussed current pharmacological approaches to ameliorate fibrosis by reducing oxidative stress focusing on selective modulation of enzymatic oxidant sources, antioxidant systems and ROS-mediated pathogenic processes.

Nonalcoholic fatty liver disease (NAFLD) has become a widely studied subject due to its increasing prevalence and links to diseases such as type 2 diabetes and obesity. It has severe complications, including nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, and portal hypertension that can lead to liver transplantation in some cases. To better prevent and treat this pathology, it is important to understand its underlying physiology. Here, we identify two main factors that play a crucial role in the pathophysiology of NAFLD: oxidative stress and the key role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). We discuss the pathophysiology linking these factors to NAFLD pathophysiology.

Nonalcoholic fatty liver disease (NAFLD) is a global health problem that is closely associated with obesity and metabolic syndrome. Spatholobi caulis (SC) is a herbal medicine with potential hepatoprotective effects; however, its active compounds and underlying mechanisms have not been fully explored. In this study, we combined a multiscale network-level approach with experimental validation to investigate SC's antioxidant properties and their impact on NAFLD. Data collection and network construction were performed, and active compounds and key mechanisms were identified through multi-scale network analysis. Validation was conducted using in vitro steatotic hepatocyte models and in vivo high-fat diet-induced NAFLD models. Our findings revealed that SC treatment improved NAFLD by modulating multiple proteins and signaling pathways, including AMPK signaling pathways. Subsequent experiments showed that SC treatment reduced lipid accumulation and oxidative stress. We also validated SC's effects on AMPK and its crosstalk pathways, emphasizing their role in hepatoprotection. We predicted procyanidin B2 to be an active compound of SC and validated it using a lipogenesis in vitro model. Histological and biochemical analyses confirmed that SC ameliorated liver steatosis and inflammation in mice. This study presents SC's potential use in NAFLD treatment and introduces a novel approach for identifying and validating active compounds in herbal medicine.

Atherosclerosis and non-alcoholic fatty liver disease (NAFLD) are pathologies related to ectopic fat accumulation, both of which are continuously increasing in prevalence. These threats are prompting researchers to develop effective therapies for their clinical management. One of the common pathophysiological alterations that underlies both diseases is oxidative stress (OxS), which appears as a result of lipid deposition in affected tissues. However, the molecular mechanisms that lead to OxS generation are different in each disease. Non-coding RNAs (ncRNAs) are RNA transcripts that do not encode proteins and function by regulating gene expression. In recent years, the involvement of ncRNAs in OxS modulation has become more recognized. This review summarizes the most recent advances regarding ncRNA-mediated regulation of OxS in atherosclerosis and NAFLD. In both diseases, ncRNAs can exert pro-oxidant or antioxidant functions by regulating gene targets and even other ncRNAs, positioning them as potential therapeutic targets. Interestingly, both diseases have common altered ncRNAs, suggesting that the same molecule can be targeted simultaneously when both diseases coexist. Finally, since some ncRNAs have already been used as therapeutic agents, their roles as potential drugs for the clinical management of atherosclerosis and NAFLD are analyzed.

Reactive oxygen species (ROS) represent a group of high reactive molecules with dualistic natures since they can induce cytotoxicity or regulate cellular physiology. Among the ROS, the superoxide anion radical (O2·-) is a key redox signaling molecule prominently generated by the NADPH oxidase (NOX) enzyme family and by the mitochondrial electron transport chain. Notably, altered redox balance and deregulated redox signaling are recognized hallmarks of cancer and are involved in malignant progression and resistance to drugs treatment. Since oxidative stress and metabolism of cancer cells are strictly intertwined, in this review, we focus on the emerging roles of NOX enzymes as important modulators of metabolic reprogramming in cancer. The NOX family includes seven isoforms with different activation mechanisms, widely expressed in several tissues. In particular, we dissect the contribute of NOX1, NOX2, and NOX4 enzymes in the modulation of cellular metabolism and highlight their potential role as a new therapeutic target for tumor metabolism rewiring.

Introduction: Non-alcoholic fatty liver disease (NAFLD) incidence has been rapidly increasing, and it has emerged as one of the major diseases of the modern world. NAFLD constitutes a simple fatty liver to chronic non-alcoholic steatohepatitis (NASH), which often leads to liver fibrosis or cirrhosis, a serious health condition with limited treatment options. Many a time, NAFLD progresses to fatal hepatocellular carcinoma (HCC). Nuclear receptors (NRs), such as liver X receptor-α (LXR-α) and closely associated farnesoid X receptor (FXR), are ligand-inducible transcription factors that regulate various metabolism-associated gene expressions and repression and play a major role in controlling the pathophysiology of the human liver. Withaferin A is a multifaceted and potent natural dietary compound with huge beneficial properties and plays a vital role as an anti-inflammatory molecule. Methods: In vivo: Swill albino mice were fed with western diet and sugar water (WDSW) for 12, 16, and 20 weeks with suitable controls. Post necropsy, liver enzymes (AST, ALT, and ALP) and lipid profile were measured by commercially available kits using a semi-auto analyzer in serum samples. Liver histology was assessed using H&E and MTS stains to check the inflammation and fibrosis, respectively, using paraffin-embedded sections and mRNA expressions of these markers were measured using qRT-PCR method. TGF-β1 levels in serum samples were quantified by ELISA. In vitro: Steatosis was induced in HepG2 and Huh7 cells using free fatty acids [Sodium Palmitate (SP) and Oleate (OA)]. After induction, the cells were treated with Withaferin A in dose-dependent manner (1, 2.5, and 5 μM, respectively). In vitro steatosis was confirmed by Oil-Red-O staining. Molecular Docking: Studies were conducted using Auto Dock Vina software to check the binding affinity of Withaferin-A to LXR-α and FXR. Results: We explored the dual receptor-activating nature of Withaferin A using docking studies, which potently improves high-fat diet-induced NAFLD in mice and suppresses diet-induced hepatic inflammation and liver fibrosis via LXR/FXR. Our in vitro studies also indicated that Withaferin A inhibits lipid droplet accumulation in sodium palmitate and oleate-treated HepG2 and Huh7 cells, which may occur through LXR-α and FXR-mediated signaling pathways. Withaferin A is a known inhibitor of NF-κB-mediated inflammation. Intriguingly, both LXR-α and FXR activation inhibits inflammation and fibrosis by negatively regulating NF-κB. Additionally, Withaferin A treatment significantly inhibited TGF-β-induced gene expression, which contributes to reduced hepatic fibrosis. Discussion: Thus, the LXR/ FXR dual receptor activator Withaferin A improves both NAFLD-associated liver inflammation and fibrosis in mouse models and under in vitro conditions, which makes Withaferin A a possibly potent pharmacological and therapeutic agent for the treatment of diet-induced NAFLD.

In alcohol-induced liver disease (ALD) and in non-alcoholic fatty liver disease (NAFLD), there are abnormal accumulations of fat in the liver. This phenomenon may be related to excessive alcohol consumption, as well as the combination of alcohol consumption and medications. There is an evolution from simple steatosis to steatohepatitis, fibrosis and cirrhosis leading to hepatocellular carcinoma (HCC). Hepatic pathology is very similar regarding non-alcoholic fatty liver disease (NAFLD) and ALD. Initially, there is lipid accumulation in parenchyma and progression to lobular inflammation. The morphological changes in the liver mitochondria, perivenular and perisinusoidal fibrosis, and hepatocellular ballooning, apoptosis and necrosis and accumulation of fibrosis may lead to the development of cirrhosis and HCC. Medical history of ethanol consumption, laboratory markers of chronic ethanol intake, AST/ALT ratio on the one hand and features of the metabolic syndrome on the other hand, may help in estimating the contribution of alcohol intake and the metabolic syndrome, respectively, to liver steatosis.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in the general population with a global prevalence of 25%. It is often associated with metabolic syndrome and type 2 diabetes, as insulin resistance and hyperinsulinemia are known to be favoring factors. Recent studies have described growing incidence of NAFLD in type 1 diabetes (T1D) as well. Although increasing prevalence of metabolic syndrome in these patients seems to explain part of this increase in NAFLD, other underlying mechanisms may participate in the emergence of NAFLD. Notably, some genetic factors are more associated with fatty liver disease, but their prevalence in T1D has not been evaluated. Moreover, oxidative stress, poor glucose control and long-lasting hyperglycemia, as well as exogenous insulin administration play an important role in intrahepatic fat homeostasis. The main differential diagnosis of NAFLD in T1D is glycogenic hepatopathy, which needs to be considered mostly in T1D patients with poor glycemic control. This article aims to review the prevalence and pathophysiology of NAFLD in T1D and open perspectives for clinicians taking care of T1D patients with potential hepatopathy.