Epigenetics and mitochondrial dysfunction insights into the impact of the progression of non-alcoholic fatty liver disease.

A metabolic problem occurs when regular functions of the body are disrupted due to an undesirable imbalance. Nonalcoholic fatty liver disease (NAFLD) is considered as one of the most common in this category. NAFLD is subclassified and progresses from lipid accumulation to cirrhosis before advancing to hepatocellular cancer. In spite of being a critical concern, the standard treatment is inadequate. Metformin, silymarin, and other nonspecific medications are used in the management of NAFLD. Aside from this available medicine, maintaining a healthy lifestyle has been emphasized as a means of combating this. Epigenetics, which has been attributed to NAFLD, is another essential feature of this disease that has emerged as a result of several sorts of research. The mechanisms by which DNA methylation, noncoding RNA, and histone modification promote NAFLD have been extensively researched. Another organelle, mitochondria, which play a pivotal role in biological processes, contributes to the global threat. Individuals with NAFLD have been documented to have a multitude of alterations and malfunctioning. Mitochondria are mainly concerned with the process of energy production and regulation of the signaling pathway on which the fate of a cell relies. Modulation of mitochondria leads to elevated lipid deposition in the liver. Further, changes in oxidation states result in an impaired balance between the antioxidant system and reactive oxygen species directly linked to mitochondria. Hence mitochondria have a definite role in potentiating NAFLD. In this regard, it is essential to consider the role of epigenetics as well as mitochondrial contribution while developing a medication or therapy with the desired accuracy.

The relevance of acid sphingomyelinase as a potential target for therapeutic intervention in hepatic disorders: current scenario and anticipated trends.

Acid sphingomyelinase (ASMase) serves as one of the most remarkable enzymes in sphingolipid biology. ASMase facilitates the hydrolysis of sphingomyelin, yielding ceramide and phosphorylcholine via the phospholipase C signal transduction pathway. Owing to its prominent intervention in apoptosis, ASMase, and its product ceramide is now at the bleeding edge of lipid research due to the coalesced efforts of several research institutions over the past 40 years. ASMase-catalyzed ceramide synthesis profoundly alters the physiological properties of membrane structure in response to a broad range of stimulations, orchestrating signaling cascades for endoplasmic reticulum stress, autophagy, and lysosomal membrane permeabilization, which influences the development of hepatic disorders, such as steatohepatitis, hepatic fibrosis, drug-induced liver injury, and hepatocellular carcinoma. As a result, the potential to modulate the ASMase action with appropriate pharmaceutical antagonists has sparked a lot of curiosity. This article emphasizes the fundamental mechanisms of the systems that govern ASMase aberrations in various hepatic pathologies. Furthermore, we present an insight into the potential therapeutic agents used to mitigate ASMase irregularities and the paramountcy of such inhibitors in drug repurposing.

The prominence of potential biomarkers in the diagnosis and management of hepatocellular carcinoma: Current scenario and future anticipation.

Hepatocellular carcinoma (HCC) is one of the most aggressive and truculent types of cancer. Early detection of HCC is a massive concern that can boost the overall survival rates of HCC patients. As a result, there is a continual quest for advancements in screening, diagnosis, and treatment strategies to enhance the prognosis at its early stages. However, the confluence of inflammation and cirrhosis hampers the early detection of HCC. The analysis of different types of biomarkers such as tissue biomarkers, serum biomarkers, protein biomarkers, autoantibody markers, and improved imaging techniques has played a vital role in ameliorating HCC monitoring responses. Therefore biomarkers that can identify HCC early with a high degree of sensitivity and specificity might be prodigiously serviceable in the diagnosis and treatment of this notorious disorder. This study offers an overview of the contemporary understanding of several types of biomarkers implicated in hepatocarcinogenesis and their applications in monitoring, diagnosis, and prognosis presage. In additament, we address the role of image techniques associated with HCC diagnosis.

Targeting molecular signal transduction pathways in hepatocellular carcinoma and its implications for cancer therapy.

Hepatocellular carcinoma is a substantial health concern. It is currently the third dominating cause of mortality associated with cancer worldwide. The development of hepatocellular carcinoma is an intricate process that encompasses the impairment of genetic, epigenetic, and signal transduction mechanisms contributing to an aberrant metabolic system, enabling tumorigenesis. Throughout the past decade, research has led to the revelation of molecular pathways implicated in the progression of this notorious disorder. The altered signal transduction pathways, such as the mitogen-activated protein kinase pathway, phosphoinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, WNT/ß-catenin pathway, hepatocyte growth factor/c-MET pathway, and just another kinase/signal transducers and activators of transcription signaling pathway is of much therapeutic significance, as targeting them may avail to revert, retard or avert hepatocarcinogenesis. The present review article sums up the contemporary knowledge of such signaling mechanisms, including their therapeutic targets and betokens that novel and efficacious therapies can be developed only by the keen understanding of their character in hepatocarcinogenesis. In additament, we address the role of consequential therapeutic agents and preclinical nondrug therapies known for combating hepatocarcinogenesis.

Elucidation of escitalopram oxalate and related antidepressants as putative inhibitors of PTP4A3/PRL-3 protein in hepatocellular carcinoma: A multi-computational investigation.

Hepatocellular carcinoma (HCC) persists to be one of the most devastating and deadliest malignancies globally. Recent research into the molecular signaling networks entailed in many malignancies has given some prominent insights that can be leveraged to create molecular therapeutics for combating HCC. Therefore, in the current communication, an in-silico drug repurposing approach has been employed to target the function of PTP4A3/PRL-3 protein in HCC using antidepressants: Fluoxetine hydrochloride, Citalopram, Amitriptyline, Imipramine, and Escitalopram oxalate as the desired ligands. The density function theory (DFT) and chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters for the chosen ligands were evaluated to comprehend the pharmacokinetics, drug-likeness properties, and bioreactivity of the ligands. The precise interaction mechanism was explored using computational methods such as molecular docking and molecular dynamics (MD) simulation studies to assess the inhibitory effect and the stability of the interactions against the protein of interest. Escitalopram oxalate exhibited a comparatively significant docking score (-7.4 kcal/mol) compared to the control JMS-053 (-6.8 kcal/mol) against the PRL-3 protein. The 2D interaction plots exhibited an array of hydrophobic and hydrogen bond interactions. The findings of the ADMET forecast confirmed that it adheres to Lipinski's rule of five with no violations, and DFT analysis revealed a HOMO-LUMO energy gap of -0.26778 ev, demonstrating better reactivity than the control molecule. The docked complexes were subjected to MD studies (100 ns) showing stable interactions. Considering all the findings, it can be concluded that Escitalopram oxalate and related therapeutics can act as potential pharmacological candidates for targeting the activity of PTP4A3/PRL-3 in HCC.

Elucidation of 7,8-dihydroxy flavone in complexing with the oxidative stress-inducing enzymes, its impact on radical quenching and DNA damage: an in silico and in vitro approach.

Oxidative stress (OS) has been attributed to the progression of various disorders, including cancer, diabetes, and cardiovascular diseases. Several antioxidant compounds and free radical quenchers have been shown to mitigate oxidative stress. However, large-scale randomized controlled trials of such compounds on chronic disease aversion have yielded paradoxical and disappointing results due to the constrained cognizance of their oxidative mechanisms and therapeutic targets. The current study sought to identify the potential therapeutic targets of 7,8-Dihydroxyflavone (7,8-DHF) by analyzing its interactions with the enzymes implicated in oxidative stress and also to explore its radicle quenching potential and prophylactic impact on the H2O2-induced DNA damage. Through the in silco approach, we investigated the antioxidant potential of 7,8-DHF by evaluating its interactions with the human oxidative stress-inducing enzymes such as myeloperoxidase (MPO), NADPH oxidase (NOX), nitric oxide synthase (NOS), and xanthine oxidase (XO) and a comparative analysis of those interactions with known antioxidants (Ascorbic acid, Melatonin, Tocopherol) used as controls. The best-scoring complex was adopted for the simulation analysis in investigating protein-ligand conformational dynamics. The in vitro radicle quenching potential was evaluated by performing a spectrum of antioxidant assays, and radical quenching was observed in a dose-dependent fashion with IC50 values of < 60 µM/mL. Further, we probed its anti-hemolytic potential and prophylactic impact in avian erythrocytes subjected to H2O2-induced hemolysis and DNA damage by implementing hemolysis and comet assays. The protective effect was more pronounced at higher concentrations of the drug.Communicated by Ramaswamy H. Sarma.

Nutrient mixture from germinated legumes: Enhanced medicinal value with herbs-attenuated liver cirrhosis.

Among various food processing strategies, germination and dehulling enhance the nutritional content of the food, and the addition of herbs to this could improve the medicinal value. The milled powders of germinated Macrotyloma uniflorum (horse gram) and Vigna radiata (green gram) were used to make the nutrient mixture. Further, Curcuma longa (turmeric) and Trigonella foenum graecum (fenugreek) were used to improve its medicinal value. The prepared nutrient mixture has high nutritional value, antioxidant potential, and reduced antinutrient factors. Supplementation of nutrient mixture reduced oxidative stress-mediated hepatocyte injury on the CCl4 -induced liver cirrhosis model. Further, histological examination (H&E and Sirius red), matrix metalloproteinase gelatin zymography, and Western blot revealed the management of hepatic stellate cells in an inactive stage thereby reduced cirrhosis. These findings conclude that the supplementation of nutrient mixture formulation protected and effectively prevented liver cirrhosis. PRACTICAL APPLICATIONS: This study has a good impact on nutritional therapy for liver diseases. Many of the chronic liver diseases are associated with severe malnutrition and hypoalbuminemia, which further worsens the condition. This study would emphasize the nutritional therapy to treat such imbalance and enriching the medicinal value of nutrition mixture with herbs could target different pathophysiological changes and provide better defense in liver disease patients. Since this nutrient mixture is from common edible natural resources, it could reach the pharmaceutical industry's attention to the highest production and marketing.