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.

Inhibition of glutathione generation in hepatic steatotic rats augments oxidative stress.

Fatty liver disease has been strongly associated with a low glutathione (GSH) level in hepatocytes with increased oxidative stress, which is critically involved in the initiation and progression of the disease. The study investigated whether the GSH deficiency induced by buthionine sulfoximine (BSO), an inhibitor of γ-glutamyl cysteine synthetase, can be restored by the administration of GSH ester. We showed that mice fed a diet with cholesterol plus sodium cholate developed steatosis followed by hepatic GSH reduction. Moreover, the GSH level in the cytosol and mitochondria of steatosis plus BSO decreased than that of steatosis alone. Subsequent studies with the liver tissues and plasma of BSO plus steatosis revealed the accumulation of cholesterol in the hepatocytes, downregulating the concentration of GSH, antioxidant enzymes, and GSH metabolizing enzymes with a significant rise in reactive oxygen species (ROS), blood glucose level and plasma lipid profile. The administration of GSH ester in BSO-administered mice, prevented the depletion of GSH by upregulating the GSH concentration, antioxidant enzymes, and GSH metabolizing enzymes, followed by a reduction in ROS and plasma lipid concentration. The histopathological analysis showed a marked increase in inflammation followed by hepatocytes ballooning in BSO-induced group and steatosis control group, which was ameliorated by GSH ester administration. In conclusion, our data suggest that the restoration of GSH in the cytosol and mitochondria through the injection with GSH ester plays a principal role in maintaining the GSH level in the liver, thereby delaying the progression of fatty liver disease.

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.

Arsenic trioxide, a cancer chemo drug hampers fibrotic liver regeneration by interrupting oxidative stress rekindling and stellate cell rejuvenation.

After withdrawal of liver toxic insult, the spontaneous regenerative potential of the liver is well reported in the literature. On the other hand, various molecules have been reported to promote as well as delay such natural regeneration. This current study investigates the involvement of arsenic trioxide (ATO) medication at chemotherapeutic dose on the spontaneous regeneration of the CCl4 induced fibrotic liver. Liver injury markers, such as albumin and SGOT, SGPT, and ALP activities, in serum indicated that ATO supplementation during liver regeneration hampers the rejuvenation process. The hepatic architecture as well as the degree of fibrosis by hematoxylin and eosin and Sirius red staining confirms the above findings. The reduced hepatic antioxidant system and elevated oxidative stress markers, such as lipid peroxidation and 8-hydroxy deoxy-guanosine-positive hepatocytes in ATO supplied rats, display the persistence of oxidative stress when compared with healthy controls and the normal regeneration model. Immuno-histochemical localization of Ki-67 indicates that mitotically active hepatocytes were fewer in the ATO given rats when compared with normal regeneration rats. Further delay in hepatic fibrinolysis was monitored by matrix metalloproteinase zymography assay in the ATO-given animals. Poly(ADP-ribose) polymerase 1 expression demonstrates elevated hepatocyte apoptosis with ATO. Furthermore, increased α-smooth muscle actin indicates that the stellate cells are in an activated state in ATO supplemented fibrotic animals. In conclusion, it's observed that ATO supplementation to the fibrotic liver delays oxidative stress revitalization and maintains stellate cells in the active form, thereby delaying liver regeneration, and the health status of the liver must be taken into account before administering drugs like ATO.

Chemotherapeutic doses of arsenic trioxide delays hepatic regeneration by oxidative stress and hepatocyte apoptosis in partial hepatectomy rat.

The extensive regeneration potential of the liver makes use of hepatic re-sectioning and split liver transplantation for treating advanced liver diseases. Heavy metals such as cisplatin, carboplatin, and arsenic trioxide (ATO) are being practiced as chemotherapeutic agents for different cancers. Further, research is progressed on using different heavy metal nano-particles as a drug, drug carrier and diseases detective agent. Since liver is the chief organ metabolize ingested materials, the current study focuses on the involvement of ATO on acute liver injury regeneration using a partially hepatectomised (PHx) rat model. Scrutiny of serum liver markers such as albumin, AST, ALT & ALP and hepatic antioxidants like reduced glutathione, glutathione peroxidase, glutathione S-transferase, catalase & superoxide dismutase reveled ATO mediated hepatocyte injury and oxidative stress. Further, oxidative stress is confirmed with elevated TBARS and 8-OHdG in the hepatocyte nucleus in ATO supplemented healthy and regenerating liver and are co-relating with the H&E histological observations. It is noticed that ATO supplementation reduced liver regeneration potential as evidenced by reduced proliferative markers (Ki-67 and PCNA) and meanwhile increases apoptotic protein PARP-1. ICP-MS analysis displayed several-fold hiked serum and liver arsenic in ATO administrated normal and liver regenerating animals. This study concludes that ATO at a chemotherapeutic concentration augments oxidative stress and hepatocytes apoptosis, thereby delays liver regeneration potential and could affect the outcome of liver transplantation.

Augmenter of liver regeneration enhances cell proliferation through the microRNA-26a/Akt/cyclin D1 pathway in hepatic cells.

AIM: Hepatocytes can proliferate and regenerate when injured by toxins, viral infections, and so on. Augmenter of liver regeneration (ALR) is a key regulator of liver regeneration, but the mechanism is unknown. The role of ALR in other cell types is not known. In the present study, we investigated the relationship between microRNA (miRNA)-26a and ALR in the Huh7 cell line and adipose tissue-derived mesenchymal cells from chronic liver disease patients and healthy individuals. METHODS: Huh7 cells were transfected independently with ALR and miRNA-26a expression vectors, and their effects on cell proliferation, the expression of miRNA-26a, and activation of the phosphatase and tensin homolog and Akt signaling pathways were determined. The experiments were repeated on mesenchymal stem cells derived from healthy individuals and chronic liver disease patients to see whether the observations can be replicated in primary cells. RESULTS: Overexpression of ALR or miRNA-26a resulted in an increase of the phosphorylation of Akt and cyclin D1 expression, whereas it resulted in decreased levels of p-GSK-3ß and phosphatase and tensin homolog in Huh7 cells. The inhibition of ALR expression by ALR siRNA or anti-miR-26a decreased the Akt/cyclin D1 signaling pathway, leading to decreased proliferation. Mesenchymal stem cells isolated from the chronic liver disease patients had a higher ALR expression, while the mesenchymal stem cells isolated from healthy volunteers responded to the growth factor treatments for increased ALR expression. It was found that there was a significant increase in miRNA-26a expression and proliferation. CONCLUSIONS: These data clearly showed that ALR induced the expression of miRNA-26a, which downregulated phosphatase and tensin homolog, resulting in an increased p-Akt/cyclin D1 pathway and enhanced proliferation in hepatic cells.

Neutrophil extracellular traps in acrolein promoted hepatic ischemia reperfusion injury: Therapeutic potential of NOX2 and p38MAPK inhibitors.

Neutrophil is a significant contributor to ischemia reperfusion (IR) induced liver tissue damage. However, the exact role of neutrophils in IR induced innate immune activation and liver damage is not quite clear. Our study sheds light on the role of chronic oxidative stress end products in worsening the IR inflammatory process by neutrophil recruitment and activation following liver surgery. We employed specific inhibitors for molecular targets-NOX2 (NADPH oxidase 2) and P38 MAPK (Mitogen activated protein kinase) signal to counteract neutrophil activation and neutrophil extracellular trap (NET) release induced liver damage in IR injury. We found that acrolein initiated neutrophil chemotaxis and induced NET release both in vitro and in vivo. Acrolein exposure caused NET induced nuclear and mitochondrial damage in HepG2 cells as well as aggravated the IR injury in rat liver. Pretreatment with F-apocynin and naringin, efficiently suppressed acrolein induced NET release in vitro. Notably, it suppressed the expression of inflammatory cytokines, P38MAPK-ERK activation, and apoptotic signals in rat liver exposed to acrolein and subjected to IR. Moreover, this combination effectively attenuated acrolein induced NET release and hepatic IR injury. In the current study we have shown that the acrolein accumulation in liver due to chronic stress, is responsible for neutrophil recruitment and its activation leading to NET induced liver damage during surgery. Our study shows that therapeutic targeting of NOX2 and P38MAPK signaling in patients with chronic hepatic disorders would improve post operative hepatic function and survival.

Troxerutin with copper generates oxidative stress in cancer cells: Its possible chemotherapeutic mechanism against hepatocellular carcinoma.

Troxerutin (TXER) a rutin derivative is known for its anticancer effect against hepatocellular carcinoma (HCC). As part of large study, recently we have shown TXER interact with genetic material and its anti-mutagenic property. In the present study we have explored its possible mode of action in HCC. Since TXER alone did not show significant anticancer effect on Huh-7 cells, in vitro biochemical assays were performed for determining anticancer efficacy of TXER + metal complex using transition metals such as Cu, Zn, and Fe. The anticancer efficacy of TXER + Cu on Huh-7 cells were evaluated using MTT assay, DCFDA, JC-1 staining, comet assay, cell cycle analysis, immunocytochemistry, and Western blotting. Non-toxic nature of TXER was analyzed on primary rat hepatocytes. The in vivo efficacy of TXER was tested in N-nitrosodiethylamine initiated and γ-benzene hexachloride and partial hepatectomy promoted rat liver cancer. Liver markers, transition metal levels, histopathological examination, and expression levels of GST-P, 8-OHdG and Ki-67 were studied to assess the in vivo anticancer effect of TXER. We observed that TXER + Cu induced extensive cellular death on Huh-7 cells through generating free radicals and did not possess any toxic effect on normal hepatocytes. The in vivo studies revealed that TXER possess significant anti-cancer effect as assessed through improved liver markers and suppressed GST-P, 8-OHdG, and Ki-67 expression. TXER treatment reduced the hepatic Cu level in cancer bearing animals. Current study brings the putative mechanism involved in anti-cancer effect of TXER, further it will help to formulate phytoconstituents coupled anti-cancer drug for effective treatment of HCC.

Preconditioning methods in the management of hepatic ischemia reperfusion- induced injury: Update on molecular and future perspectives.

Hepatic IR (ischemia reperfusion) injury is a commonly encountered obstacle in the post-operative management of hepatic surgery. Hepatic IR occurs during 'Pringle maneuver' for reduction of blood loss or during a brief period of cold storage followed by reperfusion of liver grafts. The stress induced during hepatic IR, triggers a spectrum of cellular responses leading to the varying degrees of hepatic complications which in turn affect the post operative care. Different preconditioning methods either activate or subdue different sets of molecular signals, resulting in varied levels of protection against hepatic IR injury. Yet, there is a serious lacuna in the knowledge regarding the choice of preconditioning methods and the resulting molecular changes in order to assess the efficiency and choice of these methods correctly. This review provides an update on the various preconditioning approaches such as surgical/ischemic, antioxidant, pharmaceutical and genetic preconditioning strategies published during last six years (2009-2015). Further, we discuss the attenuation or inhibition of specific inflammatory, apoptotic and necrotic markers in the various experimental models of liver IR subjected to different preconditioning strategies. While enlisting the controversies in the ischemic preconditioning strategy, we bring out the uncertainties in the existing molecular targets and their reliability in the attenuation of hepatic IR injury. Future research studies would include the novel preconditioning strategies employ i) the targeted gene silencing of key molecular targets inducing IR, ii) hyper expression of beneficial molecular signals against IR via gene transfer techniques. The above studies would see the combination of these latest techniques with the established preconditioning strategies for better post-operative hepatic management.

TNF-α suppression by glutathione preconditioning attenuates hepatic ischemia reperfusion injury in young and aged rats.

BACKGROUND AND AIM: Hepatic ischemia reperfusion (I/R) stimulates Kupffer cells and initiates injury through tumor necrosis factor-α (TNF-α) upregulation. Aim of this study was to compare the variable effects of reduced glutathione (GSH) pre-treatment on I/R liver injury in young and aged rats. METHODS: Wistar male rats were sorted into young (groups I-III) and aged (groups IV-VI). All groups except sham (groups I and IV) were subjected to 90-min ischemia and 2-h reperfusion. The treatment groups received 200 mg/kg bwt (groups III and VI) of GSH, 30 min prior to I/R. Variable effects of GSH were studied by transaminase activities, thiobarbituric acid-reactive substances (TBARS), GSH level, GSH/oxidized GSH (GSSG) ratio, TNF-α level, apoptotic markers and confirmed by histopathological observations. RESULTS: Our findings revealed that I/R inflicted more liver damage in aged rats than young rats. The GSH treatment prior to surgery significantly lowered the serum transaminase activities, hepatic TBARS level and effectively restored the GSH/GSSG ratio in both young and aged rats more remarkably in the mitochondria. Western analysis depicted that the GSH treatment effectively suppressed TNF-α expression and apoptotic markers in both young and aged rats. These findings were further confirmed by terminal deoxynucleotide transferase dUTP nick end labeling assay and histopathological observations of liver sections of young and aged rats. CONCLUSION: Restoration of GSH/GSSG ratio through GSH pre-conditioning inhibits TNF-α and apoptosis in hepatic I/R injury. Hence, GSH pre-conditioning may be utilized in both young and aged individuals during liver transplantation/surgery for better post-operative outcomes.

Synthesis and biological evaluation of isoindoloisoquinolinone, pyroloisoquinolinone and benzoquinazolinone derivatives as poly(ADP-ribose) polymerase-1 inhibitors.

A series of novel fused isoquinolinones with isoindoloisoquinolinone, pyroloisoquinolinone, and benzoquinalizinone skeletons were synthesized from corresponding phenethylimides. The isoquinolinone derivatives were evaluated for their protective effect on chicken erythrocytes subjected to oxidative damage. The effect of isoquinolinone derivatives were analysed by estimation of cell viability, antioxidant enzyme activities, DNA damage (comet assay), PARP-1 inhibition assay and molecular docking of the compounds with PARP-1 active site. The compounds CRR-271, CRR-288 and CRR-224+225 showed significant protective effect at 100 µM concentration. The PARP-1 inhibition assay revealed the IC50 values of CRR-271, CRR-288 and CRR-224+225 as <200 nM, further molecular docking studies shows higher binding energies with PARP-1 active site. Interesting findings in this study suggest that the novel isoquinolinone derivatives inhibit PARP-1 activity and protect cells against oxidative DNA damage, which could be implemented in the treatment of inflammatory diseases.

Nutrient profile of porridge made from Eleusine coracana (L.) grains: effect of germination and fermentation.

Porridge (koozh) is one of the traditional foods made from Eleusine coracana L. grains (Finger millet). It is a soft food prepared from processed (germinated & fermented) finger millet flour (FMF). However, in the modern world of fast food, koozh is usually prepared from non-processed (non-germinated & non-fermented) FMF. Hence, present study was undertaken to evaluate the macro and micro nutrient contents in koozh prepared from germinated (fermented & non-fermented) and non-germinated (fermented & non-fermented) FMF. Highest protein, carbohydrate and glycoprotein contents were found in koozh prepared from germinated & non-fermented FMF. The free amino acid contents are higher in germinated & fermented condition when compare to other preparations. No significant change was observed in the calorific value of all preparations. There is no statistical difference in macro-nutrients & micro-nutrients minerals such as calcium, iron, magnesium, manganese, phosphorous and zinc among all the preparations. However, copper content is higher in non-germinated condition, whereas selenium, silicon and sulphur are higher in germinated FMF when compared to others. Significant level of total phenol, total flavonoid and free radical scavenging activity was observed in all preparations, which increased further during fermentation. The present observations, lead us to conclude that koozh prepared from germinated & non-fermented FMF contains higher level of carbohydrate, protein and glycoprotein, however germinated & fermented koozh has increased aminoacids, phytochemicals and free radical scavenging activity. Hence it is suggested that the consumption of koozh made from germinated & fermented FMF may provide easily digestible and energetic nutrients for healthier life.

Gut Microbiome and Cancer: From Cancer Development to Therapeutics with a Special Focus on Hepatocellular Carcinoma.

The body of a human has a vast array of microorganisms termed the microbiome that impacts almost every function of the body. Gene-environment interactions play a major role in making us susceptible to cancer and the microbiome is such an environmental factor that we are exposed to from the very beginning of our lives to the very end. Increasing pieces of evidence are pointing towards an association of cancer and the microbiome. The bacteria inside our body might help us prevent some cancers as well as may increase the risk of carcinogenesis and treatment responses. Many studies are suggesting that tinkering with the microbiome might be a new way to treat and prevent many kinds of cancer. Although information on the roles of the microbiome in carcinogenesis is scant and almost no direct links have been found between these two yet. This review offers some of the recent evidences of the association between cancer and the microbiome, discuss the impact of gut bacteria on cancer and provide a detailed discussion on gut microbiota mediated therapeutic approaches with a special focus on Hepatocellular Carcinoma. The implementation of the new knowledge discovered in this subject calls for a great deal of research.

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.

Selenium Nanoparticles Show Anticancer Activity Through Regulation of HIF-1α and HIF-2α Under Hypoxic Condition in Liver Cancer Cells.

Tumor microenvironment has significant influence in therapeutic response and clinical outcome. Combination therapy is more effective in cancer treatment compared with monotherapy. Any chemical or drug that targets tumor microenvironment pathway, will be a boon to combination cancer chemotherapy. Combination therapy through micronutrient may have added advantage in clinical applications. Selenium (Se) is an essential micronutrient; Se in the form of Se nanoparticles (SeNPs) show efficient anticancer properties and may have the potential to target tumor niche such as hypoxic environment. The aim of this study was to find out the anticancer effect of SeNPs on cell line HepG2 under hypoxic condition and also to evaluate their effect on the translocation of hypoxia-inducible factors (HIFs) from cytoplasm to nucleus that help the cells to survive under hypoxic condition. It was found that the SeNPs induce HepG2 cell death in normoxic and hypoxic conditions, however, hypoxic condition showed higher LD50. SeNP concentration is directly proportional to cell death in both the conditions. Furthermore, intracellular accumulation of Se is not affected by hypoxia. SeNP-induced HepG2 cell death is due to increased DNA damage, nuclear condensation, and mitochondrial membrane potential disturbance. Furthermore, SeNPs were also found to decrease the translocation of HIFs from cytosol to the nucleus. After analyzing the results, it is concluded that SeNP treatment disturbs tumor niche through the inhibition of HIFs' translocation from cytosol to nucleus. SeNPs in synergy with primary drug, such as doxorubicin (DOX), may enhance the anticancer efficacy of DOX through regulation of HIFs, warranting further research.

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.

Transcriptional profiling reveals ataxia telangiectasia mutated pathways regulate joint copper and arsenic toxicity for hepatic metalloplasia and anti-cancer therapies.

AIMS: Exposures to toxic metals, including arsenic (As), pose health risks but joint effects of physiologically needed metals, e.g., copper (Cu), are ill-defined for regulated metal-dependent cell proliferation (or metalloplasia). This study elucidated hepatic toxicities of As and Cu. MAIN METHODS: Human HuH-7 cells were exposed to As and Cu and mRNA profiling obtained for molecular networks, regulators and signaling pathways. This followed biological testing of ATM signaling-related DNA damage response, mitochondrial dysfunction and lysosome activity using HuH-7 cells and primary hepatocytes. Free Cu ions were bound to 3-indole propionic acid for finding their contribution in toxicity. KEY FINDINGS: The As or As plus Cu toxicities in HuH-7 cells produced dimorphic down- or up-regulation patterns in mRNA profiles. Significant differences extended for ontologies in protein synthesis, intermediary metabolism, mitochondrial function, autophagy, or cell survival and growth. Bioassays revealed ATM signaling regulated As and Cu toxicity for oxidative phosphorylation, mitochondrial membrane potential, lysosomal activity, DNA damage response, and cell growth-arrest. Removal of reactive Cu ions decreased As and Cu toxicity. Primary hepatocytes withstood Cu and As toxicity better. SIGNIFICANCE: This joint As and Cu toxicity offers further mechanisms for metalloplasia, carcinogenesis and tissue damage in other settings, e.g., during excess Cu accumulation in Wilson disease. Moreover, joint As and Cu toxicities are relevant for anti-cancer therapies, potentially including manipulations to increase intracellular Cu through altered uptake or efflux processes and incorporating ATM-related checkpoint inhibitors. Superior tolerance of healthy hepatocytes to Cu and As toxicity should improve safety margins for anti-cancer therapies.

Prevalence and characteristics of microplastics present in the street dust collected from Chennai metropolitan city, India.

In the present study, we assessed the extent of microplastic pollution in the road dust of Chennai, the fifth largest metropolitan city in India. This study is the first of its kind to be reported from India. Sixteen different locations were selected from which road dust samples were collected. The average microplastic abundance was estimated to be 227.94 ± 91.37 per hundred grams of street dust sample. Nile Red dye was used for microplastic identification and quantification. 92.46% of the quantified microplastics were fragments. Raman spectroscopy of a representative sample identified nine types of polymers viz. polyvinyl chloride, poly(ethylene-co-vinyl-acetate), HDPE, poly(tetrafluoroethylene), cellulose microcrystalline, lyocell, superflex-200, wax-1032, and AC-395. SEM-EDS analysis highlighted the presence of various trace elements pertaining to automobile exhausts. Assessment of microplastic pollution rampant in street dust, especially in coastal cities as Chennai, is a dire need as it pertains to the concerns of human health and escape into the marine environment.