Fisetin Inhibits Autophagy in HepG2 Cells via PI3K/Akt/mTOR and AMPK Pathway.

The effect of fisetin on autophagy in hepatocellular carcinoma remains uncovered. HepG2 cells were exposed to different concentrations of fisetin (25, 50, and 100 µM) for 24 h. The cells were also treated with rapamycin and chloroquine alone or in combination with fisetin. Autophagic flux formation and ATP levels were determined. The changes in autophagic markers and AMPK signaling proteins were analyzed using qRT-PCR and Western blotting. Cyto-ID staining followed by flow cytometry showed that fisetin decreased autophagic flux formation in a dose-dependent manner. In gene expression analysis, the mRNA levels of mTOR, Atg5, Atg16L, and LC3A were elevated, whereas the mRNA levels of Atg7 and Beclin1 were downregulated in a dose-dependent manner compared to control. In the Western blotting analysis, fisetin treatment inhibited the expression of Atg7, Atg16L, mTOR, and pACC and elevated the expression of Atg5, AMPKα, AMPKß1/2, ACC and Akt. Taken together, the results revealed that fisetin inhibited autophagy by the activation of PI3K/Akt/mTOR and modulation of AMPK signaling pathways. Our findings indicate that suppression of autophagy by fisetin may serve as an effective therapeutic strategy against HCC.

Ferulic acid attenuates arsenic-induced cardiotoxicity in rats.

Arsenic (As), a potent environmental toxin, causes cardiac functional impairments. Ferulic acid (FA), a ubiquitous dietary hydroxycinnamate, exerts beneficial effects on human health. Hence, the present study investigated the effect of FA on myocardial oxidative stress parameters, ATP level, the status of cardiac cytoskeleton intermediate filaments-desmin and vimentin, and AMPK signaling proteins in As-intoxicated rats. Wistar rats were administered orally with FA-40 mg/kg and As-5 mg/kg alone and in combination for 30 days. Myocardial As content, serum cardiac marker enzyme activities including creatine kinase-isoenzyme, lactate dehydrogenase, and aspartate aminotransferase were increased in As-exposed rats. An accumulation of myocardial oxidants such as reactive oxygen species, lipid peroxidation, nitric oxide, protein carbonyl content, and histological aberrations was observed. A significant decrease of myocardial antioxidants comprises superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, and ascorbic acid and declined expression of desmin and vimentin was noted. Impaired energy signaling molecules AMPKα (Thr172), AMPKß1/2 (Ser108), ACC (Ser79), and intracellular myocardial ATP depletion were observed in As-intoxicated animals. FA attenuates As-induced cardiac dysfunction by restoring the expression of intermediate filaments and AMPK proteins. Based on the above findings, FA treatment could be used as a novel therapeutic against As-induced cardiac dysfunction.

Acute fluoride exposure alters myocardial redox and inflammatory markers in rats.

Acute fluoride (F-) exposure adversely impairs cardiac functions. We previously reported that acute F- toxicity causes modulation in oxidant and antioxidant systems, heat shock proteins, cytoskeletal proteins and AMPK signaling proteins in the myocardium of rats. With these findings, we hypothesized that acute F- intoxication may trigger an acute myocardial inflammatory response through the activation of NF-κB signaling and reduction of redox signaling regulatory system. To test this hypothesis, we treated male Wistar rats with single oral doses of 45 and 90 mg/kg of F- for 24 h. The myocardium of F- treated rats showed increased expression of pNF-κB, pIκKα/ß eventually leading to the increased expression of downstream target TNFα-a major proinflammatory cytokine secreted in the inflammatory process. F- intoxication decreased the mRNA expression of redox genes-Sirt1, Sirt3, Prdx2, Glrx1, Trx1, and Trx2. In addition, we observed decreased protein expression of Nrf2, GCLC, and NQO1 in the cardiac tissues of F- treated rats. This study reveals that F- toxicity triggers myocardial inflammatory response and depletes redox signaling molecules in the myocardium of rats. We conclude that NF-κB activation with decreased redox gene expression might be associated with the pathophysiology of F- induced cardiac dysfunction in rats. This finding provides new insights into the cardiovascular pathophysiology in acute F- toxicity.

Genome-wide identification and analysis of Nrf2 binding sites - Antioxidant response elements in zebrafish.

In the post-genomic era, deciphering the Nrf2 binding sites - antioxidant response elements (AREs) is an essential task that underlies and governs the Keap1-Nrf2-ARE pathway - a cell survival response pathway to environmental stresses in the vertebrate model system. AREs regulate the transcription of a repertoire of phase II detoxifying and/or oxidative-stress responsive genes, offering protection against toxic chemicals, carcinogens, and xenobiotics. In order to identify and analyze AREs in zebrafish, a pattern search algorithm was developed to identify AREs and computational tools available online were utilized to analyze the identified AREs in zebrafish. This study identified the AREs within 30 kb upstream from the transcription start site of antioxidant genes and mitochondrial genes. We report for the first time the AREs of all the known protein coding genes in the zebrafish genome. Western blotting, RT2 profiler array PCR, and qRT-PCR were performed to test whether AREs influence the Nrf2 target genes expression in the zebrafish larvae using sulforaphane. This study reveals unique AREs that have not been previously reported in the cytoprotective genes. Nine TGAG/CNNNTC and six TGAG/CNNNGC AREs were observed significantly. Our findings suggest that AREs drive the dynamic transcriptional events of Nrf2 target genes in the zebrafish larvae on exposure to sulforaphane. The identified abundant putative AREs will define the Keap1-Nrf2-ARE network and elucidate the precise regulation of Nrf2-ARE pathway in not only diseases but also in embryonic development, inflammation, and aerobic respiration. Our results help to understand the dynamic complexity of the Nrf2-ARE system in zebrafish.

Iron oxide nanoparticles modulate heat shock proteins and organ specific markers expression in mice male accessory organs.

With increased industrial utilization of iron oxide nanoparticles (Fe2O3-NPs), concerns on adverse reproductive health effects following exposure have been immensely raised. In the present study, the effects of Fe2O3-NPs exposure in the seminal vesicle and prostate gland were studied in mice. Mice were exposed to two different doses (25 and 50 mg/kg) of Fe2O3-NPs along with the control and analyzed the expressions of heat shock proteins (HSP60, HSP70 and HSP90) and organ specific markers (Caltrin, PSP94, and SSLP1). Fe2O3-NPs decreased food consumption, water intake, and organo-somatic index in mice with elevated iron levels in serum, urine, fecal matter, seminal vesicle and prostate gland. FTIR spectra revealed alterations in the functional groups of biomolecules on Fe2O3-NPs treatment. These changes are accompanied by increased lactate dehydrogenase levels with decreased total protein and fructose levels. The investigation of oxidative stress biomarkers demonstrated a significant increase in reactive oxygen species, nitric oxide, lipid peroxidation, protein carbonyl content and glutathione peroxidase with a concomitant decrement in the glutathione and ascorbic acid in the male accessory organs which confirmed the induction of oxidative stress. An increase in NADPH-oxidase-4 with a decrease in glutathione-S-transferase was observed in the seminal vesicle and prostate gland of the treated groups. An alteration in HSP60, HSP70, HSP90, Caltrin, PSP94, and SSLP1 expression was also observed. Moreover, accumulation of Fe2O3-NPs brought pathological changes in the seminal vesicle and prostate gland of treated mice. These findings provide evidence that Fe2O3-NPs could be an environmental risk factor for reproductive disease.

Repeated exposure to iron oxide nanoparticles causes testicular toxicity in mice.

The aim of this study was to determine whether repeated exposure to iron oxide nanoparticles (Fe2 O3 -NPs) could be toxic to mice testis. Fe2 O3 -NPs (25 and 50 mg/kg) were intraperitoneally administered into mice once a week for 4 weeks. Our study showed that Fe2 O3 -NPs have the ability to cross the blood-testis barrier to get into the testis. The findings showed that exposure resulted in the accumulation of Fe2 O3 -NPs which was evidenced from the iron content and accumulation in the testis. Furthermore, 25 and 50 mg/kg Fe2 O3 -NPs administration increased the reactive oxygen species, lipid peroxidation, protein carbonyl content, glutathione peroxidase activity, and nitric oxide levels with a concomitant decrease in the levels of antioxidants-superoxide dismutase, catalase, glutathione, and vitamin C. Increased expression of Bax, cleaved-caspase-3, and cleaved-PARP confirms apoptosis. Serum testosterone levels increased with increased concentration of Fe2 O3 -NPs exposure. In addition, the histopathological lesions like vacuolization, detachment, and sloughing of germ cells were also observed in response to Fe2 O3 -NPs treatment. The data from our study entailed that testicular toxicity caused by Fe2 O3 -NPs exposure may be associated with Fe2 O3 -NPs accumulation leading to oxidative stress and apoptosis. Therefore, precautions should be taken in the safe use of Fe2 O3 -NPs to avoid complications in the fertility of males. Further research will unravel the possible molecular mechanisms on testicular toxicity of Fe2 O3 -NPs. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 594-608, 2017.

Acute and sub-lethal exposure to copper oxide nanoparticles causes oxidative stress and teratogenicity in zebrafish embryos.

Nano-copper oxides are a versatile inorganic material. As a result of their versatility, the immense applications and usage end up in the environment causing a concern for the lifespan of various beings. The ambiguities surround globally on the toxic effects of copper oxide nanoparticles (CuO-NPs). Hence, the present study endeavored to study the sub-lethal acute exposure effects on the developing zebrafish embryos. The 48 hpf LC50 value was about 64 ppm. Therefore, we have chosen the sub-lethal dose of 40 and 60 ppm for the study. Accumulation of CuO-NPs was evidenced from the SEM-EDS and AAS analyzes. The alterations in the AChE and Na(+)/K(+)-ATPase activities disrupted the development process. An increment in the levels of oxidants with a concomitant decrease in the antioxidant enzymes confirmed the induction of oxidative stress. Oxidative stress triggered apoptosis in the exposed embryos. Developmental anomalies were observed with CuO-NPs exposure in addition to oxidative stress in the developing embryos. Decreased heart rate and hatching delay hindered the normal developmental processes. Our work has offered valuable data on the connection between oxidative stress and teratogenicity leading to lethality caused by CuO-NPs. A further molecular mechanism unraveling the uncharted connection between oxidative stress and teratogenicity will aid in the safe use of CuO-NPs.

Micro-RNAs and their roles in eye disorders.

Micro-RNAs (miRNAs) are members of the family of noncoding RNA molecules that regulate gene expression by translational repression and mRNA degradation. Initial identification of miRNAs revealed them only as developmental regulators; later, their radiated roles in various cellular processes have been established. They regulate several pathways, including developmental timing, hematopoiesis, organogenesis, apoptosis, cell differentiation and proliferation. Their roles in eye disorders are being explored by biologists around the world. Eye physiology requires the perfect orchestration of all the regulatory networks; any defect in any of the networks leads to eye disorders. The dysregulation of miRNA expression has been reported in many eye disorders, which paves the way for new therapeutics. This review summarizes the biogenesis of miRNAs and their role in eye disorders. miRNA studies also have implications for the understanding of various complex metabolic pathways leading to disorders of the eye. The ultimate understanding leads to potential opportunities in evaluating miRNAs as molecular biomarkers, prognostic tools, diagnostic tools and therapeutic agents for eye disorders.

Rbm8a deficiency causes hematopoietic defects by modulating Wnt/PCP signaling.

Defects in blood development frequently occur among syndromic congenital anomalies. Thrombocytopenia-Absent Radius (TAR) syndrome is a rare congenital condition with reduced platelets (hypomegakaryocytic thrombocytopenia) and forelimb anomalies, concurrent with more variable heart and kidney defects. TAR syndrome associates with hypomorphic gene function for RBM8A/Y14 that encodes a component of the exon junction complex involved in mRNA splicing, transport, and nonsense-mediated decay. How perturbing a general mRNA-processing factor causes the selective TAR Syndrome phenotypes remains unknown. Here, we connect zebrafish rbm8a perturbation to early hematopoietic defects via attenuated non-canonical Wnt/Planar Cell Polarity (PCP) signaling that controls developmental cell re-arrangements. In hypomorphic rbm8a zebrafish, we observe a significant reduction of cd41-positive thrombocytes. rbm8a-mutant zebrafish embryos accumulate mRNAs with individual retained introns, a hallmark of defective nonsense-mediated decay; affected mRNAs include transcripts for non-canonical Wnt/PCP pathway components. We establish that rbm8a-mutant embryos show convergent extension defects and that reduced rbm8a function interacts with perturbations in non-canonical Wnt/PCP pathway genes wnt5b, wnt11f2, fzd7a, and vangl2. Using live-imaging, we found reduced rbm8a function impairs the architecture of the lateral plate mesoderm (LPM) that forms hematopoietic, cardiovascular, kidney, and forelimb skeleton progenitors as affected in TAR Syndrome. Both mutants for rbm8a and for the PCP gene vangl2 feature impaired expression of early hematopoietic/endothelial genes including runx1 and the megakaryocyte regulator gfi1aa. Together, our data propose aberrant LPM patterning and hematopoietic defects as consequence of attenuated non-canonical Wnt/PCP signaling upon reduced rbm8a function. These results also link TAR Syndrome to a potential LPM origin and a developmental mechanism.

Evaluation of Maghemite Nanoparticles-Induced Developmental Toxicity and Oxidative Stress in Zebrafish Embryos/Larvae.

Maghemite nanoparticles ([Formula: see text] NPs) have a wide array of applications in various industries including biomedical field. There is an absence of legislation globally for the regulation of the production, use, and disposal of such NPs as they are eventually dumped into the environment where these NPs might affect the living systems. This study evaluates the effect of the [Formula: see text] NP-induced developmental toxicity in zebrafish embryos/larvae. The commercially available Fe2O3 NPs were purchased, and zebrafish embryos toxicity test was done by exposing embryos to various concentrations of [Formula: see text] NPs at 1 hpf and analyzed at 96 hpf. Based on the LC50 value (60.17 ppm), the sub-lethal concentrations of 40 and 60 ppm were used for further experiments. Hatching, lethality, developmental malformations, and heartbeat rate were measured in the control and treated embryos/larvae. The ionic Fe content in the media, and the larvae was quantified using ICP-MS and AAS. The biomolecular alterations in the control and treated groups were analyzed using FT-IR. The Fe ions present in the larvae were visualized using SEM-EDXS. In situ detection of AChE and apoptotic bodies was done using staining techniques. Biochemical markers (total protein content, AChE, and Na+ K+-ATPase) along with oxidants and antioxidants were assessed. A significant decrease in the heartbeat rate and hatching delay was observed in the treated groups affecting the developmental processes. Teratogenic analysis showed increased developmental deformity incidence in treated groups in a dose-dependent manner. The accumulation of Fe was evidenced from the ICP-MS, AAS, and SEM-EDXS. Alterations in AChE and Na+ K+-ATPase activity were observed along with an increment in the oxidants level with a concomitant decrease in antioxidant enzymes. These results show [Formula: see text] NP exposure leads to developmental malformation and results in the alteration of redox homeostasis.

Fishing for answers to hemostatic and thrombotic disease: Genome editing in zebrafish.

Over the past two decades, the teleost vertebrate Danio rerio (zebrafish) has emerged as a model for hemostasis and thrombosis. At genomic and functional levels, there is a high degree of conservation of the hemostatic system with that of mammals. Numerous features of the fish model offer unique advantages for investigating hemostasis and thrombosis. These include high fecundity, rapid and external development, optical transparency, and extensive functional homology with mammalian hemostasis and thrombosis. Zebrafish are particularly suited to genome-wide mutagenesis experiments for the study of modifier genes. They are also amenable to whole-organism small-molecule screens, a feature that is exceptionally relevant to hemostasis and thrombosis. Zebrafish coagulation factor knockouts that are in utero or neonatal lethal in mammals survive into adulthood before succumbing to hemorrhage or thrombosis, enabling studies not possible in mammals. In this illustrated review, we outline how zebrafish have been employed for the study of hemostasis and thrombosis using modern genome editing techniques, coagulation assays in larvae, and in vivo evaluation of patient-specific variants to infer causality and demonstrate pathogenicity. Zebrafish hemostasis and thrombosis models will continue to serve as a clinically directed basic research tool and powerful alternative to mammals for the development of new diagnostic markers and novel therapeutics for coagulation disorders through high-throughput genetic and small-molecule studies.

Chronic exposure to copper oxide nanoparticles causes muscle toxicity in adult zebrafish.

Repeated deposition of copper oxide nanoparticles (CuO-NPs) into aquatic systems makes them a global threat since the NPs accumulate in various organs of the fish particularly skeletal muscle. In the present study, adult zebrafish were exposed to different concentrations of CuO-NPs (1 and 3 mg/L) for a period of 30 days. The status of functional markers (acetylcholinesterase, creatine kinase-MB, and lactate dehydrogenase) and oxidative stress markers (oxidants and antioxidants) were analyzed. The histological changes in muscle were studied followed by the immunohistochemistry expression for catalase. Further, the expression of myoD, myogenin, pax7, ß-actin, and desmin was examined by semi-quantitative reverse transcriptase polymerase chain reaction. The results indicated that chronic exposure to CuO-NPs causes muscular damage as evidenced by elevated levels of functional markers. There was a significant increase in the oxidants with reduction in the antioxidant levels, implying that the antioxidant enzymes were unable to scavenge the free radicals induced by the CuO-NPs. The histopathological analysis showed degeneration and atrophy in the treated groups confirming muscle damage. The immunohistochemical catalase expression in the muscle was reduced in the treated groups further supporting the evidence that the antioxidant has suffered a decline. The altered gene expression indicates skeletal muscle damage due to the CuO-NPs exposure. Overall, the data suggest that chronic exposure to CuO-NPs caused muscular toxicity which may lead to muscle degeneration in adult zebrafish.

Fisetin, a phytopolyphenol, targets apoptotic and necroptotic cell death in HepG2 cells.

Fisetin (3,7,3',4'-tetrahydroxyflavone), a bioactive dietary flavonoid, intrigued scientists for its anticancer potential against various cancer types. We investigated the fisetin-induced inhibition of growth and survival of human hepatocellular carcinoma. Fisetin decreased cell viability and proliferation of HepG2 cells as revealed from MTT and clonogenicity assays. Cell cycle arrest in the G2/M phase was observed. Annexin V/propidium iodide (PI) staining followed by flow cytometry revealed that fisetin induced both apoptosis and necroptosis in HepG2 cells. Apoptotic cells were significantly increased on fisetin treatment as observed in morphological evaluations and 4',6-diamidino-2-phenylindole and Acridine orange staining. Flow cytometry, fluorescence imaging, and 2', 7'-dichlorofluorescein diacetate analyses showed an increase in reactive oxygen species (ROS) generation on fisetin treatment. Pretreatment with N-acetyl cysteine inhibited ROS production and also rescued mitochondrial membrane potential in HepG2 cells. The underlying mechanisms of apoptosis and necroptosis were determined by analysis of their respective signaling molecules using qRT-PCR and Western blotting. Fisetin showed a marked increase in the expression of TNFα and IKκB with a decrease in NF-κB, pNF-κB and pIKκB expression. Fisetin reduced the expression of Bcl2, and elevated levels of Bax, caspase-3, and PARP and thus induced apoptosis in HepG2 cells. zVAD suppressed the fisetin-induced expression of caspase-8, RIPK1, RIPK3, and MLKL as opposed to fisetin treatment. Nec-1 + fisetin could not completely block necroptosis, which warrants further investigation. Taken together, our findings demonstrate that the fisetin exhibited anti-proliferative effects on HepG2 cells through apoptosis and necroptosis via multiple signaling pathways. Fiestin has potential as a therapeutic agent against hepatocellular carcinoma.

Selective detection of pyrophosphate anion by zinc ensemble of C3-symmetric triaminoguanidine-pyrrole conjugate and its biosensing applications.

A new-fangled C3-symmetric triaminoguanidine-pyrrole conjugate has been constructed and utilized for sensing applications. The probe selectively detects zinc ions (Zn2+) by colorimetric as well as turn-on fluorescent manner. Further, the in-situ formed zinc ensemble displays turn-off fluorescence response towards the pyrophosphate anion (PPi) via displacement approach. Emissive off-on-off sensing characteristics of the probe has been successfully exploited to construct the INHIBIT logic gate, coding/decoding of messages and in vivo imaging of Zn2+/PPi in zebrafish larvae. Further, PPi detection characteristics of zinc ensembles were established for the sensing of PPi discharged from DNA synthesis and other biological reactions.

Role of epigenetics in zebrafish development.

The role of epigenetics in development has garnered attention in recent years due to their ability to modulate the embryonic developmental gene expression in response to the environmental cues. The epigenetic mechanisms - DNA methylation, histone modification, and non-coding RNAs have a unique impact on vertebrate development. Zebrafish, a model vertebrate organism is being used widely in developmental studies due to their high fecundability and rapid organogenesis. With increased studies on various aspects of epigenetics in development, this review gives a glimpse of the major epigenetic modifications and their role in zebrafish development. In this review, the basic mechanism behind each modification followed by their status in zebrafish has been reviewed. Further, recent advancements in the epigenetic aspect of zebrafish development have been discussed.

Identification of compounds that inhibit the binding of Keap1a/Keap1b Kelch DGR domain with Nrf2 ETGE/DLG motifs in zebrafish.

The Keap1-Nrf2-ARE system serves as a premier defence mechanism to curb oxidative stress, which remains as one of the major causes of ageing and pathogenesis in various diseases. Nrf2 is the principal master regulator of the cellular defence system, and its activation remains the prospective therapeutic approach against chronic diseases. One of the recent strategies is to disrupt Keap1-Nrf2 protein-protein interaction (PPI) that alters the docking of Keap1 with Nrf2 by compounds occupying a position in the Keap1 blocking the interface with Nrf2. In this study, we made an attempt to identify the compounds with anticancer, antioxidant and anti-inflammatory properties to disrupt Keap1a/b-Nrf2 PPI through in silico molecular docking in zebrafish. The phylogenetic analysis of Keap1 proteins revealed the existence of orthologous Keap1-Nrf2-ARE system in lower vertebrates that includes zebrafish. The DGR domains of zebrafish Keap1a and Keap1b were modelled with Modeller 9.19 using Keap1 of Mus musculus (PDB ID:5CGJ) as template. Based on the docking calculations, top hit compounds were identified to disrupt both Keap1a and Keap1b interaction with Nrf2 which include quercetin 3,4'-diglucoside, flavin adenine dinucleotide disodium salt hydrate, salvianolic acid A, tunicamycin and esculin. The LC50 of esculin in 3 dpf zebrafish larvae is 5 mmol/L, and the qRT-PCR results showed that esculin significantly increased the transcription of Nrf2 target genes-Gstpi, Nqo1, Hmox1a and Prdx1 in 3 dpf zebrafish larvae. These potential hits could serve as safer Nrf2 activators due to their non-covalent disruption of Keap1-Nrf2 PPI and be developed into efficacious preventive/therapeutic agents for various diseases.

Analysis of Lethality and Malformations During Zebrafish (Danio rerio) Development.

The versatility offered by zebrafish (Danio rerio) makes it a powerful and an attractive vertebrate model in developmental toxicity and teratogenicity assays. Apart from the newly introduced chemicals as drugs, xenobiotics also induce abnormal developmental abnormalities and congenital malformations in living organisms. Over the recent decades, zebrafish embryo/larva has emerged as a potential tool to test teratogenicity potential of these chemicals. Zebrafish responds to compounds as mammals do as they share similarities in their development, metabolism, physiology, and signaling pathways with that of mammals. The methodology used by the different scientists varies enormously in the zebrafish embryotoxicity test. In this chapter, we present methods to assess lethality and malformations during zebrafish development. We propose two major malformations scoring systems: binomial and relative morphological scoring systems to assess the malformations in zebrafish embryos/larvae. Based on the scoring of the malformations, the test compound can be classified as a teratogen or a nonteratogen and its teratogenic potential is evaluated.

Tamarind seed coat extract restores fluoride-induced hematological and biochemical alterations in rats.

Fluoride (F-) is becoming an ineluctable environmental pollutant causing deleterious effects in humans. In the present study, we examined whether tamarind seed coat extract (TSCE) is beneficial against the F--induced systemic toxicity and hematological changes. Wistar rats were randomly grouped as follows: group I served as control; group II intoxicated with sodium fluoride (NaF, 300 ppm) in drinking water; group III was administered through oral intubation with TSCE (100 mg/kg bw); group IV was treated with NaF (300 ppm) in association with TSCE (100 mg/kg bw) for 30 days. The results indicated that F- exposure induced oxidative stress as evidenced by elevated levels of reactive oxygen species and lipid peroxidation in the brain, liver, and kidney. F- administration modulates hematological indices-WBC, RBC, and mean corpuscular volume. Moreover, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acetylcholinesterase, and monoamine oxidase significantly increased on F- exposure. Conversely, δ-aminolevulinic acid dehydratase and glutathione/reduced glutathione ratio were decreased. Activity of antioxidants-superoxide dismutase, catalase, glutathione peroxidase, and vitamin C-was also significantly decreased due to F- administration. Treatment with TSCE effectively mitigated the alterations through its antioxidant potential. The data suggested that the TSCE had beneficial effects in alleviating the F--induced toxicity and hence can serve as a promising neutraceutical agent.

A review on the chemotherapeutic potential of fisetin: In vitro evidences.

During the past five decades, cancer cell lines are being successfully used as an in vitro model to discover the anti-cancer potential of plant secondary metabolites. Fisetin - the most popular polyphenol from fruits and vegetables, exhibits a repertoire of promising pharmacological features. Such versatile properties make fisetin an excellent anticancer agent and its efficacy as a chemotherapeutic agent against tumor heterogeneity from in vitro studies are encouraging. Fisetin is like a Pandora's box, as more research studies are being carried out, it reveals its new molecules within the cancer cells as therapeutic targets. These molecular targets orchestrate processes such as apoptosis, autophagic cell death, cell cycle, invasion, metastasis and angiogenesis in cancer cells. Besides apoptotic elicitation, fisetin's ability to induce autophagic cell death in cancer cells has been reported. This review examines the various molecular mechanisms of action elicited by fisetin leading to apoptosis and autophagic cell death as evidenced from cancer cell lines. In addition, the increased bioavailability and sustained release of fisetin improved through conjugation and enhanced effect of fisetin through synergism on various cancers are also highlighted.

Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance.

The liver executes versatile functions and is the chief organ for metabolism of toxicants/xenobiotics. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third foremost cause of cancer death worldwide. Oxidative stress is a key factor related with the development and progression of HCC. Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2) is a cytosolic transcription factor, which regulates redox homeostasis by activating the expression of an array of antioxidant response element-dependent genes. Nrf2 displays conflicting roles in normal, healthy liver and HCC; in the former, Nrf2 offers beneficial effects, whereas in the latter it causes detrimental effects favouring the proliferation and survival of HCC. Sustained Nrf2 activation has been observed in HCC and facilitates its progression and aggressiveness. This review summarizes the role and mechanism(s) of action of Nrf2 dysregulation in HCC and therapeutic options that can be employed to modulate this transcription factor.