MicroRNAs in fluorosis pathogenesis: impact on dental, skeletal, and soft tissues.

Fluoride-induced toxicity (fluorosis) poses a significant health concern globally, affecting millions of individuals. Understanding the molecular mechanisms underlying fluorosis, particularly the role of microRNAs (miRNAs), is crucial for developing effective preventive and therapeutic strategies. This review explores the pivotal role of miRNAs in the pathogenesis of fluorosis, particularly examining its impact on both hard (skeletal and dental) and soft (brain, liver, kidney, heart, and reproductive organs) tissues. Skeletal fluorosis manifests as abnormal bone mineralization and structure, while dental fluorosis affects enamel formation. In vitro and in vivo studies suggest a significant involvement of miRNAs in the progression of these conditions. For skeletal fluorosis, miR-124, miR-155, and miR-200c-3p have been identified as key regulators, while miR-296-5p and miR-214-3p are implicated in dental fluorosis. Moreover, soft tissue fluorosis encompasses a spectrum of adverse effects on various organs, including the brain, liver, kidneys, heart, and reproductive system. In soft tissues, miRNAs, such as miR-124, miR-200c-3p, miR-132, and miR-34b-5p, have been linked to cellular damage and dysfunction. Notably, miRNAs exert their effects through the modulation of critical pathways involved in fluorosis pathology, including Wnt signaling, apoptosis, cell cycle, and autophagy. Understanding the regulatory roles of miRNAs in fluorosis pathogenesis holds promise for identifying biomarkers and therapeutic targets. However, further research is needed to elucidate the molecular mechanisms underlying miRNA-mediated responses to fluoride exposure. Integration of miRNA research into fluorosis studies could facilitate the development of diagnostic tools and therapeutic interventions, thus mitigating the detrimental effects of fluorosis on both hard and soft tissues.

Acute exposure to environmentally relevant concentrations of pharmaceutical pollutants induces neurobehavioral toxicity in zebrafish (Danio rerio).

Pharmaceutical waste from point and non-point sources enters, persists, or disseminates in the environment and is known as environmentally persistent pharmaceutical pollutants. Understanding the impacts of pharmaceutical pollutants on the environment and health is essential. This study investigates the behavioral impacts of pharmaceutical pollutants on aquatic organisms and delineates the possible nexus of oxidative stress. The male zebrafish were exposed to four major representative pharmaceutical pollutants, viz., acetaminophen, carbamazepine, metformin, and trimethoprim at environmentally relevant concentrations individually as well as in a mixture for seven days. Substantial alterations in social interaction, aggressive nature, novel tank exploration, and light and dark zone preferences were recorded and the degree varied to different pharmaceutical pollutants. The activity of oxidative stress markers, superoxide dismutase, glutathione-S-transferase, and catalase, was found to be suppressed to 66-20%, 42-25%, and 59-20% respectively with the elevated malondialdehyde generation (180-260%) compared to control. The activity level of acetylcholine esterase was found to be increased to 200-500% across all treatment groups. Despite the synergistic impacts of pharmaceutical pollutants on the whole system that could not be ascertained, this comprehensive study highlights their toxicity nature to induce neurobehavioral toxicity in zebrafish through oxidative stress mechanisms and altered cholinergic systems.

Acute Hypobaric Hypoxia Exposure Causes Neurobehavioral Impairments in Rats: Role of Brain Catecholamines and Tetrahydrobiopterin Alterations.

Hypoxia is a state in which the body or a specific part of the body is deprived of adequate oxygen supply at the tissue level. Sojourners involved in different activities at high altitudes (> 2500 m) face hypobaric hypoxia (HH) due to low oxygen in the atmosphere. HH is an example of generalized hypoxia, where the homeostasis of the entire body of an organism is affected and results in neurochemical changes. It is known that lower O2 levels affect catecholamines (CA), severely impairing cognitive and locomotor behavior. However, there is less evidence on the effect of HH-mediated alteration in brain Tetrahydrobiopterin (BH4) levels and its role in neurobehavioral impairments. Hence, this study aimed to shed light on the effect of acute HH on CA and BH4 levels with its neurobehavioral impact on Wistar rat models. After HH exposure, significant alteration of the CA levels in the discrete brain regions, viz., frontal cortex, hippocampus, midbrain, and cerebellum was observed. HH exposure significantly reduced spontaneous motor activity, motor coordination, and spatial memory. The present study suggests that the HH-induced behavioral changes might be related to the alteration of the expression pattern of CA and BH4-related genes and proteins in different rat brain regions. Overall, this study provides novel insights into the role of BH4 and CA in HH-induced neurobehavioral impairments.

Screening of potent STAT3-SH2 domain inhibitors from JAK/STAT compound library through molecular dynamics simulation.

The Signal Transducer and Activator of Transcription 3 (STAT3) protein is activated consistently in the tumor cells and thus studied as a potent target for cancer prevention. The TYR705-phosphorylated (pTyr) STAT3 forms a homo-dimer by binding to its recognition site in the Src Homology 2 (SH2) domain of another STAT3 monomer, causing cellular survival, proliferation, inflammation, and tumor invasion. Many inhibitors of STAT3-SH2 have recently been identified using both computational and experimental approaches. In this study, we used molecular docking, Absorption, Distribution, Metabolism, and Excretion/Toxicological (ADME/tox) and molecular dynamics modeling to examine binding affinities and specificities of 191 inhibitor drugs from the SELLECKCHEM database. The binding free energies of the inhibitors were calculated by Induced Fit Docking (IFD) prime energy. The binding hotspots of STAT3-SH2 were evaluated via binding energy decomposition and hydrogen bond distribution analysis, and the inhibitor compound's stability was assessed through MD simulation. (-)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, Picroside I, Saikosaponin D, and Ginsenoside Rk1 were found to be the top hit inhibitor compounds. They exhibited an exceptional docking score, a low binding free energy, interacted with the key amino acid residue, and showed significant ADME/tox moderation. These compounds were further proved to be favorable by their stability in an MD simulation run for 100 ns using GROMACS software. The inhibitors (-)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, and Saikosaponin D show improved stability in molecular dynamic modeling and are expected to have a significant STAT3-SH2 inhibitory effect against cancer.

Virtual screening of FOXO3a activators from natural product-like compound library.

FOXO3a is an inevitable transcription factor, which is involved in the regulation of biological processes such as proliferation, DNA damage repair, cell cycle arrest and cell death. Previous studies confirmed that FOXO3a is an excellent tumor suppressor and in cancer cells, it gets phosphorylated followed by proteasomal degradation. FOXO3a is found to be inactivated in cancer cells, whereas in normal cells it gets activated and upregulates its downstream targets, which induces apoptotic pathways. Hence, activation of FOXO3a can be implicated in cancer prevention and treatment. A variety of commercially available FOXO3a activators such as doxorubicin and metformin possess undesirable adverse effects to normal cells and tissues, which are their major limitations. Natural bioactive compounds, eliminating the limitations of such compounds, become an excellent choice for the treatment and prevention of cancer. In this study, a library of natural product-like compounds was screened for their FOXO3a activation potential through in silico approach, which included the use of several bioinformatics tools and processes. Other molecular interaction studies as well as binding and specificity studies were carried out with the help of molecular dynamics simulation. Virtual screening of 7700 small molecules from the Natural Products-like Compound Library revealed the top three FOXO3a activators F3385-6269, F2183-0033 and F3351-0330. Further validation studies are warranted to confirm these findings.

A systematic review on fluoride-induced epigenetic toxicity in mammals.

Fluoride, one of the global groundwater contaminants, is ubiquitous in our day-to-day life from various natural and anthropogenic sources. Numerous in vitro, in vivo, and epidemiological studies are conducted to understand the effect of fluoride on biological systems. A low concentration of fluoride is reported to increase oral health, whereas chronic exposure to higher concentrations causes fluoride toxicity (fluorosis). It includes dental fluorosis, skeletal fluorosis, and fluoride toxicity in soft tissues. The mechanism of fluoride toxicity has been reviewed extensively. However, epigenetic regulation in fluoride toxicity has not been reviewed. This systematic review summarizes the current knowledge regarding fluoride-induced epigenetic toxicity in the in vitro, in vivo, and epidemiological studies in mammalian systems. We examined four databases for the association between epigenetics and fluoride exposure. Out of 932 articles (as of 31 March 2022), 39 met our inclusion criteria. Most of the studies focused on different genes, and overall, preliminary evidence for epigenetic regulation of fluoride toxicity was identified. We further highlight the need for epigenome studies rather than candidate genes and provide recommendations for future research. Our results indicate a correlation between fluoride exposure and epigenetic processes. Further studies are warranted to elucidate and confirm the mechanism of epigenetic alterations mediated fluoride toxicity.

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.

Ameliorative Effect of Hesperidin Against Motion Sickness by Modulating Histamine and Histamine H1 Receptor Expression.

Motion sickness (MS) is the visceral discomfort caused due to contradicting visual and vestibular inputs to the brain leading to nausea and vomiting. Sensory conflict theory which proves histamine elevations as the primary reason for MS provides a path for an effective pharmaco-therapy. We aimed to evaluate the anti-MS effect of hesperidin (HSP) by modulating histamine and histamine receptor H1 (HRH1) expression. The inhibitory effect of HSP on histamine release was studied in KU812 cells treated with 10 µM calcium ionophore. The in vivo anti-MS effect of HSP was evaluated in Balb/c mice. Thirty six mice were divided into six groups namely, normal control (NC, no rotation), hesperidin at 80 mg/kg body weight control (HSP80, no rotation), motion sickness (MS, rotation induced), dimenhydrinate (Standard drug) at 20 mg/kg body weight + rotation (STD + MS), hesperidin at 40 mg/kg body weight + rotation (HSP40 + MS) and hesperidin at 80 mg/kg body weight + rotation (HSP80 + MS). Hypothalamus and brainstem samples were analysed for histamine levels and HRH1 expression by RT-PCR, Western blot and immunohistochemistry analysis. Calcium ionophore treated KU812 cells significantly increased histamine release when compared to control cells. Pre-treatment with HSP inhibited histamine, HRH1 mRNA and protein expression. Histamine, HRH1 mRNA and protein expression in hypothalamus and brainstem samples of MS group increased significantly when compared to the NC group. Pre-treatment with HSP significantly reduced histamine, HRH1 mRNA and protein expression. Thus, indicating that HSP has a potent anti- MS effect by decreasing the elevated levels of histamine, HRH1 mRNA and protein expression in hypothalamus and brainstem regions.

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.

Iron Oxide Nanoparticles Affects Behaviour and Monoamine Levels in Mice.

Iron oxide (Fe2O3) nanoparticles (NPs) attract the attention of clinicians for its unique magnetic and paramagnetic properties, which are exclusively used in neurodiagnostics and therapeutics among the other biomedical applications. Despite numerous research findings has already proved neurotoxicity of Fe2O3-NPs, factors affecting neurobehaviour has not been elucidated. In this study, mice were exposed to Fe2O3-NPs (25 and 50 mg/kg body weight) by oral intubation daily for 30 days. It was observed that Fe2O3-NPs remarkably impair motor coordination and memory. In the treated brain regions, mitochondrial damage, depleted energy level and decreased ATPase (Mg2+, Ca2+ and Na+/K+) activities were observed. Disturbed ion homeostasis and axonal demyelination in the treated brain regions contributes to poor motor coordination. Increased intracellular calcium ([Ca2+]i) and decreased expression of growth associated protein 43 (GAP43) impairs vesicular exocytosis could result in insufficient signal between neurons. In addition, levels of dopamine (DA), norepinephrine (NE) and epinephrine (EP) were found to be altered in the subjected brain regions in correspondence to the expression of monoamine oxidases (MAO). Along with all these factors, over expression of glial fibrillary acidic protein (GFAP) confirms the neuronal damage, suggesting the evidences for behavioural changes.

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.

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but patients suffer from various kinds of adverse effects, including hypertension. The signal-transducer-and-activator-of-transcription 3 (STAT3) protein, one of the members of STATs transcription factor family, has been implicated in signal transduction by different cytokines, growth factors and oncogenes. In normal cells, STAT3 activation is tightly controlled to prevent dysregulated gene transcription, whereas constitutively activated STAT3 plays an important role in tumorigenesis through the upregulation of genes involved in anti-apoptosis, proliferation and angiogenesis. Thus, pharmacologically safe and effective agents that can block STAT3 activation have the potential both for the prevention and treatment of HCC. In the present review, we discuss the possible role of STAT3 signaling cascade and its interacting partners in the initiation of HCC and also analyze the role of various STAT3 regulated genes in HCC progression, inflammation, survival, invasion and angiogenesis.

Integrated in silico analysis of transcriptomic alterations in nanoparticle toxicity across human and mouse models.

Nanoparticles, due to their exceptional physicochemical properties are used in our day-to-day environment. They are currently not regulated which might lead to increased levels in the biological systems causing adverse effects. However, the overall mechanism behind nanotoxicity remains elusive. Previously, we analysed the transcriptome datasets of copper oxide nanoparticles using in silico tools and identified IL-17, chemokine signaling pathway, and cytokine-cytokine receptor interaction as the key pathways altered. Based on the findings, we hypothesized a common pathway could be involved in transition metal oxide nanoparticles toxicity irrespective of the variables. Further, there could be unique transcriptome changes between metal oxide nanoparticles and other nanoparticles. To accomplish this, the overall transcriptome datasets of nanoparticles consisting of microarray and RNA-Seq were obtained. >90 studies for 17 different nanoparticles, performed in humans, rats, and mice were assessed. After initial screening, 24 mouse studies (with 196 datasets) and 34 human studies (with 200 datasets) were used for further analyses. The common genes that are dysregulated upon NPs exposure were identified for human and mouse datasets separately. Further, an overrepresentation functional enrichment analysis was performed. The common genes, their gene ontology, gene-gene, and protein-protein interactions were assessed. The overall results suggest that IL-17 and its related pathways might be commonly altered in nanoparticle exposure with lung as one of the major organs affected.

Natural bioactive compounds and FOXO3a in cancer therapeutics: An update.

Forkhead box protein 3a (FOXO3a) is a transcription factor that regulates various downstream targets upon its activation, leading to the upregulation of tumor suppressor and apoptotic pathways. Hence, targeting FOXO3a is an emerging strategy for cancer prevention and treatment. Recently, Natural Bioactive Compounds (NBCs) have been used in drug discovery for treating various disorders including cancer. Notably, several NBCs have been shown as potent FOXO3a activators. NBCs upregulate FOXO3a expressions through PI3K/Akt, MEK/ERK, AMPK, and IκB signaling pathways. FOXO3a promotes its anticancer effects by upregulating the levels of its downstream targets, including Bim, FasL, and Bax, leading to apoptosis. This review focuses on the dysregulation of FOXO3a in carcinogenesis and explores the potent FOXO3a activating NBCs for cancer prevention and treatment. Additionally, the review evaluates the safety and efficacy of NBCs. Looking ahead, NBCs are anticipated to become a cost-effective, potent, and safer therapeutic option for cancer, making them a focal point of research in the field of cancer prevention and treatment.

Acute copper oxide nanoparticles exposure alters zebrafish larval microbiome.

Copper oxide nanoparticles (CuO NPs) are being used in healthcare industries due to its antimicrobial properties. The increased consumption of NPs could lead to the rise of these NPs in the environment affecting the biological systems. Altered microbiome has been correlated to disease pathology in humans as well as xenobiotic toxicity in experimental animal models. However, CuO NPs-induced microbiome alterations in vertebrates have not been reported so far. In this study, for the first time, zebrafish larvae at 96 hpf (hours post fertilization) were exposed to CuO NPs for 24 h at 10, 20, and 40 ppm. After exposure, the control and treated larvae were subjected to 16S rRNA amplicon sequencing followed by relative taxa abundance, alpha and beta diversity analysis, single factor analysis, LEfSe, Deseq2, and functional profiling. No significant alteration was detected in the microbial richness and diversity, however, specific taxa constituting the core microbiome such as phylum Proteobacteria were significantly increased and Bacterioidetes and Firmicutes were decreased in the treated groups, indicating a core microbiota dysbiosis. Further, the family Lachnospiraceae, and genus Syntrophomonas involved in butyrate production and the metabolism of lipids and glucose were significantly altered. In addition, the opportunistic pathogens belonging to order Flavobacteriales were increased in CuO NPs treated groups. Moreover, the taxa involved in host immune response (Shewanella, Delftia, and Bosea) were found to be enriched in CuO NPs exposed larvae. These results indicate that CuO NPs exposure causes alteration in the core microbiota, which could cause colitis or inflammatory bowel disease.