Identification of key genes and signalling pathways in clear cell renal cell carcinoma: An integrated bioinformatics approach.

BACKGROUND: Clear cell Renal Cell Carcinoma (ccRCC) is one of the most prevalent types of kidney cancer. Unravelling the genes responsible for driving cellular changes and the transformation of cells in ccRCC pathogenesis is a complex process. OBJECTIVE: In this study, twelve microarray ccRCC datasets were chosen from the gene expression omnibus (GEO) database and subjected to integrated analysis. METHODS: Through GEO2R analysis, 179 common differentially expressed genes (DEGs) were identified among the datasets. The common DEGs were subjected to functional enrichment analysis using ToppFun followed by construction of protein-protein interaction network (PPIN) using Cytoscape. Clusters within the DEGs PPIN were identified using the Molecular Complex Detection (MCODE) Cytoscape plugin. To identify the hub genes, the centrality parameters degree, betweenness, and closeness scores were calculated for each DEGs in the PPIN. Additionally, Gene Expression Profiling Interactive Analysis (GEPIA) was utilized to validate the relative expression levels of hub genes in the normal and ccRCC tissues. RESULTS: The common DEGs were highly enriched in Hypoxia-inducible factor (HIF) signalling and metabolic reprogramming pathways. VEGFA, CAV1, LOX, CCND1, PLG, EGF, SLC2A1, and ENO2 were identified as hub genes. CONCLUSION: Among 8 hub genes, only the expression levels of VEGFA, LOX, CCND1, and EGF showed a unique expression pattern exclusively in ccRCC on compared to other type of cancers.

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.

Angiogenesis Assay for Live and Fixed Zebrafish Embryos/Larvae.

Angiogenesis is the process of new blood vessel formation from preexisting vasculature. It is an integral component in normal embryonic development and tissue repair. Dysregulation of angiogenesis might lead to tissue ischemia (resulting from reduced blood vessel formation) or major diseases such as cancer (abnormal vascular growth). This makes angiogenesis an excellent area of research for cancer therapeutics, and various animal models including zebrafish are used to study blood vessel development. As most of the techniques used to study angiogenesis are complex and cumbersome, in this chapter, we provide two simple assays to study angiogenesis with live and fixed zebrafish embryos/larvae.

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.

Natural bioactive compounds and STAT3 against hepatocellular carcinoma: An update.

Hepatocellular carcinoma (HCC) is a challenging and very fatal liver cancer. The signal transducer and activator of transcription 3 (STAT3) pathway is a crucial regulator of tumor development and are ubiquitously active in HCC. Therefore, targeting STAT3 has emerged as a promising approach for preventing and treating HCC. Various natural bioactive compounds (NBCs) have been proven to target STAT3 and have the potential to prevent and treat HCC as STAT3 inhibitors. Numerous kinds of STAT3 inhibitors have been identified, including small molecule inhibitors, peptide inhibitors, and oligonucleotide inhibitors. Due to the undesirable side effects of the conventional therapeutic drugs against HCC, the focus is shifted to NBCs derived from plants and other natural sources. NBCs can be broadly classified into the categories of terpenes, alkaloids, carotenoids, and phenols. Most of the compounds belong to the family of terpenes, which prevent tumorigenesis by inhibiting STAT3 nuclear translocation. Further, through STAT3 inhibition, terpenes downregulate matrix metalloprotease 2 (MMP2), matrix metalloprotease 9 (MMP9) and vascular endothelial growth factor (VEGF), modulating metastasis. Terpenes also suppress the anti-apoptotic proteins and cell cycle markers. This review provides comprehensive information related to STAT3 abrogation by NBCs in HCC with in vitro and in vivo evidences.

Fluoride Binding Potential of Selected Phytochemicals: A Pilot Study.

Fluoride (F-) contamination in drinking water is a major global concern. According to several studies, India and China are the most affected by the presence of excess F-. Long-time exposure to F- concentrations above 1.5 ppm can lead to hard and soft tissue fluorosis (F- toxicity). There are no effective cure or treatment for fluorosis and the condition is almost irreversible. Considering water to be the prime media through which F- reaches humans, maintaining optimal F- levels in water remains the only possible remedy. F- endemic areas have adapted several conventional defluoridation techniques to resolve the issue. Among these, adsorption with plant compounds is widely used for F- removal. Studies have shown that plant metabolites can ameliorate the toxic effects of F-. Based on this, we attempt to elucidate the potential binding and electrochemical bio-sensing properties of selected phytochemicals towards F-. The focus of the present work is to evaluate the interactions of phytochemicals with F-; for which, the binding studies of phytochemicals with F- have been elaborated by UV-visible spectroscopy and emission techniques. Benesi-Hildebrand's (BH) plot was used to calculate the binding constant (CUR - 34.9 × 103 (M-1), QUER - 13 × 103 (M-1), ESC -6.3 × 103 (M-1), FIS - 5.36 × 103 (M-1) and PCA -1.5 × 103 (M-1), and detection limit (CUR - 1.54 × 10-7 M, QUER - 0.156 × 10-6 M, ESC - 0.221 × 10-6 M, FIS - 0.175 × 10-6 M, and PCA - 5.8 × 10-6 M) for the F-:phytochemical mixtures. Further, the binding characteristics were confirmed using 1H-NMR titration experiments. Our findings highlight the potential of phytochemicals as effective binding agents for F-, thereby reducing its bioavailability.

Acute exposure to tenorite nanoparticles induces phenotypic and behavior alterations in zebrafish larvae.

Tenorite or copper oxide nanoparticles (CuO NPs) are extensively used in biomedical fields due to their unique physicochemical properties. Increased usage of these NPs leads to release in the environment, affecting varied ecosystems and the biota within them, including humans. The effect of these NPs can be evaluated with zebrafish, an excellent complementary model for nanotoxicity studies. Previous reports focusing on CuO NPs-induced teratogenicity in zebrafish development have not elucidated the phenotypical changes in detail. In most of the studies, embryos at 3 hpf with a protective chorion layer were exposed to CuO NPs, and their effect on the overall developmental process is studied. Hence, in this study, we focused on the effect of acute exposure to CuO NPs (96-120 hpf) and its impact on zebrafish larvae. Larvae were exposed to commercially available CuO NPs (<50 nm) at various concentrations to obtain the LC50 value (52.556 ppm). Based on the LC50, three groups (10, 20, and 40 ppm) were taken for further analysis. Upon treatment, bradycardia, and impaired swim bladder (reduced/absence of inflation) were found in the treated groups along with alterations in the erythrocyte levels. Also, the angles and distance between the cartilages varied in the treated larvae affecting their craniofacial structures. There was a significant behavior change, as evidenced by the reduced touch escape response and locomotion (speed, distance, time mobile, time frozen, and absolute turn angle). Further, the acetylcholinesterase activity was reduced. Overall, our results suggest that acute exposure to CuO NPs elicits morphological defects in zebrafish larvae.

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.

Toxicogenomic analysis of physiologically important metals: An integrated in silico approach.

Biologically important metals regulate cellular homeostasis in living systems. Anthropogenic exposure to these metals can cause adverse effects, including an increased incidence of diseases in humans such as cancer, lung, and cardiovascular defects. However, the effects of metals and the common genes/signaling pathways involved in metal toxicity have not been elucidated. Hence, the present study used toxicogenomic data mining with the comparative toxicogenomics database to explore the impact of these metals. The metals were categorized into transition, alkali, and alkaline earth. The common genes were identified and subjected to functional enrichment analysis. Further, gene-gene and protein-protein interactions were assessed. Also, the top ten transcription factors and miRNAs that regulate the genes were identified. The phenotypes and diseases that have increased incidence upon alterations of these genes were detected. Overall, we were able to identify IL1B and SOD2 as the common genes, along with the AGE-RAGE signaling pathway in diabetic complications as the common pathway altered. Enriched genes and pathways specific to each metal category were also found. Further, we identified heart failure as the major disease that could have increase in the incidence upon these metals' exposure. In conclusion, exposure to essential metals might cause adverse effects via inflammation and oxidative stress.

MAO inhibiting phytochemicals from the roots of Glycyrrhiza glabra L.

Glycyrrhizin, a natural compound that is substantially present in Glycyrrhiza glabra L. (Gg) root. Monoamine oxidase B (MAOB) inhibitor is used for the treatment of several important neuropsychological diseases like Parkinson's disease. Gg is known to possess psychoactive properties which relates to its MAO inhibitory potential. This study sought to determine the MAO inhibition property of glycyrrhizin from Gg root extract. The Aqueous extract containing glycyrrhizin was isolated from the root of Gg and characterized using TLC, HPLC, and LC-MS techniques. In silico docking was conducted using Extra precision Glide 2018, Schrödinger docking suite. In addition, the pharmacokinetic properties of the compounds were predicted using SwissADME. The binding energies of the glycyrrhizin correlated well with their in vitro MAO inhibitory potential. Glycyrrhizin exhibited potent inhibitory activity towards MAOB whereas, an aqueous extract of Gg root inhibits both A and B forms of MAO enzyme. Further, molecular docking and molecular dynamics simulation showed that liquiritigenin and methoxyglabridin showed higher stability than other inhibitor compounds from the Gg root extract. These observations suggest that the phytochemicals from the Gg root extract have potent MAO inhibition properties, which can be exploited for the treatment of neurodegenerative disorders.Communicated by Ramaswamy H. Sarma.

Potent FOXO3a Activators from Biologically Active Compound Library for Cancer Therapeutics: An in silico Approach.

The forkhead transcription factor FOXO3a is a member of the FOXO subfamily, which controls a number of cellular processes including apoptosis, proliferation, cell cycle progression, DNA damage, and carcinogenesis. In addition, it reacts to a number of biological stressors such as oxidative stress and UV radiation. FOXO3a has been predominantly associated with many diseases including cancer. Recent research suggests that FOXO3a suppresses tumor growth in cancer. By cytoplasmic sequestration of the FOXO3a protein or mutation of the FOXO3a gene, FOXO3a is commonly rendered inactive in cancer cells. Furthermore, the onset and development of cancer are linked to its inactivation. In order to reduce and prevent tumorigenesis, FOXO3a needs to be activated. So, it is critical to develop new strategies to enhance FOXO3a expression for cancer therapy. Hence, the present study has been aimed to screen small molecules targeting FOXO3a using bioinformatics tools. Molecular docking and molecular dynamic simulation studies reveal the potent FOXO3a activating small molecules such as F3385-2463, F0856-0033, and F3139-0724. These top three compounds will be subjected to further wet experiments. The findings of this study will lead us to explore the potent FOXO3a activating small molecules for cancer therapeutics.

Garcinia gummi-gutta: Phytochemicals and pharmacological applications.

Garcinia gummi-gutta, also known as Garcinia cambogia, is a member of the Guttiferae family. Garcinia is a polygamous genus consisting 200 species of trees and shrubs. It is found in different zones of the planet including Asia's tropical regions. In India alone, around 30 species have been discovered. They are widely used as a flavoring agent to garnish fish curry in southern India, particularly in Kerala and Karnataka. The fruit rind of G. gummi-gutta has traditionally been used to treat gastrointestinal problems, diarrhea, and ulcers. South Indian people have been utilizing it traditionally as evidenced by its ethnobotanical properties. In vivo and in vitro effects of the crude fruit extract showed anti-inflammatory, anti-cancer, anthelmintic, anti-microbial, and antioxidant activities. G. gummi-gutta fruit rind is medicinally significant and is frequently used in ayurvedic and traditional medicine for many diseases. Various secondary metabolites such as organic acids-hydroxycitric acid (HCA), flavonoids, terpenes, polysaccharides and polyisoprenylated benzophenones-garcinol, xanthochymol, guttiferone, benzophenone, xanthone, biflavonoids, alkaloids, tannins, phenols, and saponins isolated from the G. gummi-gutta have diverse pharmacological activities. This review provides a summary of G. gummi-gutta, including its biological activities, phytochemistry, and ethnobotanical applications.

Fluoride Induced Neurobehavioral Impairments in Experimental Animals: a Brief Review.

Fluoride is one of the major toxicants in the environment and is often found in drinking water at higher concentrations. Living organisms including humans exposed to high fluoride levels are found to develop mild-to-severe detrimental pathological conditions called fluorosis. Fluoride can cross the hematoencephalic barrier and settle in various brain regions. This accumulation affects the structure and function of both the central and peripheral nervous systems. The neural ultrastructure damages are reflected in metabolic and cognitive activities. Hindrances in synaptic plasticity and signal transmission, early neuronal apoptosis, functional alterations of the intercellular signaling pathway components, improper protein synthesis, dyshomeostasis of the transcriptional and neurotrophic factors, oxidative stress, and inflammatory responses are accounted for the fluoride neurotoxicity. Fluoride causes a decline in brain functions that directly influence the overall quality of life in both humans and animals. Animal studies are widely used to explore the etiology of fluoride-induced neurotoxicity. A good number of these studies support a positive correlation between fluoride intake and toxicity phenotypes closely associated with neurotoxicity. However, the experimental dosages highly surpass the normal environmental concentrations and are difficult to compare with human exposures. The treatment procedures are highly dependent on the dosage, duration of exposure, sex, and age of specimens among other factors which make it difficult to arrive at general conclusions. Our review aims to explore fluoride-induced neuronal damage along with associated histopathological, behavioral, and cognitive effects in experimental models. Furthermore, the correlation of various molecular mechanisms upon fluoride intoxication and associated neurobehavioral deficits has been discussed. Since there is no well-established mechanism to prevent fluorosis, phytochemical-based alleviation of its characteristic indications has been proposed as a possible remedial measure.

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.

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.

Chemotherapeutic Potential of Saikosaponin D: Experimental Evidence.

Saikosaponin D (SSD), an active compound derived from the traditional plant Radix bupleuri, showcases potential in disease management owing to its antioxidant, antipyretic, and anti-inflammatory properties. The toxicological effects of SSD mainly include hepatotoxicity, neurotoxicity, hemolysis, and cardiotoxicity. SSD exhibits antitumor effects on multiple targets and has been witnessed in diverse cancer types by articulating various cell signaling pathways. As a result, carcinogenic processes such as proliferation, invasion, metastasis, and angiogenesis are inhibited, whereas apoptosis, autophagy, and differentiation are induced in several cancer cells. Since it reduces side effects and strengthens anti-cancerous benefits, SSD has been shown to have an additive or synergistic impact with chemo-preventive medicines. Regardless of its efficacy and benefits, the considerations of SSD in cancer prevention are absolutely under-researched due to its penurious bioavailability. Diverse studies have overcome the impediments of inadequate bioavailability using nanotechnology-based methods such as nanoparticle encapsulation, liposomes, and several other formulations. In this review, we emphasize the association of SSD in cancer therapeutics and the discussion of the mechanisms of action with the significance of experimental evidence.

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.

Potential role of Marine Bioactive Compounds in cancer signaling pathways: A review.

Cancer is characterized by alterations that cause the over-proliferation of cells and hyperactivation of signaling pathways. Alterations of signaling molecules dysregulate physiological functions like cell growth, proliferation, metastasis, and cell death. Hence, the potential anticancer compounds primarily target signaling networks for therapeutic interventions in cancer. In the past few years, cancer therapy directed its focus on bioactive compounds that originated from marine sources considering their diverse and untapped nature. These Marine Bioactive Compounds (MBCs) are broadly classified into distinct categories such as alkaloids, carbohydrates, fatty acids, peptides, phenols, quinones, terpenes, and saponins. Bioactive compounds from each class initiate cell death via different signaling pathways. The primary objective of this review is to provide comprehensive information about the pathways that are predominantly targeted by every class of MBCs and integrating data from several marine anticancer research. Here, we studied the role of MBCs in signaling networks that inhibit various cancer types. As a result, we concluded that PI3K/AKT, ROS, and p53 are the three prime signaling pathways targeted by the MBCs to induce apoptosis in cancer cells. Carbohydrates, peptides, and terpenes are the major MBCs classes that regulate signaling pathways in cancer. Hence it is concluded that future anticancer research can be primarily focused on the MBCs derived from the scrutinized classes that adhere to pathways like PI3K/AKT, ROS, and p53 to achieve par excellence results.

Role of oxidative stress-mediated cell death and signaling pathways in experimental fluorosis.

Free radicals and other oxidants have enticed the interest of researchers in the fields of biology and medicine, owing to their role in several pathophysiological conditions, including fluorosis (Fluoride toxicity). Radical species affect cellular biomolecules such as nucleic acids, proteins, and lipids, resulting in oxidative stress. Reactive oxygen species-mediated oxidative stress is a common denominator in fluoride toxicity. Fluorosis is a global health concern caused by excessive fluoride consumption over time. Fluoride alters the cellular redox homeostasis, and its toxicity leads to the activation of cell death mechanisms like apoptosis, autophagy, and necroptosis. Even though a surfeit of signaling pathways is involved in fluorosis, their toxicity mechanisms are not fully understood. Thus, this review aims to understand the role of reactive species in fluoride toxicity with an outlook on the effects of fluoride in vitro and in vivo models. Also, we emphasized the signal transduction pathways and the mechanism of cell death implicated in fluoride-induced oxidative stress.

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.