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Recent mounting evidence has revealed extensive genetic heterogeneity within tumors that drive phenotypic variation affecting key cancer pathways, making cancer treatment extremely challenging. Diverse cancer types display resistance to treatment and show patterns of relapse following therapy. Therefore, efforts are required to address tumor heterogeneity by developing a broad-spectrum therapeutic approach that combines targeted therapies. Inflammation has been progressively documented as a vital factor in tumor advancement and has consequences in epigenetic variations that support tumor instigation, encouraging all the tumorigenesis phases. Increased DNA damage, disrupted DNA repair mechanisms, cellular proliferation, apoptosis, angiogenesis, and its incursion are a few pro-cancerous outcomes of chronic inflammation. A clear understanding of the cellular and molecular signaling mechanisms of tumor-endorsing inflammation is necessary for further expansion of anti-cancer therapeutics targeting the crosstalk between tumor development and inflammatory processes. Multiple inflammatory signaling pathways, such as the NF-κB signaling pathway, JAK-STAT signaling pathway, MAPK signaling, PI3K/AKT/mTOR signaling, Wnt signaling cascade, and TGF-ß/Smad signaling, have been found to regulate inflammation, which can be modulated using various factors such as small molecule inhibitors, phytochemicals, recombinant cytokines, and nanoparticles (NPs) in conjugation to phytochemicals to treat cancer. Researchers have identified multiple targets to specifically alter inflammation in cancer therapy to restrict malignant progression and improve the efficacy of cancer therapy. siRNA-and shRNA-loaded NPs have been observed to downregulate STAT3 signaling pathways and have been employed in studies to target tumor malignancies. This review highlights the pathways involved in the interaction between tumor advancement and inflammatory progression, along with the novel approaches of nanotechnology-based drug delivery systems currently used to target inflammatory signaling pathways to combat cancer.
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Nanomedicina , Fosfatidilinositol 3-Quinases , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Compreensão , Recidiva Local de Neoplasia , Transdução de Sinais , Inflamação/tratamento farmacológicoRESUMO
Brain tumors are most often diagnosed with solid neoplasms and are the primary reason for cancer-related deaths in both children and adults worldwide. With recent developments in the progression of novel targeted chemotherapies, the prognosis of malignant glioma remains dismal. However, the high recurrence rate and high mortality rate remain unresolved and are closely linked to the biological features of cancer stem cells (CSCs). Research on tumor biology has reached a new age with more understanding of CSC features. CSCs, a subpopulation of whole tumor cells, are now regarded as candidate therapeutic targets. Therefore, in the diagnosis and treatment of tumors, recognizing the biological properties of CSCs is of considerable significance. Here, we have discussed the concept of CSCs and their significant role in brain cancer growth and propagation. We have also discussed personalized therapeutic development and immunotherapies for brain cancer by specifically targeting CSCs.
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Neoplasias Encefálicas , Criança , Adulto , Humanos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Células-Tronco Neoplásicas/patologia , Transdução de SinaisRESUMO
Nanotechnology has been the latest approach for diagnosis and treatment for cancer, which opens up a new alternative therapeutic drug delivery option to treat disease. Nanoparticles (NPs) display a broad role in cancer diagnosis and has various advantages over the other conventional chemotherapeutic drug delivery. NPs possess more specific and efficient drug delivery to the targeted tissue, cell, or organs and minimize the risk of side effects. NPs undergo passive and active mode of drug targets to tumor area with less elimination of the drug from the system. Size and surface characteristics of nanoparticles play a crucial role in modulating nanocarrier efficiency and the biodistribution of chemo drugs in the body. Several types of nanocarriers, such as polymers, dendrimers, liposome-based, and carbon-based, are studied widely in cancer therapy. Although FDA approved very few nanotechnology drugs for cancer therapy, a large number of studies are undergoing for the development of novel nanocarriers for potent cancer therapy. In this review, we discuss the details of the nano-based therapeutics and diagnostics strategies, and the potential use of nanomedicines in cancer therapy and cancer drug delivery.
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Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanomedicina , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Humanos , Nanopartículas/química , Neoplasias/patologia , Especificidade de Órgãos , Distribuição TecidualRESUMO
Head and neck cancer is the sixth most common cancer across the globe. This is generally associated with tobacco and alcohol consumption. Cancer in the pharynx majorly arises through human papillomavirus (HPV) infection, thus classifying head and neck squamous cell carcinoma (HNSCC) into HPV-positive and HPV-negative HNSCCs. Aberrant, mesenchymal-epithelial transition factor (c-MET) signal transduction favors HNSCC progression by stimulating proliferation, motility, invasiveness, morphogenesis, and angiogenesis. c-MET upregulation can be found in the majority of head and neck squamous cell carcinomas. c-MET pathway acts on several downstream effectors including phospholipase C gamma (PLCγ), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K), alpha serine/threonine-protein kinase (Akt), mitogen-activated protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. c-MET also establishes a crosstalk pathway with epidermal growth factor receptor (EGFR) and contributes towards chemoresistance in HNSCC. In recent years, the signaling communications of c-MET/HGF in metabolic dysregulation, tumor-microenvironment and immune modulation in HNSCC have emerged. Several clinical trials have been established against c-MET/ hepatocyte growth factor (HGF) signaling network to bring up targeted and effective therapeutic strategies against HNSCC. In this review, we discuss the molecular mechanism(s) and current understanding of c-MET/HGF signaling and its effect on HNSCC.
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Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Gerenciamento Clínico , Suscetibilidade a Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Metabolismo Energético , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Imunidade , Resultado do Tratamento , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
The discovery of new drugs is a time consuming and expensive process. Methods such as virtual screening, which can filter out ineffective compounds from drug libraries prior to expensive experimental study, have become popular research topics. As the computational drug discovery community has grown, in order to benchmark the various advances in methodology, organizations such as the Drug Design Data Resource have begun hosting blinded grand challenges seeking to identify the best methods for ligand pose-prediction, ligand affinity ranking, and free energy calculations. Such open challenges offer a unique opportunity for researchers to partner with junior students (e.g., high school and undergraduate) to validate basic yet fundamental hypotheses considered to be uninteresting to domain experts. Here, we, a group of high school-aged students and their mentors, present the results of our participation in Grand Challenge 4 where we predicted ligand affinity rankings for the Cathepsin S protease, an important protein target for autoimmune diseases. To investigate the effect of incorporating receptor dynamics on ligand affinity rankings, we employed the Relaxed Complex Scheme, a molecular docking method paired with molecular dynamics-generated receptor conformations. We found that Cathepsin S is a difficult target for molecular docking and we explore some advanced methods such as distance-restrained docking to try to improve the correlation with experiments. This project has exemplified the capabilities of high school students when supported with a rigorous curriculum, and demonstrates the value of community-driven competitions for beginners in computational drug discovery.
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Benchmarking , Desenho de Fármacos , Sítios de Ligação , Criança , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , TermodinâmicaRESUMO
Sperm concentration and sperm motility are the two major causes of male infertility. Having spermatozoa in semen without motility or flagellum tail defect is a major concern needed to be investigated. The CatSper genes are the novel family of four sperm-specific Ca2+-permeable channels which plays an important role in sperm motility, acrosome reaction, sperm, and oocyte fusion. CatSper1, CatSper2, and CatSper3 are very well-studied genes for their role in asthenozoospermia, but the association of these genes with metabolic genes is still unstudied. Another unrevealed aspect is how ROS alter the function of CatSper genes. Among the Catsper family genes, the role of CatSper4 gene must be explored more. In this study, we have used the in silico approach to find the connection between the CatSper family gene with glycolytic genes and also the involvement of CATSPER4 protein in sperm flagellum using the STRING database. Connection of CATSPER1 protein with lipid metabolic gene is also found in Reactome database, and after that gene ontology of these genes was done by using DAVID and Enrichr databases. This analysis showed a strong interaction between CATSPER1, CATSPER2, and CATSPER3 protein with glycolytic protein (i.e., GAPDHS and PGK2), and CATSPER4 protein shows strong relation in the function of sperm flagellum. We also found a novel gene, i.e., APOB contributing to sperm motility. Gene ontology showed the role of APOB and glycolytic proteins in sperm motility. Enrichr analysis showed the association of APOB and glycolytic proteins in asthenozoospermia and CATSPER4 protein with sperm flagellum. Elsevier Pathway Collection also showed proteins involved in male infertility (i.e., GAPDHS). Therefore, we report the role of the CatSper4 gene in sperm tail function and the APOB novel gene involved in sperm motility. Understanding the molecular mechanism(s) of regulations of the CatSper family gene will help us to develop new therapeutic approaches in infertile males.
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Infertilidade Masculina , Família Multigênica , Humanos , Masculino , Infertilidade Masculina/genética , Canais Iônicos , Sêmen , Motilidade dos Espermatozoides/genéticaRESUMO
Male infertility is one of the major challenging and prevalent diseases having diverse etiologies of which bacteriospermia play a significant role. It has been estimated that approximately 15% of all infertility cases are due to infections caused by uropathogens and in most of the cases bacteria are involved in infection and inflammation leading to the development of bacteriospermia. In response to bacterial load, excess infiltration of leukocytes in the urogenital tract occurs and concomitantly generates oxidative stress (OS). Bacteria may induce infertility either by directly interacting with sperm or by generating reactive oxygen species (ROS) and impair sperm parameters such as motility, volume, capacitation, hyperactivation. They may also induce apoptosis leading to sperm death. Acute bacteriospermia is related with another clinical condition called leukocytospermia and both compromise male fertility potential by OS-mediated damage to sperm leading to male infertility. However, bacteriospermia as a clinical condition as well as the mechanism of action remains poorly understood, necessitating further research in order to understand the role of individual bacterial species and their impact in male infertility.
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Infertilidade Masculina , Antioxidantes/farmacologia , Humanos , Infertilidade Masculina/etiologia , Infertilidade Masculina/metabolismo , Masculino , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Espermatozoides/fisiologiaRESUMO
Nowadays, about 14% of couples have difficulty in conceiving, and half of the cases are attributed to men. Asthenozoospermia or poor sperm motility is considered as the cause of infertility in males which is most common. Even though energy metabolism is considered the main reason for the etiology of asthenospermia, few attempts are made to determine the pathway of its metabolic potential. Recognition of cellular as well as molecular pathways that lead to reduced sperm motility may lead to the implementation of new therapeutic strategies to eliminate low sperm motility in people with asthenozoospermia. This review article discusses the key causes of decreased sperm motility and some of the muted genes and metabolic causes of the same.
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Astenozoospermia , Infertilidade Masculina , Astenozoospermia/genética , Astenozoospermia/metabolismo , Metabolismo Energético , Humanos , Infertilidade Masculina/genética , Infertilidade Masculina/metabolismo , Masculino , Motilidade dos Espermatozoides/genética , Espermatozoides/metabolismoRESUMO
This article examines the environmental factor-induced oxidative stress (OS) and their effects on male reproductive and sexual health. There are several factors that induce OS, i.e. radition, metal contamination, xenobiotic compounds, and cigarette smoke and lead to cause toxicity in the cells through metabolic or bioenergetic processes. These environmental factors may produce free radicals and enhance the reactive oxygen species (ROS). Free radicals are molecules that include oxygen and disbalance the amount of electrons that can create major chemical chains in the body and cause oxidation. Oxidative damage to cells may impair male fertility and lead to abnormal embryonic development. Moreover, it does not only cause a vast number of health issues such as ageing, cancer, atherosclerosis, insulin resistance, diabetes mellitus, cardiovascular diseases, ischemia-reperfusion injury, and neurodegenerative disorders but also decreases the motility of spermatozoa while increasing sperm DNA damage, impairing sperm mitochondrial membrane lipids and protein kinases. This chapter mainly focuses on the environmental stressors with further discussion on the mechanisms causing congenital impairments due to poor sexual health and transmitting altered signal transduction pathways in male gonadal tissues.
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Saúde Sexual , Sementes , Estresse Oxidativo , Radicais LivresRESUMO
Head and neck squamous cell carcinoma (HNSCC) glycolysis is an important factor for the advancement of the disease and metastasis. Upregulation of glycolysis leads to decreased sensitivity to chemotherapy and radiation. HNSCC cells maintain constitutive glycolytic flux generating metabolic intermediates for the synthesis of amino acids, nucleotides, and fats for cell survival and disease progression. There are several pathways such as PI3K/Akt, EGFR, and JAK-STAT that contribute a major role in metabolic alteration in HNSCC. Recent studies have demonstrated that cancer-associated fibroblasts abundant in the HNSCC tumor microenvironment play a major role in HNSCC metabolic alteration via hepatocyte growth factor (HGF)/c-Met cross signaling. Despite therapeutic advancement, HNSCC lacks broad range of therapeutic interventions for the treatment of the disease. Thus, understanding the different key players involved in glucose metabolism and targeting them would lead to the development of novel drugs for the treatment of HNSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Glicólise , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Fosfatidilinositol 3-Quinases/genética , Microambiente TumoralRESUMO
The novel coronavirus, SARS-CoV-2, has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of a vaccine and potential therapeutics are critically essential. The crystal structure for the main protease (Mpro) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CLpro), was recently made available and is considerably similar to the previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, a computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against the 3-chymotrypsin-like cysteine protease (3CLpro) enzyme was accomplished, and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus, a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound 16 with a docking score of -8.955 adhered to drug-like parameters, and the structure-activity relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular dynamics (MD) simulation analysis performed at 100 ns supported the stability of 16 within the binding pocket. Largely, our results supported that this novel compound 16 binds with domains I and II, and the domain II-III linker of the 3CLpro protein, suggesting its suitability as a strong candidate for therapeutic discovery against COVID-19.
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Antivirais/química , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus/metabolismo , Etanolaminas/química , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , Sítios de Ligação , Desenho de Fármacos , Etanolaminas/farmacologia , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-AtividadeRESUMO
Familial and idiopathic Parkinson's disease (PD) is associated with the abnormal neuronal accumulation of α-synuclein (aS) leading to ß-sheet-rich aggregates called Lewy Bodies (LBs). Moreover, single point mutation in aS gene and gene multiplication lead to autosomal dominant forms of PD. A connection between PD and the 14-3-3 chaperone-like proteins was recently proposed, based on the fact that some of the 14-3-3 isoforms can interact with genetic PD-associated proteins such as parkin, LRRK2 and aS and were found as components of LBs in human PD. In particular, a direct interaction between 14-3-3η and aS was reported when probed by co-immunoprecipitation from cell models, from parkinsonian brains and by surface plasmon resonance in vitro. However, the mechanisms through which 14-3-3η and aS interact in PD brains remain unclear. Herein, we show that while 14-3-3η is unable to bind monomeric aS, it interacts with aS oligomers which occur during the early stages of aS aggregation. This interaction diverts the aggregation process even when 14-3-3η is present in sub-stoichiometric amounts relative to aS. When aS level is overwhelmingly higher than that of 14-3-3η, the fibrillation process becomes a sequestration mechanism for 14-3-3η, undermining all processes governed by this protein. Using a panel of complementary techniques, we single out the stage of aggregation at which the aS/14-3-3η interaction occurs, characterize the products of the resulting processes, and show how the processes elucidated in vitro are relevant in cell models. Our findings constitute a first step in elucidating the molecular mechanism of aS/14-3-3η interaction and in understanding the critical aggregation step at which 14-3-3η has the potential to rescue aS-induced cellular toxicity.
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Proteínas 14-3-3/metabolismo , Amiloidose/metabolismo , Agregação Patológica de Proteínas , Transdução de Sinais , alfa-Sinucleína/metabolismo , Proteínas 14-3-3/química , Proteínas 14-3-3/genética , Humanos , Cinética , Ligação Proteica , Isoformas de Proteínas , alfa-Sinucleína/química , alfa-Sinucleína/genéticaRESUMO
Background and Aims: Several studies have revealed that Epstein-Barr virus (EBV) infection raised the likelihood of developing Alzheimer's disease (AD) via infecting B lymphocytes. The purpose of the current investigation was to assess the possible association between EBV infection and AD. Methods: The microarray datasets GSE49628, GSE126379, GSE122063, and GSE132903 were utilized to extract DEGs by using the GEO2R tool of the GEO platform. The STRING tool was used to determine the interaction between the DEGs, and Cytoscape was used to visualize the results. The DEGs that were found underwent function analysis, including pathway and GO, using the DAVID 2021 and ClueGo/CluePedia. By using MNC, MCC, Degree, and Radiality of cytoHubba, we identified seven common key genes. Gene co-expression analysis was performed through the GeneMANIA web tool. Furthermore, expression analysis of key genes was performed through GTEx software, which have been identified in various human brain regions. The miRNA-gene interaction was performed through the miRNet v 2.0 tool. DsigDB on the Enrichr platform was utilized to extract therapeutic drugs connected to key genes. Results: In GEO2R analysis of datasets with |log2FC|≥ 0.5 and p-value <0.05, 8386, 10,434, 7408, and 759 genes were identified. A total of 141 common DEGs were identified by combining the extracted genes of different datasets. A total of 141 nodes and 207 edges were found during the PPI analysis. The DEG GO analysis with substantial alterations disclosed that they are associated to molecular functions and biological processes, such as positive regulation of neuron death, autophagy regulation of mitochondrion, response of cell to insulin stimulus, calcium signaling regulation, organelle transport along microtubules, protein kinase activity, and phosphoserine binding. Kyoto Encyclopedia of Genes and Genomes analysis discovered the correlation between the DEGs in pathways of neurodegeneration: multiple disease, cell cycle, and cGMP-PKG signaling pathway. Finally, YWHAH, YWHAG, YWHAB, YWHAZ, MAP2K1, PPP2CA, and TUBB genes were identified that are strongly linked to EBV and AD. Three miRNAs, i.e., hsa-mir-15a-5p, hsa-let-7a-5p, and hsa-mir-7-5p, were identified to regulate most of hub genes that are associated with EBV and AD. Further top 10 significant therapeutic drugs were predicted. Conclusion: We have discovered new biomarkers and therapeutic targets for AD, as well as the possible biological mechanisms whereby infection with EBV may be involved in AD susceptibility for the first time.
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BACKGROUND: Glioblastoma multiforme (GBM) is a highly heterogeneous brain tumor with limited treatment options and a poor prognosis. Cancer stem cells (CSCs) have emerged as a critical factor in GBM resistance and management, contributing to tumor growth, heterogeneity, and immunosuppression. The transcription factor FOXM1 has been identified as a key player in the progression, spread, and therapy resistance of various cancers, including GBM. OBJECTIVE: In this research, the objective was to perform structure-based in silico screening with the aim of identifying natural compounds proficient in targeting the DNA-binding domain (DBD) of the FOXM1 protein. METHODS: In this study, in silico tools were employed for screening a hundred naturally occurring compounds capable of targeting the FOXM1 protein. Through molecular docking analysis and pharmacokinetic profiling, five compounds were found to be promising candidates for extensive interaction with the FOXM1 protein. Further, these compounds were validated for the stability of the FOXM1-natural compound complex using molecular dynamics (MD) simulations. RESULTS: Four compounds, such as Withaferin A, Bryophyllin A, Silybin B, Sanguinarine and Troglitazone (control compound), emerged as promising candidates with substantial interactions with FOXM1, suggesting their potential as a protein inhibitor based on molecular docking investigations. After MD simulation analysis, the FOXM1- Bryophyllin A complex was found to maintain the highest stability, and the other three ligands had moderate but comparable binding affinities over a period of 100 ns. CONCLUSION: This study provides valuable insights into four promising FOXM1 inhibitors that have the ability to induce senescence in GBM stem cells. These findings contribute to the development of structure-based designing strategies for FOXM1 inhibitors and innovative therapeutic approaches for the treatment of Glioblastoma.
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In this study, a comprehensive investigation of a set of phytochemicals to identify potential inhibitors for the Forkhead box protein M1 (FOXM1) was conducted. FOXM1 is overexpressed in glioblastoma (GBM) cells and plays a crucial role in cell cycle progression, proliferation, and invasion. FOXM1 inhibitors have shown promising results in preclinical studies, and ongoing clinical trials are assessing their efficacy in GBM patients. However, there are limited studies on the identification of novel compounds against this attractive therapeutic target. To address this, the NPACT database containing 1,574 phytochemicals was used, employing a hierarchical multistep docking approach, followed by an estimation of relative binding free energy. By fixing user-defined XP-dock and MM-GBSA cut-off scores of -6.096 and -37.881 kcal/mol, the chemical space was further narrowed. Through exhaustive analysis of molecular binding interactions and various pharmacokinetics profiles, we identified four compounds, namely NPACT00002, NPACT01454, NPACT00856, and NPACT01417, as potential FOXM1 inhibitors. To assess the stability of protein-ligand binding in dynamic conditions, 100 ns Molecular dynamics (MD) simulations studies were performed. Furthermore, Molecular mechanics with generalized Born and surface area solvation (MM-GBSA) based binding free energy estimations of the entire simulation trajectories revealed a strong binding affinity of all identified compounds towards FOXM1, surpassing that of the control drug Troglitazone. Based on extensively studied multistep docking approaches, we propose that these molecules hold promise as FOXM1 inhibitors for potential therapeutic applications in GBM. However, experimental validation will be necessary to confirm their efficacy as targeted therapies.Communicated by Ramaswamy H. Sarma.
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The present study was carried out in the village Kaliprasad of Bhagalpur district of Bihar to know the arsenic exposure effect in the exposed population. A total of n = 102 households were studied, and their water and biological samples such as urine and hair were collected and analyzed in a graphite furnace atomic absorption spectrophotometer (GF-AAS). The assessment of arsenic-exposed village population reveals that the villagers were suffering from serious health-related problems such as skin manifestations (hyperkeratosis and melanosis in their palm and soles), breathlessness, general body weakness, mental disorders, diabetes, hypertension (raised blood pressure), hormonal imbalance, neurological disorders, and few cancer cases. About 77% of household hand pump water had arsenic level more than the WHO recommended level of 10 µg/L, with highest level of 523 µg/L. Moreover, in 60% individual's urine samples, arsenic concentration was very high with maximum 374 µg/L while in hair 64% individuals had arsenic concentration above the permissible limit with maximum arsenic concentration of 11,398 µg/kg. The hazard quotient (HQ) was also calculated to know the arsenic risk percentage in children as 87.11%, in females as 83.15%, and in males as 82.27% by groundwater. This has surpassed the threshold value of 1 × 10 - 6 for carcinogenic risk (CR) in children, female, and male population group in the village. Hence, the exposed population of Kaliprasad village are at very high risk of the disease burden.
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Intoxicação por Arsênico , Arsênio , Água Subterrânea , Poluentes Químicos da Água , Criança , Humanos , Masculino , Feminino , Arsênio/análise , Grupos Populacionais , Poluentes Químicos da Água/análise , Intoxicação por Arsênico/epidemiologia , Índia/epidemiologia , ÁguaRESUMO
Lead poisoning in the recent times has caused serious health threats in the exposed human population. It is estimated that about 815 million people are exposed to lead poisoning worldwide and in India total 275 million children are exposed to blood lead contamination. The present study was carried outed in 6 districts of Bihar to know the extent of lead exposure in the children through their mother's breastmilk. The biological samples such as breastmilk, mother's urine, child's urine, and mother's blood samples were collected for quantitative lead estimation. Moreover, the selected household water sources (handpump) and the food consumed by the individuals-wheat, rice and potato samples were also collected for lead quantification. The study reveals that the breastmilk had high lead content in 92% of the samples (highest value 1309 µg/L), in blood presence of lead was observed in 87% studied samples (highest value 677.2 µg/L). In mother's urine the highest lead value was 4168 µg/L (62%) and in child's urine the highest value was 875.4 µg/L (62%) respectively of the studied samples. Moreover, in the studied food samples, wheat had lead content in 45% the studied samples (highest value 7910 µg/kg). In rice in 40% of the studied samples (highest value 6972 µg/kg) and in potato 90% of the studied samples (highest value = 13786 µg/kg) were found with elevated lead content respectively. The hazard quotient (HQ) and the cancer risk (CR) for lead contamination was very much higher in mothers followed by their children. The entire study indicated that lead exposure through food (wheat, rice and potato) has reached the mother's breastmilk and from their it has reached their child's body. This could cause serious hazards in the exposed children causing serious neurological damages, low IQ, low memory, and low mental growth in them. Therefore, a strategic action is required to control the present problem.
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BACKGROUND: Autophagy is an indispensable lysosomal self-digestion process involved in the degradation of aggregated proteins and damaged organelles. Autophagy is associated with the several pathological processes, including cancer. Cancer stem cells (CSCs) play significant roles in cancer initiation, progression and drug resistance. Recent studies have demonstrated the antitumor activities of plant-derived chemopreventive agent rottlerin (Rott). However, the molecular mechanism by which Rott induces autophagy in breast CSCs has not been investigated. RESULTS: The objectives of this study were to examine the molecular mechanism by which Rott induces autophagy which leads to apoptosis in breast CSCs. Treatment of breast CSCs with Rott for 24 h resulted in a concentration dependent induction of autophagy, followed by apoptosis as measured by flow cytometry. Electron microscopy confirmed the presence of autophagosomes in Rott treated breast CSCs. Western blot analysis showed that Rott treatment increased the expression of LC3, Beclin-1 and Atg12 that are accumulated during autophagy. Prolonged exposure of breast CSCs to Rott caused apoptosis which was associated with the suppression of phosphorylated Akt and mTOR, upregulation of phosphorylated AMPK, and downregulation of anti-apoptosis Bcl-2, Bcl-X(L), XIAP and cIAP-1. Knock-down of Atg7 or Beclin-1 by shRNA inhibited Rott-induced autophagy at 24 h. Our study also demonstrates that pre-treatment of breast CSCs with autophagosome inhibitors 3-methyladenine and Bafilomycin, as well as protein synthesis inhibitor cycloheximide inhibited Rott-induced autophagy and apoptosis. Rott induces autophagy via extensive cytoplasmic vacuolization in breast CSCs. Molecular docking results between C2-domain of protein kinase C-delta and Rott indicated that both hydrogen bonding and hydrophobic interactions contributed significantly for ligand binding with minimum binding affinity of ≈ 7.5 Kcal/mol. Although, autophagy inhibitors suppress the formation of cytoplasmic vacuolization and autophagy in breast CSCs, the potency of Rott to induce autophagy and apoptosis might be based on its capability to activate several pathways such as AMPK and proteasome inhibition. CONCLUSIONS: A better understanding of the relationship between autophagy and apoptosis would eventually allow us to discover novel drugs for the treatment of breast cancer by eliminating CSCs.
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Acetofenonas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Autofagia , Benzopiranos/farmacologia , Células-Tronco Neoplásicas/fisiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Acetofenonas/química , Antineoplásicos Fitogênicos/química , Benzopiranos/química , Neoplasias da Mama , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Simulação de Acoplamento Molecular , Proteína Quinase C-delta/química , Proteína Quinase C-delta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas , Vacúolos/metabolismoRESUMO
Changes in DNA methylation levels, changes in histones, and noncoding RNA functions (ncRNAs) are common among different diseases and epigenetic component mutations. The ability to distinguish between the roles of drivers and passengers in epigenetic changes will allow to identify diseases where epigenetics could influence diagnosis, prediction and treatment. In addition, by examining the interaction between epigenetic components and other pathways of disease, a combination intervention approach will be developed. A comprehensive study of the association of specific cancer types or the cancer genome atlas project has revealed frequent mutations in genes encoded by the epigenetic components. These include mutations in DNA methylase and demethylase, the cytoplasm and the change of cytoplasm, as well as genes involved in the restoration of chromatins and the structure of chromosomes, also, the metabolic genes isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) affect histone and DNA methylation, disrupting the architecture of the 3D genome, but also affect the metabolic genes IDH1 and IDH2. Repeated DNA elements also cause cancer. In the 21st century, epigenetic research has rapidly accelerated, causing legitimate excitement and hope, and causing a certain level of excitement. New epigenetic tools can be used as prevention, diagnosis and therapeutic markers. Drug development targets specific epigenetic mechanisms that regulate gene expression and promotes gene expression. The development and use of epigenetic tools is an appropriate and effective method for treating various diseases clinically.
Assuntos
Isocitrato Desidrogenase , Medicina de Precisão , Humanos , Isocitrato Desidrogenase/genética , Histonas , Cromatina , Epigênese GenéticaRESUMO
GLI gene-mediated hedgehog (Hh) signaling pathway plays a substantial role in brain cancer development and growth including glioblastoma multiforme (GBM), lower-grade glioma (LGG), and medulloblastoma (MB). GLI2 and GLI3 gene expression levels are extremely enhanced in these cancers with poor patient survival. Moreover, GLI genes are correlated with stemness-related factors SOX2, SOX9, POU5F1, and NANOG that work as the driving factors for brain cancer stem cells (CSCs) progression. It's critical to find new ways to combat this deadly malignancy and CSCs. Using in silico approaches, our study explored the role of GLI genes (GLI1, GLI2, and GLI3), the primary transcription factors of the sonic hedgehog (SHH) signaling pathway, in GBM, LGG, MB, and glioblastoma stem-like cells (GSCs). Additionally, we found strong association of angiogenic-related gene VEGFA, metabolic genes ENO1, ENO2, and pluripotency-related genes SOX2, SOX9, NANOG, POU5F1 with GLI genes, suggesting their role in brain tumor initiation and progression. We also studied their transcriptional network and functional category enrichment analysis about brain tumor development to find a better therapeutic strategy against brain cancer and their stem cells. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03419-5.