Systemic impact of heavy metals and their role in cancer development: a review.

Heavy metals are well-recognised as environmental hazards due to their toxicity, environmental persistence, and bioaccumulation in living organisms. Human health is a crucial concern related to terrestrial and aquatic ecosystems poisoned by harmful heavy metals. Most heavy metals pollute the air, water, and soil, which can be fatal to humans. Humans and other species can be exposed to heavy metals through the food chain if the metals oxidise or combine with other environmental elements (such as water, soil, or air). Their entry into the food chain assures interactions with biological macromolecules in living systems, including humans, resulting in undesirable outcomes. Human poisonings have typically been caused by mercury, lead, chromium, cadmium, and arsenic. The build-up of these metals in living organisms causes various harmful consequences on different organs and tissues. The gravitas of heavy metal toxicity regarding molecular impact and carcinogenesis needs in-depth understanding despite the plethora of available data. Hence, additionally, we attempt to elaborate on the multi-level impact of five heavy metals and emphasise their role in cancer development. The rationale of this essay is thus to understand the role of five heavy metals, viz., lead (Pb), cadmium (Cd), chromium (Cr), arsenic (As), and mercury (Hg), in carcinogenesis. Heavy metals interfere with various biological functions, including proliferation, differentiation, repair of damage, and apoptosis. By comparing their modes of action, we see that these metals share common mechanisms for inducing toxicity, such as reactive oxygen species (ROS) production, antioxidant defence weakening, enzyme inactivation, and oxidative stress.

Looking beyond the cytogenetics in haematological malignancies: decoding the role of tandem repeats in DNA repair genes.

BACKGROUND: In cancer research, one of the most significant findings was to characterize the DNA repair deficiency as carcinogenic. Amongst the various repair mechanisms, mismatch repair (MMR) and direct reversal of DNA damage systems are designated as multilevel safeguards in the human genome. Defects in these elevate the rate of mutations and results in dire consequences like cancer. Of the several molecular signatures in human genome, tandem repeats (TRs) appear at various frequencies in the exonic, intronic, and regulatory regions of the DNA. Hypervariability among these repeats in the coding and non-coding regions of the genes is well characterized for solid tumours, but its significance in haematologic malignancies remains to be explored. The purpose of our study was to elucidate the role of nucleotide repeat instability in the coding and non-coding regions of 10 different repair genes in myeloid and lymphoid cell lines compared to the control samples. METHODS AND RESULTS: We selected MMR deficient extensively studied microsatellite instable colorectal cancer (HCT116), and MMR proficient breast cancer (MCF-7) cells along with underemphasized haematologic cancer cell lines to decipher the hypermutability of tandem repeats. A statistically significant TR variation was observed for MSH2 and MSH6 genes in 4 and 3 of the 6 cell lines respectively. KG1 (AML) and Daudi (Burkitt's lymphoma) were found to have compromised DNA repair competency with highly unstable nucleotide repeats. CONCLUSION: Taken together, the results suggest that mutable TRs in intronic and non-intronic regions of repair genes in blood cancer might have a tumorigenic role. Since this is a pilot study on cell lines, high throughput research in large cohorts can be undertaken to reveal novel diagnostic markers for unexplained blood cancer patients with normal karyotypes or otherwise with karyotypic defects.

Revisiting the melanomagenic pathways and current therapeutic approaches.

Melanoma is one of the most aggressive forms of skin cancer with a steady increase in global incidence and mortality rate over the past five decades. Paradoxically, both reduced and excessive sun exposure has been linked to increased risk of melanoma incidence and death. Although the histological classification of melanoma is useful in diagnosis, its molecular subtypes are often determined by somatic mutations, which could be UV-dependent or -independent. Multiple genes involved in cancer development are often mutated dysregulating molecular pathways with concomitant phenotypic heterogeneity. Hence, treating melanoma has been a challenge, with patients experiencing poor clinical outcomes to current therapeutic options. This presents an unmet need to understand the interaction of molecular networks underpinning melanogenesis. This review describes the crosstalk of signaling cascades in melanoma development and the putative druggable targets, with the view of elucidating newer and better therapeutic strategies for the disease.

Melanoma therapeutics: a literature review.

Melanoma is a relentless type of skin cancer which involves myriad signaling pathways which regulate many cellular processes. This makes melanoma difficult to treat, especially when identified late. At present, therapeutics include chemotherapy, surgical resection, biochemotherapy, immunotherapy, photodynamic and targeted approaches. These interventions are usually administered as either a single-drug or in combination, based on tumor location, stage, and patients' overall health condition. However, treatment efficacy generally decreases as patients develop treatment resistance. Genetic profiling of melanocytes and the discovery of novel molecular factors involved in the pathogenesis of melanoma have helped to identify new therapeutic targets. In this literature review, we examine several newly approved therapies, and briefly describe several therapies being assessed for melanoma. The goal is to provide a comprehensive overview of recent developments and to consider future directions in the field of melanoma.

Role of aberrant Sonic hedgehog signaling pathway in cancers and developmental anomalies.

Development is a sophisticated process maintained by various signal transduction pathways, including the Hedgehog (Hh) pathway. Several important functions are executed by the Hh signaling cascade such as organogenesis, tissue regeneration, and tissue homeostasis, among various others. Considering the multiple functions carried out by this pathway, any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers. In the present review article, we explored a wide range of diseases caused by aberrant Hh signaling, including developmental defects and cancers. Finally, we concluded this mini-review with various treatment strategies for Hh-induced diseases.

A study of deregulated MMR pathways and anticancer potential of curcuma derivatives using computational approach.

Plant derived products have steadily gained momentum in treatment of cancer over the past decades. Curcuma and its derivatives, in particular, have diverse medicinal properties including anticancer potential with proven safety as supported by numerous in vivo and in vitro studies. A defective Mis-Match Repair (MMR) is implicated in solid tumors but its role in haematologic malignancies is not keenly studied and the current literature suggests that it is limited. Nonetheless, there are multiple pathways interjecting the mismatch repair proteins in haematologic cancers that may have a direct or indirect implication in progression of the disease. Here, through computational analysis, we target proteins that are involved in rewiring of multiple signaling cascades via altered expression in cancer using various curcuma derivatives (Curcuma longa L. and Curcuma caesia Roxb.) which in turn, profoundly controls MMR protein function. These biomolecules were screened to identify their efficacy on selected targets (in blood-related cancers); aberrations of which adversely impacted mismatch repair machinery. The study revealed that of the 536 compounds screened, six of them may have the potential to regulate the expression of identified targets and thus revive the MMR function preventing genomic instability. These results reveal that there may be potential plant derived biomolecules that may have anticancer properties against the tumors driven by deregulated MMR-pathways.

Medulloblastoma: "Onset of the molecular era".

Among brain tumors, Medulloblastoma (MB) is one of the most common, malignant, pediatric tumors of the cerebellum. It accounts for ~20% of all childhood central nervous system (CNS) tumors. Despite, tremendous advances in drug development processes, as well as novel drugs for MB the morbidity and mortality rates, remain high. Craniospinal radiation, high-dose chemotherapy, and surgical resection are the primary therapeutic strategies. Tremendous progress in the field of "genomics" with vast amounts of data has led to the identification of four distinct molecular subgroups in medulloblastoma: WNT group, SHH group, group-III, and group-IV. The identification of these subgroups has led to individualized treatment strategies for each subgroup. Here, we discuss the various molecular subgroups of medulloblastoma as well as the differences between them. We also highlight the latest treatment strategies available for medulloblastoma.

Toxic impacts and industrial potential of graphene.

Advancement in the field of nanotechnology has increased the synthesis and exploitation of graphene-like nanomaterials. Graphene is a two-dimensional planar and hexagonal array of carbon atoms. Due to its flexible nature graphene and its derivatives have several significant prospects extending from electronics to life sciences and drug delivery systems. In this review, we enlist some of the toxic effects of graphene family nanomaterials (GFNs) in various aspects of biosystems viz., in vitro, in vivo, microbial, molecular and environmental. We also appreciate their extensive and promising applications though with some underlying challenges. This review also draws attention toward current and future prospect of global graphene market for wide-range commercialization.

D224V and S128Y mutation in FSHRED influence thumb movement differentially: An intricate insight gained by short-term molecular dynamics simulation.

Follicle-stimulating hormone-follicle-stimulating hormone receptor (FSH-FSHR) interaction is one of the most thoroughly studied signaling pathways primarily because of being implicated in sexual reproduction in mammals by way of maintaining gonadal function and sexual fertility. Despite material advances in understanding the role of point mutations, their mechanistic basis in FSH-FSHR signaling is still confined to mystically altered behavior of sTYS335 (sulfated tyrosine) yet lacking a substantial theory. To understand the structural basis of receptor modulation, we choose two behaviorally contradicting mutations, namely S128Y (activating) and D224Y (inactivating), found in FSH receptor responsible for ovarian hyperstimulation syndrome and ovarian dysgenesis, respectively. Using short-term molecular dynamics simulations, the atomic scale investigations reveal that the binding pattern of sTYS with FSH and movement of the thumb region of FSHR show distinct contrasting patterns in the two mutants, which supposedly could be a critical factor for differential FSHR behavior in activating and inactivating mutations.

Microsatellite Instability and Promoter Hypermethylation of DNA repair genes in Hematologic Malignancies: a forthcoming direction toward diagnostics.

OBJECTIVE: The objective of our review is to highlight the significance of microsatellite hypervariation in diagnostics of hematologic malignancies. METHODS: For the past few decades, extensive experiments in cancer research have explored all the possible pathways and a number of deleterious mutations that either make the tumor suppressor genes (TSGs) dysfunctional or cause the proto-oncogenes to behave abnormally by changing the cellular phenotype hence rendering disease. To prevent the deleterious effects of mutations and to protect the genomic integrity, our system possesses multiple repair mechanisms. DNA Mismatch Repair (MMR) and Direct Reversal of Damage (DRD) are two repair mechanisms which help in removal of faulty base pairs and alkyl adduct formation respectively to avoid long term effects of toxicity, tumorigenesis and mutagenesis. There are nine major MMR genes - MutS homolog (MSH2, MSH3, MSH4, MSH5, MSH6), MutL homolog (MLH1, MLH3), human post-meiotic segregation genes (PMS1, PMS2), and three major damage reversal genes - O6-methylguanine-DNA-methyltransferase (MGMT), ABH2 and DEPC1. RESULTS: Any malfunction in DNA repair machinery can cause microsatellite instability (MSI), a form of genomic abnormality with hyper mutable repeats that is directly associated with cancer. Microsatellites are short, repetitive sequences, non-randomly distributed and localized in 3'-UTR (Untranslated Region), introns, coding regions and promoters. Besides MSI, evidence on promoter hypermethylation of selected repair genes also points toward a prominent reason for cancer initiation and progression. CONCLUSION: The presence of specific microsatellite marker hyper-mutability and consistent promoter hypermethylation in leukemia or lymphoma can be considered as a part of routine diagnostic test in clinical laboratories.

Gastric cancer and related epigenetic alterations.

Gastric cancer, a malignant and highly proliferative condition, has significantly affected a large population around the globe and is known to be caused by various factors including genetic, epigenetic, and environmental influences. Though the global trend of these cancers is declining, an increase in its frequency is still a threat because of changing lifestyles and dietary habits. However, genetic and epigenetic alterations related to gastric cancers also have an equivalent contribution towards carcinogenic development. DNA methylation is one of the major forms of epigenetic modification which plays a significant role in gastric carcinogenesis. Methylation leads to inactivation of some of the most important genes like DNA repair genes, cell cycle regulators, apoptotic genes, transcriptional regulators, and signalling pathway regulators; which subsequently cause uncontrolled proliferation of cells. Mutations in these genes can be used as suitable prognostic markers for early diagnosis of the disease, since late diagnosis of gastric cancers has a huge negative impact on overall patient survival. In this review, we focus on the important epigenetic mutations that contribute to the development of gastric cancer and the molecular pathogenesis underlying each of them. Methylation, acetylation, and histone modifications play an integral role in the onset of genomic instability, one of the many contributory factors to gastric cancer. This article also covers the constraints of incomplete knowledge of epigenetic factors influencing gastric cancer, thus throwing light on our understanding of the disease.

From natural products to drugs for epimutation computer-aided drug design.

The epimutational event, i.e., ectopic methylation in tumor suppressor genes, can lead to gene silencing, thus promoting prognosis of cancer. The progression of DNA methylation is a cycle of demethylation, de novo methylation, and maintenance methylation. The enzyme responsible for maintenance of methylation status is DNA methyltransferase 1 (DNMT1), the continuous activity of which is required to maintain the pattern of epimutation; thus, its inhibition is a promising strategy for the treatment of cancer. To the best of our knowledge, this study is the first to focus on the recently developed crystal structure of the catalytic site of DNMT1. Here in this study, we have used the crystal structure for the development of non-nucleoside DNMT1 inhibitors using virtual screening (VS), absorption, distribution, metabolism, elimination/toxicology analysis, and molecular docking studies. In this study, VS was carried out on 48,531 natural products to create a subset of lead-like natural products. Three of them were found to form hydrogen bonds with the catalytic site of the DNMT1 (Cys 1226). Thus, this study adumbrates potential lead compounds for treatment of epimutation.

N-nitrosodimethylamine in the Kashmiri diet and possible roles in the high incidence of gastrointestinal cancers.

The Kashmiri population is culturally distinct with special dietary features owing to the temperate climatic conditions of Kashmir valley. This has habituated the population to preserve food in smoked, pickled and sundried forms which include considerable amounts of N-nitroso compounds (NOCs). These are known to cause cytotoxicity, DNA damage, mutation, unscheduled DNA synthesis and DNA methylation. All of these changes at molecular level are known to contribute to the pathogenesis of cancer. One of the prominent NOCs found in Kashmiri food is N-Nitrosodimethylamine (NDMA). Here we review the occurrence of NDMA in sundried foods, dried fish, kehwa, traditional pickle, Brassica oleracia and tobbaco. We also discuss its possible role in the high prevalence of gastrointestinal cancers in Kashmir.

Catharanthus roseus: a natural source for the synthesis of silver nanoparticles.

OBJECTIVE: To develop a simple rapid procedure for bioreduction of silver nanoparticles (AgNPs) using aqueous leaves extracts of Catharanthus roseus (C. roseus). METHODS: Characterization were determined by using UV-Vis spectrophotometry, scanning electron microscopy (SEM), energy dispersive X-ray and X-ray diffraction. RESULTS: SEM showed the formation of silver nanoparticles with an average size of 67 nm to 48 nm. X-ray diffraction analysis showed that the particles were crystalline in nature with face centered cubic geometry. CONCLUSIONS: C. roseus demonstrates strong potential for synthesis of silver nanoparticles by rapid reduction of silver ions (Ag(+) to Ag(0)). This study provides evidence for developing large scale commercial production of value-added products for biomedical/nanotechnology-based industries.