Resveratrol: biology, metabolism, and detrimental role on the tumor microenvironment of colorectal cancer.

A substantial increase in colorectal cancer (CRC)-associated fatalities can be attributed to tumor recurrence and multidrug resistance. Traditional treatment options, including radio- and chemotherapy, also exhibit adverse side effects. Ancient treatment strategies that include phytochemicals like resveratrol are now widely encouraged as an alternative therapeutic option. Resveratrol is the natural polyphenolic stilbene in vegetables and fruits like grapes and apples. It inhibits CRC progression via targeting dysregulated cancer-promoting pathways, including PI3K/Akt/Kras, targeting transcription factors like NF-κB and STAT3, and an immunosuppressive tumor microenvironment. In addition, combination therapies for cancer include resveratrol as an adjuvant to decrease multidrug resistance that develops in CRC cells. The current review discusses the biology of resveratrol and explores different mechanisms of action of resveratrol in inhibiting CRC progression. Further, the detrimental role of resveratrol on the immunosuppressive tumor microenvironment of CRC has been discussed. This review illustrates clinical trials on resveratrol in different cancers, including resveratrol analogs, and their efficiency in promoting CRC inhibition.

Epigenetics in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and has a high fatality rate. Genetic and epigenetic aberrations are commonly observed in HCC. The epigenetic processes include chromatin remodelling, histone alterations, DNA methylation, and noncoding RNA (ncRNA) expression and are connected with the progression and metastasis of HCC. Due to their potential reversibility, these epigenetic alterations are widely targeted for the development of biomarkers. In-depth understanding of the epigenetics of HCC is critical for developing rational clinical strategies that can provide a meaningful improvement in overall survival and prediction of therapeutic outcomes. In this article, we have summarised the epigenetic modifications involved in HCC progression and highlighted the potential biomarkers for diagnosis and drug development.

Targeting the tumor microenvironment of pancreatic ductal adenocarcinoma using nano-phytomedicines.

Despite advanced therapeutic strategies, the mortality and morbidity of pancreatic cancer (PC) have been increasing. This is due to the anomalous proliferation activity of stromal cells, like cancer-associated fibroblasts (CAFs), in the tumor microenvironment (TME). These cells develop resistance in the tumor cells, blocking the drug from entering the target tumor site, ultimately resulting in tumor metastasis. Additionally, the current conventional adjuvant techniques, including chemo and radiotherapy, carry higher risk due to their excess toxicity against normal healthy cells. Phytochemicals including curcumin, irinotecan and paclitaxel are anti-oxidants, less toxic, and have anti-cancerous properties; however, the use of phytochemicals is limited due to their less solubility and bioavailability. Nanotechnology offers the resources to directly target the drug to the tumor site, thereby enhancing the therapeutic efficacy of the current treatment modalities. This review focuses on the importance of nanotechnology for pancreatic ductal adenocarcinoma (PDAC) therapy and on delivering the nano-formulated phytochemicals to the target site.

Epigenetics and therapeutic targets in gastrointestinal malignancies.

Gastrointestinal (GI) malignancies account for substantial mortality and morbidity worldwide. They are generally promoted by dysregulated signal transduction and epigenetic pathways, which are controlled by specific enzymes. Recent studies demonstrated that histone deacetylases (HDACs) together with DNA methyltransferases (DNMTs) have crucial roles in the signal transduction/epigenetic pathways in GI regulation. In this review, we discuss various enzyme targets and their functional mechanisms responsible for the regulatory processes of GI malignancies. We also discuss the epigenetic therapeutic targets that are mainly facilitated by DNMT and HDAC inhibitors, which have functional consequences and clinical outcomes for GI malignancies.

Application of single-cell sequencing technologies in pancreatic cancer.

Pancreatic cancer (PC) is the third lethal disease for cancer-related mortalities globally. This is mainly because of the aggressive nature and heterogeneity of the disease that is diagnosed only in their advanced stages. Thus, it is challenging for researchers and clinicians to study the molecular mechanism involved in the development of this aggressive disease. The single-cell sequencing technology enables researchers to study each and every individual cell in a single tumor. It can be used to detect genome, transcriptome, and multi-omics of single cells. The current single-cell sequencing technology is now becoming an important tool for the biological analysis of cells, to find evolutionary relationship between multiple cells and unmask the heterogeneity present in the tumor cells. Moreover, its sensitivity nature is found progressive enabling to detect rare cancer cells, circulating tumor cells, metastatic cells, and analyze the intratumor heterogeneity. Furthermore, these single-cell sequencing technologies also promoted personalized treatment strategies and next-generation sequencing to predict the disease. In this review, we have focused on the applications of single-cell sequencing technology in identifying cancer-associated cells like cancer-associated fibroblast via detecting circulating tumor cells. We also included advanced technologies involved in single-cell sequencing and their advantages. The future research indeed brings the single-cell sequencing into the clinical arena and thus could be beneficial for diagnosis and therapy of PC patients.

Nanoparticles guided drug delivery and imaging in gastric cancer.

Gastric cancer represents a deadly malignancy worldwide, yet current therapeutic regimens remain ineffective. Nanoparticle (NP) -based solutions could allow the design of novel therapeutic methods to eliminate this fatal disease. NPs typically carry out a significant role in multifunctional, multimodal imaging, and drug delivery carriers. In the recent decade, they have emerged as candidate approaches for the design of novel treatment strategies. Tumor nanotherapeutics characteristically possess various distinct advantages compared to conventional anti-cancer medications, which suffer from nonspecific bio-distribution, low solubility, and poor bioavailability. In this review, we will discuss the application of NPs in diagnosis and controlled drug delivery in gastric cancer (GC). We will focus on various NPs-based strategies employed against GC.

Nanomaterials multifunctional behavior for enlightened cancer therapeutics.

Cancer is an outrageous disease with uncontrolled differentiation, growth, and migration to the other parts of the body. It is the second-most common cause of death both in the U.S. and worldwide. Current conventional therapies, though much improved and with better prognosis, have several limitations. Chemotherapeutic agents, for instance, are cytotoxic to both tumor and healthy cells, and the non-specific distribution of drugs at tumor sites limits the dose administered. Nanotechnology, which evolved from the coalescence and union of varied scientific disciplines, is a novel science that has been the focus of much research. This technology is generating more effective cancer therapies to overcome biomedical and biophysical barriers against standard interventions in the body; its unique magnetic, electrical, and structural properties make it a promising tool. This article reviews endogenous- and exogenous-based stimulus-responsive drug delivery systems designed to overcome the limitations of conventional therapies. The article also summarizes the study of nanomaterials, including polymeric, gold, silver, magnetic, and quantum dot nanoparticles. Though an array of drug delivery systems has so far been proposed, there remain many challenges and concerns that should be addressed in order to fill the gaps in the field. Prominence is given to drug delivery systems that employ external- and internal-based stimuli and that are emerging as promising tools for cancer therapeutics in clinical settings.

Computational analysis of nuclear factor-κB and resveratrol in colorectal cancer.

Nuclear factor κB (NF-κB), a dimeric transcription factor, is a major regulator and an important determinant of the biological characteristics of tumour cells. Some antioxidants or protease inhibitors have been found to act against NF-κB to suppress colorectal cancer (CRC). In the current investigation, a computational study was performed to investigate the molecular interaction between NF-κB and resveratrol. Molecular docking studies revealed that, resveratrol with NF-κB are predicted to be quite effective. The application of molecular dynamics simulation (MDS) tactics has considerably supported in increasing the prediction precision of the outcomes. Further, this study revealed that NF-κB could be a potential target for various anti-cancerous drugs for cancer therapeutics. Furthermore, animal investigations are necessary to confirm the efficacy and evaluate potency of target and drugs.Communicated by Ramaswamy H. Sarma.

Engineered nanoparticles for imaging and drug delivery in colorectal cancer.

Colorectal cancer (CRC) is one of the deadliest diseases worldwide due to a lack of early detection methods and appropriate drug delivery strategies. Conventional imaging techniques cannot accurately distinguish benign from malignant tissue, leading to frequent misdiagnosis or diagnosis at late stages of the disease. Novel screening tools with improved accuracy and diagnostic precision are thus required to reduce the mortality burden of this malignancy. Additionally, current therapeutic strategies, including radio- and chemotherapies carry adverse side effects and are limited by the development of drug resistance. Recent advances in nanotechnology have rendered it an attractive approach for designing novel clinical solutions for CRC. Nanoparticle-based formulations could assist early tumor detection and help to overcome the limitations of conventional therapies including poor aqueous solubility, nonspecific biodistribution and limited bioavailability. In this review, we shed light on various types of nanoparticles used for diagnosis and drug delivery in CRC. In addition, we will explore how these nanoparticles can improve diagnostic accuracy and promote selective drug targeting to tumor sites with increased efficiency and reduced cytotoxicity against healthy colon tissue.

Targeting STAT proteins via computational analysis in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide making it a serious global challenge. CRC progression results from dysregulated cytoplasmic transcription factors, including signal transducer and activator of transcription (STAT) proteins that are involved in JAK-STAT pathway. The STAT proteins contain a conserved SH2 domain that facilitates the initiation of STAT activation via binding to tyrosine motifs followed by STAT dimerization. The STAT proteins include STAT1, STAT2 and STAT3 which all facilitate therapeutic targets for many drugs, since they are associated with pathogenesis in various cancers such as CRC. Genistein is an efficient chemopreventive phytochemical drug against CRC. The current investigation presents a computational study performed to investigate the molecular interaction between STAT1, STAT2 and STAT3 proteins with genistein. The molecular dynamic simulation was conducted for STAT2 protein. The studies from molecular docking revealed that the interaction of STAT proteins and genistein is predicted to be effective with better binding energies. Furthermore, targeting STAT3 could be an efficient therapeutic target and understanding the interaction between STAT3 and genistein can help to contribute to a better inhibition process for CRC progression. Treatment with genistein led to significant suppression of cell proliferation and STAT3 protein expression in both CRC (HCT 116 and HT-29) cell lines. This further provides development of efficient STAT inhibitors with better potency and bioavailability.

Resveratrol binds and activates RKIP protein in colorectal cancer.

Raf-1 kinase inhibitory protein (RKIP) acts as a tumor cell metastasis suppressor and prognostic indicator for survival in various cancers. Its use is predicted to improve therapy for various malignancies, including colorectal cancer (CRC). RKIP, frequently denoted as phosphatidylethanolamine-binding protein 1, is expressed in all normal mammalian tissues. RKIP functions as an inhibitor of the Raf-1, PI-3K, and MAP kinase (MAPK) pathways. In this study, we found that resveratrol induced the expression of RKIP at protein levels. To elucidate the structural basis of the interaction between resveratrol and RKIP, we performed computational studies that explore the binding affinity and ligand efficacy of resveratrol against RKIP. This study reveals the prognostic significance of RKIP metastasis suppressor activity against CRC and its structural arrangements during drug-target interactions.

Advanced glycation end products in diabetes, cancer and phytochemical therapy.

The irreversible glycation and oxidation of proteins and lipids produces advanced glycation end products (AGEs). These modified AGEs are triggered to bind the receptor for AGE (RAGE), thereby activating its downstream signaling pathways, such as nuclear factor (NF)-κB and phosphoinositide 3-kinase (PI3K)/Akt, ultimately leading to diabetes and cancers. In this review, we focus on the interaction of AGE-RAGE and their associated pathways. We also consider the activity of phytochemicals, such as genistein and curcumin, that trap dicarbonyl compounds including methylglyoxal (MG) and glyoxalase that arise from multiple pathways to block AGE formation and prevent its interaction with RAGE.

Resveratrol binds and inhibits transcription factor HIF-1α in pancreatic cancer.

Hypoxia-inducible factor-1 alpha (HIF-1α) has been recognized as one of the essential regulators that is expressed in greater levels in pancreatic cancer (PC) and is connected with poor prognosis. Resveratrol was identified as a natural compound with many biological functions, with anti-inflammatory, antioxidant, and anticancer effects that inhibit the proliferation and progression of PC cells caused by HIF-1α. The current investigation explored the binding affinity and ligand efficacy of resveratrol against HIF-1α using an in silico approach, and the execution of molecular dynamics simulation (MDS) increased the prediction precision of these outcomes. This is the first study that provides an in silico characterization of the interaction between resveratrol and HIF-1α and its spatial structural arrangements in pancreatic cancer therapy, providing an in-depth analysis of their drug target interactions.

HIF-1α and RKIP: a computational approach for pancreatic cancer therapy.

Protein-protein interactions (PPIs) are important biochemical processes that represent a major challenge in modern biology. Current approaches, which include high-throughput screening and computer aided ligand design, have limitations regarding the identification of hit matter. This current investigation focuses on computational study for protein-protein docking of hypoxia inducible factor-1α (HIF-1α), a tumor inducible factor, and Raf-1 kinase inhibitory protein (RKIP), a tumor metastasis suppressor. These are individually crystallized structures of interacting proteins, which interact to generate a conformational space. HIF activity in pancreatic tumors is determined by hypoxia and HIF-1α subunit availability. RKIP can be used as a prognostic indicator in a number of tumors. The interaction of RKIP with HIF-1α protects against pancreatic cancer (PC) metastasis by inhibiting its hypoxia function. We have explored the binding affinity between both the proteins with the HADDOCK (high ambiguity driven protein-protein docking) server, which determined that 158 structures in 11 clusters represent 79.0% of water-refined models. Of the best 10 clusters, the structures of cluster 2 were found to be better, as they had the lowest Z-score. Further supporting HIF-1α-RKIP interaction, pulldown assay has shown dissociation of RKIP from HIF-1α after CoCl2 treatment in both PC cell lines.

Understanding novel COVID-19: Its impact on organ failure and risk assessment for diabetic and cancer patients.

The current pandemic outbreak of COVID-19 originated from Wuhan, China. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with significant mortality and morbidity rate. The severe risk factors are commonly detected in patients of older age and with medical comorbidities like cancer and diabetes. Scientists and doctors have scrambled to gain knowledge about the novel virus and its pathophysiology in order to discover possible therapeutic regimens and vaccines for COVID-19. The therapeutic strategies like targeting the viral genome emphasize the promising approach to target COVID-19. Additionally, blocking the receptor, ACE2 via the neutralizing antibodies for viral escape that prevents it from entering into the cells provides another therapeutic regimen. In this review article, we have presented the effect of SARS-CoV-2 infection in comorbid patients and discussed organ failure caused by this virus. Based on the data available from the scientific literature and ongoing clinical trials, we have focused on therapeutic strategies. We hope that we would fill the gaps that puzzled the researchers and clinicians with the best of our knowledge collected for the betterment of the patients for the coming future.

The Genetic Polymorphisms in Colon Cancer.

Colon cancer (CC) belongs to a widespread malignant progression from the digestive tract. Moreover, CC is the leading cause of cancer-related mortality worldwide. It was suggested that there are several causative risk factors, among which are genetic factors that play an important role in the predisposition and development of CC. Unfortunately, despite continuous vigorous research going back more than two decades regarding molecular genetics and epigenetics on the issues of CC, there were no suitable prognostic and predictive molecular biomarkers identified until now. There are several susceptible genes for CC. Researchers are still unsure about the mechanisms regarding the genetic predisposition and single nucleotide polymorphisms (SNPs). The SNPs are considered to be clinically important aspotential diagnostics and therapeutic biomarkers in the future. Thus, in this review, we revise some gene SNPs involved in inducing CC.

Colorectal Cancer Biology, Diagnosis, and Therapeutic Approaches.

Colorectal cancer (CRC) is the second most diagnosed disease worldwide. It is the fourth leading cause of cancer related mortalities. Higher probability for the occurrence of CRC is due to western lifestyle, age, and personal history of chronic diseases. The development of CRC is a multistep process that includes a sequence of genetic, histological, and morphological alterations that accumulate over time. Furthermore, depending on the origin of mutations, CRC can be classified as familial, sporadic, and inherited, based on which a therapeutic plan is created for a CRC patient. These mutations cause chromosomal alterations and translocations in genes that lead to microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN). The mutations affect dysregulation of various pathways that are responsible for cancer progression. They include the PI3K/Akt, Wnt, TP53, and MAPK pathways. Mutated genes, such as KRAS, PTEN, SMAD4, BRAF, and PTEN, are employed as predictive biomarkers for early diagnosis. The conventional therapies of CRC start with surgical resection followed by adjuvant therapies, such as radiotherapy and chemotherapy. Researchers are now developing therapies that combine triplet drugs to overcome the hurdle of multidrug resistance (MDR). The combination of chemotherapy with immunotherapy to target the dysregulated proteins, such as EGFR and VEGFR is found efficient for advanced mCRC therapy. Researchers are now developing personalized medicines by detecting and validating key biomarkers to understand the mechanism of MDR and toxicity. In this review, we address genetic alterations, current data on biomarkers, and novel therapeutic approaches for the treatment of CRC.

Pathophysiology, Etiology, Epidemiology of Type 1 Diabetes and Computational Approaches for Immune Targets and Therapy.

Autoimmune diseases occur when the body's natural defense system fails to differentiate its own cells from the foreign cells and mistakenly attacks the healthy cells. Among the autoimmune diseases, the most common serious disease is the type 1 diabetes (T1D). Biomarkers like c-peptide, autoantibodies, and glycated molecules are now widely used for the early diagnosis of diabetes. However, the diverse nature of biomarkers and the available autoantibodies as biomarkers are not enough to differentiate the heterogeneity inherent in T1D. Novel biomarkers have allowed the introduction of bioinformatics for assimilating the new data into clinical tools. Computer-aided drug design contributes to the discovery of novel autoantibodies, and molecular docking promises to enhance it. Moreover, the study of the pathophysiology of diabetes via molecular simulation has been proposed. In this review article, we focus on the characterization of the etiology, epidemiological factors, and mechanisms of hyperglycemia that induce cellular damage due to oxidative stress and proinflammatory responses. We also decribe novel biomarkers used for the detection of ß-cell destruction and diagnosis at early stages. Bioinformatics tools including molecular docking, sequence alignment, and homology modeling are also presented. This report supports researchers in drug design, in disease detection at an early phase, and in therapy development for T1D-associated complications.