Early epigenetic markers for precision medicine.

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.

Molecular mechanism(s) of regulations of cancer stem cell in brain cancer propagation.

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.

Molecular mechanism(s) of regulation(s) of c-MET/HGF signaling in head and neck cancer.

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.

Structure-based drug repurposing for targeting Nsp9 replicase and spike proteins of severe acute respiratory syndrome coronavirus 2.

Drug re-purposing might be a fast and efficient way of drug development against the novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We applied a bioinformatics approach using molecular dynamics and docking to identify FDA-approved drugs that can be re-purposed to potentially inhibit the non-structural protein 9 (Nsp9) replicase and spike proteins in SARS-CoV-2. We performed virtual screening of FDA-approved compounds, including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis, and active phytochemicals against the Nsp9 replicase and spike proteins. Selected hit compounds were identified based on their highest binding energy and favorable absorption, distribution, metabolism and excretion (ADME) profile. Conivaptan, an arginine vasopressin antagonist drug exhibited the highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present at the active site of the Nsp9 replicase. Tegobuvir, a non-nucleoside inhibitor of the hepatitis C virus, also exhibited maximum stability along with the highest binding energy (-8.1 Kcal/mol) at the active site of the spike proteins. Molecular docking scores were further validated by molecular dynamics using Schrodinger, which supported the strong stability of ligands with the proteins at their active sites through water bridges, hydrophobic interactions, and H-bonding. Our findings suggest Conivaptan and Tegobuvir as potential therapeutic agents against SARS-CoV-2. Further in vitro and in vivo validation and evaluation are warranted to establish how these drug compounds target the Nsp9 replicase and spike proteins.

Exploring state-of-the-art advances in targeted nanomedicines for managing acute and chronic inflammatory lung diseases.

Diagnosis and treatment of lung diseases pose serious challenges. Currently, diagnostic as well as therapeutic methods show poor efficacy toward drug-resistant bacterial infections, while chemotherapy causes toxicity and nonspecific delivery of drugs. Advanced treatment methods that cure lung-related diseases, by enabling drug bioavailability via nasal passages during mucosal formation, which interferes with drug penetration to targeted sites, are in demand. Nanotechnology confers several advantages. Currently, different nanoparticles, or their combinations, are being used to enhance targeted drug delivery. Nanomedicine, a combination of nanoparticles and therapeutic agents, that delivers drugs to targeted sites increases the bioavailability of drugs at these sites. Thus, nanotechnology is superior to conventional chemotherapeutic strategies. Here, the authors review the latest advancements in nanomedicine-based drug-delivery methods for managing acute and chronic inflammatory lung diseases.

Advances in pulmonary drug delivery targeting microbial biofilms in respiratory diseases.

The increasing burden of respiratory diseases caused by microbial infections poses an immense threat to global health. This review focuses on the various types of biofilms that affect the respiratory system and cause pulmonary infections, specifically bacterial biofilms. The article also sheds light on the current strategies employed for the treatment of such pulmonary infection-causing biofilms. The potential of nanocarriers as an effective treatment modality for pulmonary infections is discussed, along with the challenges faced during treatment and the measures that may be implemented to overcome these. Understanding the primary approaches of treatment against biofilm infection and applications of drug-delivery systems that employ nanoparticle-based approaches in the disruption of biofilms are of utmost interest which may guide scientists to explore the vistas of biofilm research while determining suitable treatment modalities for pulmonary respiratory infections.

Mutational heterogeneity in spike glycoproteins of severe acute respiratory syndrome coronavirus 2.

The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has led to a global crisis by infecting millions of people across the globe eventually causing multiple deaths. The prominent player of the virus has been known as the spike protein which enters the host system and leads to the infection. The S2 subunit is the most essential in this process of infection as it helps the SARS-CoV-2 to infect the host by binding to the human angiotensin converting enzyme 2 (hACE2), with the help of the receptor binding domain found at the S2 subunit of the virus. Studies also hypothesize that the S glycoproteins present in the virus interacts with different hosts in different ways which might be due to the mutations taking place in the genome of the virus over time. This work aims to decipher the similarities and differences in the sequences of spike proteins from samples of SARS-CoV-2 acquired from different infected individuals in different countries with the help of in silico methods such as multiple sequence alignment and phylogenetic analysis. It also aims to understand the differential infection rates among the infected countries by studying the amino acid composition and interactions of the virus with the host.

Regulation of Glycolysis in Head and Neck Cancer.

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.

Specific targeting cancer cells with nanoparticles and drug delivery in cancer therapy.

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.

Stem Cell Based Preclinical Drug Development and Toxicity Prediction.

Stem cell based toxicity prediction plays a very important role in the development of the drug. Unexpected adverse effects of the drugs during clinical trials are a major reason for the termination or withdrawal of drugs. Methods for predicting toxicity employ in vitro as well as in vivo models; however, the major drawback seen in the data derived from these animal models is the lack of extrapolation, owing to interspecies variations. Due to these limitations, researchers have been striving to develop more robust drug screening platforms based on stem cells. The application of stem cells based toxicity testing has opened up robust methods to study the impact of new chemical entities on not only specific cell types, but also organs. Pluripotent stem cells, as well as cells derived from them, can be evaluated for modulation of cell function in response to drugs. Moreover, the combination of state-of-the -art techniques such as tissue engineering and microfluidics to fabricate organ- on-a-chip, has led to assays which are amenable to high throughput screening to understand the adverse and toxic effects of chemicals and drugs. This review summarizes the important aspects of the establishment of the embryonic stem cell test (EST), use of stem cells, pluripotent, induced pluripotent stem cells and organoids for toxicity prediction and drug development.

Metabolic regulation in HPV associated head and neck squamous cell carcinoma.

Cancer cells exhibit distinct energy metabolic pathways due to multiple oncogenic events. In normoxia condition, the anaerobic glycolysis (Warburg effect) is highly observed in head and neck squamous cell carcinoma (HNSCC). HNSCC is associated with smoking, chewing tobacco, consumption of alcohol or Human Papillomavirus (HPV) infection primarily HPV16. In recent years, the correlation of HPV with HNSCC has significantly expanded. Despite the recent advancement in therapeutic approaches, the rate of HPV infected HNSCC has significantly increased in the last few years, specifically, in lower middle-income countries. The oncoproteins of High-risk Human Papillomavirus (HR-HPV), E6 and E7, alter the metabolic phenotype in HNSCC, which is distinct from non-HPV associated HNSCC. These oncoproteins, modulate the cell cycle and metabolic signalling through interacting with tumor suppressor proteins, p53 and pRb. Since, metabolic alteration represents a major hallmark for tumorigenesis, HPV acts as a source of biomarker linked to cancer progression in HNSCC. The dependency of cancer cells to specific nutrients and alteration of various metabolic associated genes may provide a unique opportunity for pharmacological intervention in HPV infected HNSCC. In this review, we have discussed the molecular mechanism (s) and metabolic regulation in HNSCC depending on the HPV status. We have also discussed the possible potential therapeutic approaches for HPV associated HNSCC through targeting metabolic pathways.

Molecular mechanisms of interplay between autophagy and metabolism in cancer.

Autophagy is an essential mechanism of cellular degradation, a way to protect the cells under stress conditions, such as deprivation of nutrients, growth factors and cellular damage. However, in normal physiology autophagy plays a significant role in cancer cells. Current research is in progress to understand how autophagy and cancer cells go hand in hand to support cancer cell progression. The important aspect in cancer and autophagy is the interdependence of autophagy in the survival and progression of cancer cells. Autophagy is known to be a major cause of chemotherapeutic resistance in various cancer cell types. Therefore, inhibition of autophagy as an effective therapeutic approach is being actively studied and tested in clinical studies. Multiple metabolic pathways are linked with autophagy that could potentially be a significant target for chemotherapeutic strategy. The comprehension of the interconnection of autophagy with cancer metabolism can pave a novel findings for effective combinatorial therapeutic strategies.