Identification and targeting of metastatic biomarkers for hepatocellular carcinoma therapeutics using small molecules library of curcumin analogues.

The understanding of the molecular basis of complex diseases like hepatocellular carcinoma (HCC) needs large datasets of multiple genes and proteins involved in different phenomenon of its development. This study focuses on the molecular basis of HCC and the development of therapeutic strategies. We analyzed a dataset of 5475 genes (Homo sapiens) involved in HCC hallmarks, involving comprehensive data on multiple genes and frequently mutated genes. As HCC is characterized by metastasis, angiogenesis, and oxidative stress, exploration of genes associated with them has been targeted. Through gene ontology, functional characterization, and pathway enrichment analysis, we identified target proteins such as Lysyl oxidase, Survivin, Cofilin, and Cathepsin B. A library of curcumin analogs was used to target these proteins. Tetrahrydrocurcumin showed promising binding affinities for all four proteins, suggesting its potential as an inhibitor against these proteins for HCC therapy.

The cross-talk between mucormycosis, steroids and diabetes mellitus amidst the global contagion of COVID-19.

Mucormycosis is an opportunistic fungal disease that targets individuals having an impaired immune system due to a wide array of risk factors including HIV-AIDS, immunosuppressive therapy, diabetes mellitus, etc. The current explosive outbreak of coronavirus disease 2019 (COVID-19) has become the latest threat to such patients who are already susceptible to secondary infections. Physiological outcomes of COVID-19 end up in a cascade of grave alterations to the immunological profile and irreparable harm to their respiratory passage, heart and kidneys. Corticosteroidal treatment facilitates faster recovery and alleviates the adverse pathological effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). But clinical reports lend this approach a darker perspective especially if these patients have pre-existing diabetes mellitus. The mucormycotic fungal genera belonging to the order Mucorales not only survive but thrive under the comorbidity of COVID-19 and diabetes, often staying undetected until they have inflicted irreversible damage. Steroidal usage has been noted to be a common thread in the sudden spurt in secondary fungal infections among COVID-19 cases. Once considered a rare occurrence, mucormycosis has now acquired a notoriously lethal status in mainstream medical hierarchy. We set out to investigate whether corticosteroidal therapy against COVID-19 emboldens the development of mucormycosis. We also assess the conditions brought forth by steroidal usage and uncontrolled progression of diabetes in COVID-19 cases and their effect on the susceptibility towards mucormycosis.

Network pharmacological evaluation of strigolactones efficacy as potential inhibitors against therapeutic targets of hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is the uncontrolled growth of hepatocytes which results in nearly 5 million deaths worldwide. Specific strategies have been developed to treat HCC, including surgery, chemotherapy and radiotherapy. But, the effective disease dealing requires synergistic collaboration with other approaches, which often results in moderate to severe side effects during and after the treatment period. Therefore, the focus is now shifting to explore and retrieve those plant-based products that could be utilized to treat HCC with maximum efficacy without causing any side effects. Strigolactones (SL) are compounds of plant origin derived from Striga lutea responsible for controlling the branching pattern of stem and have reported anti-cancerous activity by promoting apoptosis at micromolar concentrations. However, little work has been done concerning determining the pharmacogenomic effect of strigolactones on HCC. METHODS: Current work focuses on comparing therapeutic efficiencies of SL analogs against core targets of HCC using network pharmacology approach, pharmacokinetics analysis, gene ontogeny, functional enrichment analysis, molecular docking and Molecular Dynamics simulation. RESULTS: Drug-target prediction and functional enrichment analysis showed that HDAC1 and HDAC2 are the core proteins involved in hepatocellular carcinoma that strigolactone analogs can target. Consequently, results from molecular docking and MD simulation analyses report that among all the SL analogs strigol, epistrigol and nijmegen1 can turn out to be most effective in downregulating the expression of HDAC1, HDAC2 and CYP19A. CONCLUSION: Strigol, epistrigol and nijmegen1 could be used as potential inhibitors against HCC and can be further validated through in vitro/in vivo studies.

Comparative evaluation of divergent concoction of NGF, BDNF, EGF, and FGF growth factor's role in enhancing neuronal differentiation of adipose-derived mesenchymal stem cells.

MSCs (Mesenchymal Stem Cells) can differentiate into various lineages, including neurons and glial cells. In the past few decades, MSCs have been well explored in the context of neuronal differentiation and have been reported to have the immense potential to form distinct kinds of neurons. The distinguishing features of MSCs make them among the most desired cell sources for stem cell therapy. This study involved the trans-differentiation of Adipose-derived human Mesenchymal Stem Cells (ADMSCs) into neurons. The protocol employs a cocktail of chemical inducers in different combinations, including Brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), and Nerve growth factor (NGF) Fibroblastic growth factor (FGF), in induction media. Both types have been successfully differentiated into neurons, confirmed by morphological aspects and the presence of neural-specific markers through RT-PCR (Reverse transcription polymerase chain reaction) studies and immunocytochemistry assay. They have shown excellent morphology with long neurites, synaptic connections, and essential neural markers to validate their identity. The results may significantly contribute to cell replacement therapy for neurological disorders.

Evaluation of phytoconstituents of Tinospora cordifolia against K417N and N501Y mutant spike glycoprotein and main protease of SARS-CoV-2- an in silico study.

Coronavirus disease 2019 (COVID-19) caused appalling conditions over the globe, which is currently faced by the entire human population. One of the primary reasons behind the uncontrollable situation is the lack of specific therapeutics. In such conditions, drug repurposing of available drugs (viz. Chloroquine, Lopinavir, etc.) has been proposed, but various clinical and preclinical investigations indicated the toxicity and adverse side effects of these drugs. This study explores the inhibition potency of phytochemicals from Tinospora cordifolia (Giloy) against SARS CoV-2 drugable targets (spike glycoprotein and Mpro proteins) using molecular docking and MD simulation studies. ADMET, virtual screening, MD simulation, postsimulation analysis (RMSD, RMSF, Rg, SASA, PCA, FES) and MM-PBSA calculations were carried out to predict the inhibition efficacy of the phytochemicals against SARS CoV-2 targets. Tinospora compounds showed better binding affinity than the corresponding reference. Their binding affinity ranges from -9.63 to -5.68 kcal/mole with spike protein and -10.27 to -7.25 kcal/mole with main protease. Further 100 ns exhaustive simulation studies and MM-PBSA calculations supported favorable and stable binding of them. This work identifies Nine Tinospora compounds as potential inhibitors. Among those, 7-desacetoxy-6,7-dehydrogedunin was found to inhibit both spike (7NEG) and Mpro (7MGS and 6LU7) proteins, and Columbin was found to inhibit selected spike targets (7NEG and 7NX7). In all the analyses, these compounds performed well and confirms the stable binding. Hence the identified compounds, advocated as potential inhibitors can be taken for further in vitro and in vivo experimental validation to determine their anti-SARS-CoV-2 potential.Communicated by Ramaswamy H. Sarma.

Therapeutical growth in oligodendroglial fate induction via transdifferentiation of stem cells for neuroregenerative therapy.

The merits of stem cell therapy and research are undisputed due to their widespread usage in the treatment of neurodegenerative diseases and demyelinating disorders. Cell replacement therapy especially revolves around stem cells and their induction into different cell lineages both adult and progenitor - belonging to each germ layer, prior to transplantation or disease modeling studies. The nervous system is abundant in glial cells and among these are oligodendrocytes capable of myelinating new-born neurons and remyelination of axons with lost or damaged myelin sheath. But demyelinating diseases generate tremendous deficit between myelin loss and recovery. To compensate for this loss, analyze the defects in remyelination mechanisms as well as to trigger full recovery in such patients mesenchymal stem cells (MSCs) have been induced to transdifferentiate into oligodendrocytes. But such experiments are riddled with problems like prolonged, tenuous and complicated protocols that stretch longer than the time taken for the spread of demyelination-associated after-effects. This review delves into such protocols and the combinations of different molecules and factors that have been recruited to derive bona fide oligodendrocytes from in vitro differentiation of embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and MSCs with special focus on MSC-derived oligodendrocytes.

Modulation of GPCR receptors common to gut inflammatory diseases and neuronal disorders, Alzheimer's and Parkinson's diseases as druggable targets through Withania somnifera bioactives: an in silico study.

Microorganisms in human gastrointestinal tract have profound influence on the transformation of food into metabolites which can impact human health. Along with playing crucial roles in regulating and modulating various metabolic reactions and life processes, dysbiosis of gut microbiota also affects the permeability of gut and blood-brain barrier. This increases the chance of age-related neurological disorders' like Alzheimer's and Parkinson's diseases. Withania somnifera (W. somnifera) has been proclaimed as a virtuous plant for the treatment of neurodegenerative diseases and many other problems. We have studied the bioactive components of W. somnifera for combined treatment of gut-dysbiosis led bowel diseases (Inflammatory Bowel Disease, Irritable Bowel Syndrome) and the most common neurodegenerative diseases through common potential targets. This approach can solve along with curing the neurodegenerative diseases, the factors causing these diseases would also be obstructed from entering the brain, consonantly curing Inflammatory Bowel Disease and Irritable Bowel Syndrome. Our work on GPCR receptors common to gut inflammatory diseases and neuronal disorders through Network Pharmacology, Molecular docking and Dynamic Simulation approach has shown that modulation of these receptors with bioactive compounds present in W. somnifera can result in effective control of these diseases. We have found five proteins (HTR1A, HTR1B, HTR2A, HTR2B & HTR7) and five best lead compounds (Withanolide A, B, E, Q & Anahygrine) against these targets after molecular docking analysis. Our simulation studies have finally shown that amongst these five HTR1A and HTR7 proteins are the best targets with the leads Withanolide E and Withanolide A against them, respectively.Communicated by Ramaswamy H. Sarma.

Inhibition of LINGO1 as a therapeutic target to promote axonal regeneration and repair for neurological disorders.

The Central nervous system is blemished by the high incidence of neurodegenerative diseases, which is known to cause disfiguration of regeneration and repair of axonal growth. Recognition of proteins that act as agents of repressing such repair has become the norm to tackle these abominable conditions. One such protein is LINGO1 that act as a repressor for axonal growth. Being one of the critical causative agents of several neurodegenerative pathways. Consequently, its inhibition may tend to help the outcomes of regenerative technologies aiming to outweigh the symptoms of neurodegenerative diseases. For this objective, LINGO1 was targeted with pharmacophore analogs of Fasudil and Ibuprofen, as they are known to have a deterring effect against the concerned protein. 1-Tosyl-2-(chloromethyl)-2,3-dihydro-1H-indole was found showing the least binding score of - 6.8, with verified ADMET admissibility. The pharmacological activity of the said ligand was estimated with QSAR tool showing favourable electro-steric model. All this was finally collaborated with a molecular dynamics simulation study which exhibited a stable structure compatibility of the ligand with LINGO-1. Further, the efficacy of the compound can be evaluated through experimental studies for inferring its future potential and utilization as an effective means to tackle neuronal regeneration and remyleination. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03789-4.

Network pharmacological evaluation of Withania somnifera bioactive phytochemicals for identifying novel potential inhibitors against neurodegenerative disorder.

Neurodegenerative disorders are illnesses that are responsible for neuronal cell death and resulting in lifelong cognitive problems. Due to their unclear mechanism, there are no effective drugs available for the treatment. For a long time, herbal drugs have been used as a role model in the field of the drug discovery process. Withania somnifera (Ashwagandha) in the Indian medicinal system (Ayurveda) is used for several neuronal disorders like insomnia and memory loss for decades. This study aims to identify active components of W. somnifera (WS) as potential inhibitors for the treatment of neurodegenerative diseases (ND). To fulfill this objective, Network pharmacology approach, gene ontology, pharmacokinetics analysis, molecular docking, and molecular dynamics simulation (MDS) studies were performed. A total of 77 active components in WS, 175 predicted neurodegenerative targets of WS, and 8085 ND-related targets were identified from different databases. The network analysis showed that the top ten targets APP, EGFR, MAPK1, ESR1, HSPA4, PRKCD, MAPK3, ABL1, JUN, and GSK3B were found as significant target related to ND. On the basis of gene ontology and topology analysis results, APP was found as a significant target related to Alzheimer's disease pathways. Molecular docking results found that Anahygrine, Cuscohygrine, Isopelletierine, and Nicotine showed the best binding affinities -5.55, -4.73, -4.04, and -4.11 Kcal/mol. Further, MDS results suggested that Isopelletierine and Nicotine could be used as potential inhibitors against APP protein and could be useful for the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.

A candidate triple-negative breast cancer vaccine design by targeting clinically relevant cell surface markers: an integrated immuno and bio-informatics approach.

Triple-negative breast cancer (TNBC) is an aggressive, metastatic/invasive sub-class of breast cancer (BCa). Cell surface protein-derived multi-epitope vaccine-mediated targeting of TNBC cells could be a better strategy against the disease. Literature-based identified potential cell surface markers for TNBC cells were subjected to expression pattern and survival analysis in BCa patient sample using TCGA database. The cytotoxic and helper T-lymphocytes antigenic epitopes in the test proteins were identified, selected and fused together with the appropriate linkers and an adjuvant, to construct the multi-epitope vaccine (MEV). The immune profile, physiochemical property (PP) and world population coverage of the MEV was studied. Immune simulation, cloning in a suitable vector, molecular docking (against Toll-like receptors, MHC (I/II) molecules), and molecular dynamics simulations of the MEV was performed. Cell surface markers were differentially expressed in TNBC samples and showed poor survival in TNBC patients. Satisfactory PP and WPC (up to 89 and 99%) was observed. MEV significant stable binding with the immune molecules and induced the immune cells in silico. The designed vaccine has capability to elicit immune response which could be utilized to target TNBC alone/combination with other therapy. The experimental studies are required to check the efficacy of the vaccine. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03140-3.

Regulation of neuronal repair and regeneration through inhibition of oligodendrocyte myelin glycoprotein (OMgp).

The inability of neural cells to regenerate themselves after an injury represents the major difference between neural cells and other cells of the body. Various factors are responsible for this, as the expression of myelin-derived inhibitors of axonal outgrowth such as neurite outgrowth inhibitor (Nogo), myelin-associated growth factor, and oligodendrocyte-myelin glycoprotein (OMgp) hinder the central nervous system (CNS) axons to recover properly and inhibit the neuron regeneration. The patient with spinal cord injury can even permanently lose their function due to the inability of axons to regenerate. However, their role in neural regeneration in vivo is not known completely. During the study, we found that once CNS gets injured, the axon growth inhibitor OMgp binds to the Nogo-66 Receptor 1 (NgR1) which in turn restricts the normal functioning of CNS. Considering the OMgp as the target protein, two flavonoid libraries (curcumin and piperine) were screened against it to get potential inhibitors. The effectiveness of the ligands was first screened by three-tier structure-based virtual screening by Glide, Schrödinger. Based on the docking score, the best-docked compounds were taken for absorption, distribution, metabolism, and excretion analysis and the top two complexes from each library were chosen for simulation studies. Flavonoid ligands showed a much better binding affinity when compared with already known inhibitors Riluzole and Minocycline. To date, no natural inhibitors are known for OMgp. Hence, this study can provide novel insight for upcoming research in this area. Communicated by Ramaswamy H. Sarma.

Therapeutic Advancement in Neuronal Transdifferentiation of Mesenchymal Stromal Cells for Neurological Disorders.

Neurodegenerative disorders have become the leading cause of chronic pain and death. Treatments available are not sufficient to help the patients as they only alleviate the symptoms and not the cause. In this regard, stem cells therapy has emerged as an upcoming option for the replacement of dead and damaged neurons. Stem cells, in general, are characterized as cells exhibiting potency properties, i.e., on being subjected to specific conditions they transform into cells of another lineage. Of all the types, mesenchymal stem cells (MSCs) are known for their pluripotent nature without the obstacle of ethical concern surrounding the procurement of other cell types. Although fibroblasts are quite similar to MSCs morphologically, certain markers like CD73, CD 90 are specific to MSCs, making both the cell types distinguishable from each other. This is implemented while procuring MSCs from a plethora of sources like umbilical cord blood, adipose tissue, bone marrow, etc. Among these, bone marrow MSCs are the most widely used type for neural regeneration. Neural regeneration is achieved via transdifferentiation. Several studies have either transplanted the stem cells into rodent models or have carried out transdifferentiation in vitro. The process involves a combination of growth factors, pre-treatment factors, and neuronal differentiation inducing mediums. The results obtained are characterized by neuron-like morphology, expression of markers, along with electrophysical activity in some. Recent attempts involve exploring biomaterials that may mimic the native ECM and therefore can be directly introduced at the site of interest. The review gives a brief description of MSCs, their sources and markers, and the different attempts that have been made towards achieving the goal of differentiating MSCs into neurons.