METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma.

Neuroblastoma (NB) is the most common extracranial childhood cancer, caused by the improper differentiation of developing trunk neural crest cells (tNCC) in the sympathetic nervous system. The N-methyladenosine (mA) epitranscriptomic modification controls post-transcriptional gene expression but the mechanism by which the mA methyltransferase complex METTL3/METTL14/WTAP is recruited to specific loci remains to be fully characterized. We explored whether the mA epitranscriptome could fine-tune gene regulation in migrating/differentiating tNCC.

Design, synthesis, and evaluation of purine and pyrimidine-based G12D inhibitors: Towards potential anticancer therapy.

Oncogenic mutations, commonly observed in human tumors, affect approximately 30% of cancer cases and pose a significant challenge for effective cancer treatment. Current strategies to inhibit the G12D mutation have shown limited success, emphasizing the urgent need for new therapeutic approaches. In this study, we designed and synthesized several purine and pyrimidine analogs as inhibitors for the G12D mutation.

Identifying novel inhibitors targeting Exportin-1 for the potential treatment of COVID-19.

The nuclear export protein 1 (XPO1) mediates the nucleocytoplasmic transport of proteins and ribonucleic acids (RNAs) and plays a prominent role in maintaining cellular homeostasis. XPO1 has emerged as a promising therapeutic approach to interfere with the lifecycle of many viruses. In our earlier study, we proved the inhibition of XPO1 as a therapeutic strategy for managing SARS-COV-2 and its variants.

Discovery of novel acetylcholinesterase inhibitors through integration of machine learning with genetic algorithm based screening approaches.

Introduction: Alzheimer's disease (AD) is the most studied progressive eurodegenerative disorder, affecting 40-50 million of the global population. This progressive neurodegenerative disease is marked by gradual and irreversible declines in cognitive functions. The unavailability of therapeutic drug candidates restricting/reversing the progression of this dementia has severed the existing challenge.

Development of machine learning models for the screening of potential HSP90 inhibitors.

Heat shock protein 90 (Hsp90) is a molecular chaperone playing a significant role in the folding of client proteins. This cellular protein is linked to the progression of several cancer types, including breast cancer, lung cancer, and gastrointestinal stromal tumors. Several oncogenic kinases are Hsp90 clients and their activity depends on this molecular chaperone.

Combining structure-based pharmacophore modeling and machine learning for the identification of novel BTK inhibitors.

Bruton's tyrosine kinase (BTK) is a critical enzyme which is involved in multiple signaling pathways that regulate cellular survival, activation, and proliferation, making it a major cancer therapeutic target. We applied the novel integrated structure-based pharmacophore modeling, machine learning, and other in silico studies to screen the Korean chemical database (KCB) to identify the potential BTK inhibitors (BTKi). Further evaluation of these inhibitors on three different human cancer cell lines showed significant cell growth inhibitory activity.

Myostatin and its Regulation: A Comprehensive Review of Myostatin Inhibiting Strategies.

Myostatin (MSTN) is a well-reported negative regulator of muscle growth and a member of the transforming growth factor (TGF) family. MSTN has important functions in skeletal muscle (SM), and its crucial involvement in several disorders has made it an important therapeutic target. Several strategies based on the use of natural compounds to inhibitory peptides are being used to inhibit the activity of MSTN.

Nanomedicine for glioblastoma: Progress and future prospects.

Glioblastoma is the most aggressive form of brain tumor, accounting for the highest mortality and morbidity rates. Current treatment for patients with glioblastoma includes maximal safe tumor resection followed by radiation therapy with concomitant temozolomide (TMZ) chemotherapy. The addition of TMZ to the conformal radiation therapy has improved the median survival time only from 12 months to 16 months in patients with glioblastoma.

Investigating the Mechanism of Inhibition of Cyclin-Dependent Kinase 6 Inhibitory Potential by Selonsertib: Newer Insights Into Drug Repurposing.

Cyclin-dependent kinases (CDKs) play significant roles in numerous physiological, and are considered an attractive drug target for cancer, neurodegenerative, and inflammatory diseases. In the present study, we have aimed to investigate the binding affinity and inhibitory potential of selonsertib toward CDK6. Using the drug repurposing approach, we performed molecular docking of selonsertib with CDK6 and observed a significant binding affinity.

MIF1 and MIF2 Myostatin Peptide Inhibitors as Potent Muscle Mass Regulators.

The use of peptides as drugs has progressed over time and continues to evolve as treatment paradigms change and new drugs are developed. Myostatin (MSTN) inhibition therapy has shown great promise for the treatment of muscle wasting diseases. Here, we report the MSTN-derived novel peptides MIF1 (10-mer) and MIF2 (10-mer) not only enhance myogenesis by inhibiting MSTN and inducing myogenic-related markers but also reduce adipogenic proliferation and differentiation by suppressing the expression of adipogenic markers.

Probing the Interaction of Selonsertib with Human Serum Albumin: In silico and In vitro Approaches.

Introduction: Selonsertib, the most recently developed selective inhibitor of apoptosis signal-regulating kinase 1. We elucidated the binding characteristics, mechanism of interaction, and dynamic behaviors of selonsertib with human serum albumin (HSA), a major circulatory transport protein.

Methods: Different biophysical approaches (fluorescence quenching and isothermal titration calorimetry (ITC) were combined with various in silico techniques to examine the binding of selonsertib to HSA.

Computational screening of camostat and related compounds against human TMPRSS2: A potential treatment of COVID-19.

The global coronavirus pandemic has burdened the human population with mass fatalities and disastrous socio-economic consequences. The frequent occurrence of these new variants has fueled the already prevailing challenge. There is still a necessity for highly effective small molecular agents to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Impact of the Double Mutants on Spike Protein of SARS-CoV-2 B.1.617 Lineage on the Human ACE2 Receptor Binding: A Structural Insight.

The recent emergence of novel SARS-CoV-2 variants has threatened the efforts to contain the COVID-19 pandemic. The emergence of these "variants of concern" has increased immune escape and has supplanted the ancestral strains. The novel variants harbored by the B.

Identification of Novel FNIN2 and FNIN3 Fibronectin-Derived Peptides That Promote Cell Adhesion, Proliferation and Differentiation in Primary Cells and Stem Cells.

In recent years, a major rise in the demand for biotherapeutic drugs has centered on enhancing the quality and efficacy of cell culture and developing new cell culture techniques. Here, we report fibronectin (FN) derived, novel peptides fibronectin-based intergrin binding peptide (FNIN)2 (18-mer) and FNIN3 (20-mer) which promote cell adhesion proliferation, and the differentiation of primary cells and stem cells. FNIN2 and 3 were designed based on the in silico interaction studies between FN and its receptors (integrin α5β1, αvβ3, and αIIbβ3).

Is PF-00835231 a Pan-SARS-CoV-2 Mpro Inhibitor? A Comparative Study.

The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem.

Screening of inhibitors against SARS-CoV-2 spike protein and their capability to block the viral entry mechanism: A viroinformatics study.

SARS-CoV-2, previously named 2019 novel coronavirus (2019-nCoV), has been associated with the global pandemic of acute respiratory distress syndrome. First reported in December 2019 in the Wuhan province of China, this new RNA virus has several folds higher transmission among humans than its other family member (SARS-CoV and MERS-CoV). The SARS-CoV-2 spike receptor-binding domain (RBD) is the region mediating the binding of the virus to host cells via Angiotensin-converting enzyme 2 (ACE2), a critical step of viral.

Screening of drug databank against WT and mutant main protease of SARS-CoV-2: Towards finding potential compound for repurposing against COVID-19.

Although several pharmacological agents are under investigation to be repurposed as therapeutic against COVID-19, not much success has been achieved yet. So, the search for an effective and active option for the treatment of COVID-19 is still a big challenge. The Spike protein (S), RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro) are considered to be the primary therapeutic drug target for COVID-19.

Deciphering the Role of Autophagy in Treatment of Resistance Mechanisms in Glioblastoma.

Autophagy is a process essential for cellular energy consumption, survival, and defense mechanisms. The role of autophagy in several types of human cancers has been explicitly explained; however, the underlying molecular mechanism of autophagy in glioblastoma remains ambiguous. Autophagy is thought to be a "double-edged sword", and its effect on tumorigenesis varies with cell type.

Use of Natural Compounds as a Potential Therapeutic Agent Against COVID-19.

The current 2019-nCoV outbreak is becoming extremely harmful and has affected the whole world. Its control is challenging because there is no effective vaccine or drug available for coronavirus disease. The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), previously named as 2019 novel coronavirus (2019-nCoV), primarily targets the human respiratory system to lung lesions and lethal pneumonia.

Comparative genome analysis of novel coronavirus (SARS-CoV-2) from different geographical locations and the effect of mutations on major target proteins: An in silico insight.

A novel severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) causing COVID-19 pandemic in humans, recently emerged and has exported in more than 200 countries as a result of rapid spread. In this study, we have made an attempt to investigate the SARS-CoV-2 genome reported from 13 different countries, identification of mutations in major coronavirus proteins of these different SARS-CoV-2 genomes and compared with SARS-CoV. These thirteen complete genome sequences of SARS-CoV-2 showed high identity (>99%) to each other, while they shared 82% identity with SARS-CoV.

Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy.

Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors.

Transthyretin Maintains Muscle Homeostasis Through the Novel Shuttle Pathway of Thyroid Hormones During Myoblast Differentiation.

Skeletal muscle, the largest part of the total body mass, influences energy and protein metabolism as well as maintaining homeostasis. Herein, we demonstrate that during murine muscle satellite cell and myoblast differentiation, transthyretin (TTR) can exocytose via exosomes and enter cells as TTR- thyroxine (T) complex, which consecutively induces the intracellular triiodothyronine (T) level, followed by T secretion out of the cell through the exosomes. The decrease in T with the TTR level in 26-week-old mouse muscle, compared to that in 16-week-old muscle, suggests an association of TTR with old muscle.

ASK1 and its role in cardiovascular and other disorders: available treatments and future prospects.

: Apoptosis signal-regulating kinase 1 (ASK1), also known as MAP3K5, is a member of mitogen-activated protein kinase kinase kinase (MAP3K) family and is well reported as crucial in the regulation of the JNK and P38 pathways. ASK1 is activated in response to a diverse array of stresses such as endoplasmic reticulum stress, lipopolysaccharides, tumor necrosis factor alpha, and reactive oxygen species. The activation of ASK1 induces various stress responses.

Biophysical interactions, docking studies and cytotoxic potential of a novel propofol-linolenate: a multi-technique approach.

In the present study, we have analyzed the biophysical interactions of alpha-linolenic acid conjugate (2,6P-ALA) with human serum albumin (HSA) and calf thymus DNA (CT-DNA); and also determined its effect on human cancer cell lines. The results of interactions between 2,6P-ALA and HSA intrinsic fluorescence indicated static quenching of HSA by the target conjugate with overall Stern-Volmer quenching constant () value of 1.8 × 10 M.

Mechanistic Insights into the Antimicrobial Actions of Metallic Nanoparticles and Their Implications for Multidrug Resistance.

Multiple drug-resistant bacteria are a severe and growing public health concern. Because relatively few antibiotics have been approved over recent years and because of the inability of existing antibiotics to combat bacterial infections fully, demand for unconventional biocides is intense. Metallic nanoparticles (NPs) offer a novel potential means of fighting bacteria.