Amentoflavone and methyl hesperidin, novel lead molecules targeting epitranscriptomic modulator in acute myeloid leukemia: in silico drug screening and molecular dynamics simulation approach.

INTRODUCTION: M6A modification in transcriptome is critical in regulating different cellular processes, including cancer. In human beings, METTL3 is the major m6A writer that works in association with METTL14, an accessory protein. Extensive study revealed that cancer progression for acute myeloid leukemia, gastric cancer, colorectal cancer, hepatocellular carcinoma, and lung cancer is directly contributed by irregular expression of METTL3. OBJECTIVE: Targeting METTL3 has opened a new window in the development of novel inhibitors/drugs. METHODS: In this study, commercially available natural compounds were randomly screened to avoid the bias of screening small molecules on the basis of structural similarity. From 810 compounds that were screened, 80 commercially available compounds were showing better score when compared with the existing substrate/substrate-analogue and the inhibitor bound crystal structures in terms of docking score and binding energy calculation. RESULTS AND CONCLUSION: Among this pool of compounds, the best seven small molecules have been selected and further validated by different computational tools like binding energy calculation, molecular dynamics simulation, ADME analysis, and toxicity prediction. The novel hits found in this study can function as lead compounds which can be developed into inhibitors as well as drugs, specific against METTL3.

Network-Based Analysis of Fatal Comorbidities of COVID-19 and Potential Therapeutics.

COVID-19 is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The case-fatality rate is significantly higher in older patients and those with diabetes, cancer or cardiovascular disorders. The human proteins, angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2) and basigin (BSG), are involved in high-confidence host-pathogen interactions with SARS-CoV-2 proteins. We considered these three proteins as seed nodes and applied the random walk with restart method on the human interactome to construct a protein-protein interaction sub-network, which captures the effects of viral invasion. We found that 'Insulin resistance', 'AGE-RAGE signaling in diabetic complications' and 'adipocytokine signaling' were the common pathways associated with diabetes, cancer and cardiovascular disorders. The association of these critical pathways with aging and its related diseases explains the molecular basis of COVID-19 fatality. We further identified drugs that have effects on these proteins/pathways based on gene expression studies. We particularly focused on drugs that significantly downregulate ACE2 along with other critical proteins identified by the network-based approach. Among them, COL-3 had earlier shown activity against acute lung injury and acute respiratory distress, while entinostat and mocetinostat have been investigated for non-small-cell lung cancer. We propose that these drugs can be repurposed for COVID-19.

Preventing acute asthmatic symptoms by targeting a neuronal mechanism involving carotid body lysophosphatidic acid receptors.

Asthma accounts for 380,000 deaths a year. Carotid body denervation has been shown to have a profound effect on airway hyper-responsiveness in animal models but a mechanistic explanation is lacking. Here we demonstrate, using a rat model of asthma (OVA-sensitized), that carotid body activation during airborne allergic provocation is caused by systemic release of lysophosphatidic acid (LPA). Carotid body activation by LPA involves TRPV1 and LPA-specific receptors, and induces parasympathetic (vagal) activity. We demonstrate that this activation is sufficient to cause acute bronchoconstriction. Moreover, we show that prophylactic administration of TRPV1 (AMG9810) and LPA (BrP-LPA) receptor antagonists prevents bradykinin-induced asthmatic bronchoconstriction and, if administered following allergen exposure, reduces the associated respiratory distress. Our discovery provides mechanistic insight into the critical roles of carotid body LPA receptors in allergen-induced respiratory distress and suggests alternate treatment options for asthma.

Clinical features, MRI brain, and MRS abnormalities of drug-naïve neurologic Wilson's disease.

BACKGROUND: Magnetic resonance imaging (MRI) helps in the diagnosis of neurologic Wilson's disease (WD). The literature regarding MR spectroscopy (MRS) and diffusion-weighted imaging (DWI) in WD is limited. OBJECTIVES: To evaluate the clinical features and neuroimaging findings in drug-naïve neurologic WD and to find correlation between clinical stage and disease duration with different imaging findings. MATERIALS AND METHODS: The study subjects included consecutive and follow-up neurologic WD patients attending movement disorder clinic. The initial clinical and MRI features before commencement of chelation therapy were noted. Of 78 patients, 34 underwent DWI study and MRS was done in 38 patients and in 32 control subjects. RESULTS: Dystonia, dysarthria, tremor, and behavioral abnormality were common presenting features. All patients had MRI abnormality with major affection of basal ganglia. The clinical severity and anatomical extent of MRI abnormalities were positively correlated (P < 0.001; r s = 0.709). Presence of diffusion restriction was inversely related to duration of disease (P < 0.001; r s = 0.760). WD patients had reduced N-acetylaspartate/creatine (Cr) and choline (Cho)/Cr ratio (P < 0.001) as compared with control subjects in MRS study. CONCLUSION: Dystonia, dysarthria and tremor are common neurological features of WD. In this study, MRI abnormalities were positively correlated with disease severity; diffusion restriction was inversely correlated with the duration of the disease process. MRS was also a sensitive tool for diagnosing patient of neurologic WD.