Investigating the preferential interaction between imatinib mesylate and VEGF G-quadruplex DNA as therapeutic strategies for cancer treatment: Biophysical and molecular modelling approaches.

G-Quadruplex DNA (GQ-DNA) is one of the most important non-canonical nucleic acid structures. GQ-DNA forming sequences are present in different crucial genomic regions and are abundant in promoter regions of several oncogenes. Therefore, GQ-DNA is an important target for anticancer drugs and hence binding interactions between GQ-DNA and small molecule ligands are of great importance. Since GQ-DNA is a highly polymorphic structure, it is important to identify ligand molecules which preferentially target a particular quadruplex sequence. In this present study, we have used a FDA approved drug called imatinib mesylate (ligand) which is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia, gastrointestinal stromal tumours. Different spectroscopic techniques as well as molecular docking investigations and molecular simulations have been used to explore the interaction between imatinib mesylate with VEGF GQ DNA structures along with duplex DNA, C-Myc, H-Telo GQ DNA. We found that imatinib mesylate shows preferential interaction towards VEGF GQ DNA compared to C-Myc, H-Telo GQ and duplex DNA. Imatinib mesylate seems to be an efficient ligand for VEGF GQ DNA, suggesting that it might be used to regulate the expression of genes in cancerous cells.

Nanophytosome formulation of ß-1,3-glucan and Euglena gracilis extract for drug delivery applications.

Euglena gracilis (EG) is a unicellular freshwater alga known for its high ß-1,3-glucan (BG) content with well-known biological properties and immune response. The high molecular weight structure of BG traditionally poses a challenge in terms of its size and absorption. Therefore, the aim of this study was to develop a novel drug delivery mechanism of BG and EG to nanophytosomes (NPs) by converting the heavy molecular weight of BG and EG into lipid phosphatidylcholine (PC), which plays an important role in improving their bioavailability and entrapment in captivity. The BG and EG NPs were developed by the solvent evaporation method while varying time and temperature to optimize their drug delivery ability. The size of BG-PC and EG-PC obtained by the Dynamic Light Scattering (DLS) method was 134.62 and 158.38 nm, respectively. Chemical (Fourier Transform Infra-Red) and structural (X-Ray Diffraction) characterization of NPs improved the binding capacity and the amorphous nature of both NPs. The shape of the NPs by Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM) revealed their spherical, vesicular nature. The encapsulation efficiency of BG-PC and EG-PC was 82 ± 1.62 % and 87 ± 3.22 %, respectively, which improves the bioavailability. The developed methodology has thus proven effective in synthesizing BG-PC and EG-PC, which may be useful as NP drug delivery carriers. Future research could demonstrate the safety and effectiveness of long-term storage conditions for medical and pharmaceutical applications.•Nanophytosomes are tailored in size, shape and composition to optimize the delivery of phytochemicals/phytocompounds through nanoscale size and surface modification for better physiological absorption.•Nanophytosomes increase the stability of phytochemicals/phytocompounds and protect them from degradation due to heat or chemical reactions, leading to longer shelf life and improved therapeutic efficacy.•In this method, optimal conditions were created for the formation of ß-1,3-glucan and Euglena gracilis extract nanophytosomes for successful development of drug delivery system that can effectively deliver bioactive compounds.

Exploring the Structural Importance of the C3=C4 Double Bond in Plant Alkaloids Harmine and Harmaline on Their Binding Interactions with Hemoglobin.

Harmine and harmaline are two structurally similar heterocyclic ß-carboline plant alkaloids with various therapeutic properties, having a slight structural difference in the C3=C4 double bond. In the present study, we have reported the nature of the interaction between hemoglobin (Hb) with harmine and harmaline by employing several multispectroscopic, calorimetric, and molecular docking approaches. Fluorescence spectroscopic studies have shown stronger interaction of harmine with Hb compared to that of almost structurally similar harmaline. Steady-state anisotropy experiments further show that the motional restriction of harmine in the presence of Hb is substantially higher than that of the harmaline-Hb complex. Circular dichroism (CD) study demonstrates no conformational change of Hb in the presence of both alkaloids, but CD study in 1-cm cuvette path length also demonstrates stronger affinity of harmine toward Hb compared to harmaline. From the thermal melting study, it has been found that both harmine and harmaline slightly affect the stability of Hb. From isothermal titration calorimetry (ITC), we have found that the binding process is exothermic and enthalpy driven. Molecular docking studies indicated that both harmine and harmaline prefer identical binding sites in Hb. This study helps us to understand that slight structural differences in harmine and harmaline can alter the interaction properties significantly, and this key information may help in the drug discovery processes.

Current research status of anti-cancer peptides: Mechanism of action, production, and clinical applications.

The escalating rate of cancer cases, together with treatment deficiencies and long-term side effects of currently used cancer drugs, has made this disease a global burden of the 21st century. The number of breast and lung cancer patients has sharply increased worldwide in the last few years. Presently, surgical treatment, radiotherapy, chemotherapy, and immunotherapy strategies are used to cure cancer, which cause severe side effects, toxicities, and drug resistance. In recent years, anti-cancer peptides have become an eminent therapeutic strategy for cancer treatment due to their high specificity and fewer side effects and toxicity. This review presents an updated overview of different anti-cancer peptides, their mechanisms of action and current production strategies employed for their manufacture. In addition, approved and under clinical trials anti-cancer peptides and their applications have been discussed. This review provides updated information on therapeutic anti-cancer peptides that hold great promise for cancer treatment in the near future.

Pharmacoinformatic approach to identify potential phytochemicals against SARS-CoV-2 spike receptor-binding domain in native and variants of concern.

Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) pathogenesis is initiated by the binding of SARS-CoV-2 spike (S) protein with the angiotensin-converting enzyme 2 receptor (ACE2R) on the host cell surface. The receptor-binding domain (RBD) of the S protein mediates the binding and is more prone to mutations resulting in the generation of different variants. Recently, molecules with the potential to inhibit the interaction of S protein with ACE2R have been of interest due to their therapeutic value. In this context, the present work was performed to identify potential RBD binders from the Indian medicinal plant's phytochemical database through virtual screening, molecular docking, and molecular dynamic simulation. Briefly, 1578 compounds filtered from 9596 phytochemicals were chosen for screening against the RBD of the native SARS-CoV-2 S protein. Based on the binding energy, the top 30 compounds were selected and re-docked individually against the native and five variants of concern (VOCs: alpha, beta, gamma, delta, and omicron) of SARS-CoV-2. Four phytochemicals, namely withanolide F, serotobenine, orobanchol, and gibberellin A51, were found to be potential RBD binders in native and all SARS-CoV-2 VOCs. Among the four, withanolide F exhibited lower binding energy (- 10.84 to - 8.56 kcal/mol) and better ligand efficiency (- 0.3 to - 0.25) against all forms of RBD and hence was subjected to a 100 ns MD simulation which confirmed its stringent binding to the RBDs in native and VOCs. The study prioritizes withanolide F as a prospective COVID-19 (Coronavirus disease) therapeutic agent based on the observations. It warrants deeper investigations into the four promising leads for understanding their precise therapeutic value.

IL6/IL6R genetic diversity and plasma IL6 levels in bipolar disorder: An Indo-French study.

Reports of association of genetic variants of IL6 and its receptor (IL6R) with psychiatric disorders are inconsistent, and there are few population-based studies thus far in bipolar disorder (BD). We genotyped the IL6 rs1800795 and IL6R rs2228145 polymorphisms in two independent sets of patients exposed to different environmental stimuli such as climatic conditions or specific infectious burden - a French sample and a south Indian Tamil sample of BD with quantitation of circulating plasma IL-6 levels in the latter sub-sample. In both populations, allele and genotype frequencies did not differ significantly between cases and controls for either polymorphism. Upon stratifying based on age at onset, we found no associations with the IL6 rs1800795 variant. However, the IL6R rs2228145 C allele and CC genotype were associated with early onset of disease in the French sample when compared to late onset BD. A similar trend was observed in the Indian population where we also found that plasma IL-6 levels were significantly higher in BD and also in patients who were in residual phase or remission both as compared to controls. Our findings are in favour of a possible trans-ethnic implication of the IL6R genetic diversity in BD and reinforce the notion that IL-6 is an important marker of the operating inflammatory processes in the disease.

Scalable novel PVDF based nanocomposite foam for direct blood contact and cardiac patch applications.

Scalable novel beta phase polyvinylidene fluoride-poly(methyl methacrylate) (PVDF-PMMA) polymer blend based nanocomposite foam with hydroxyapatite (HAp) and titanium dioxide (TiO2) as nanofillers (ß-PVDF-PMMA/HAp/TiO2) (ß-PPHT-f), was prepared by using salt etching assisted solution casting method. The prepared ß-PPHT-f nanocomposite material was characterized using XRD, FT-IR, SEM-EDS. The XRD and FTIR results confirmed the formation of ß phase of ß-PPHT-f. The SEM and EDS results confirmed the formation of high porous structured closed cell type morphology of ß-PPHT-f. It also, confirmed the uniform distribution of Ti, Ca, P, N and O, in ß-PPHT-f. Contact angle measurements performed using sessile drop method with water and EDTA treated blood (EDTA blood) as probe liquids revealed that ß-PPHT-f is hydrophilic with contact angle of 48.2° as well as hemophilic with contact angle of 13.7°. Porosity, fluid absorption and retention investigation by gravimetric analysis revealed that ß-PPHT-f was 89.2% porous and can absorb and retain 139.15% and 87.05% of water and blood, respectively. The hemolysis assay performed as per ASTM F756 procedure revealed that ß-PPHT-f is non hemolytic. Also, the Leishman stained blood smears prepared from whole blood incubated with ß-PPHT-f for 3, 4, 5 and 6 h at 37 °C revealed that the blood cells were not affected by ß-PPHT-f, its surface morphology and elemental composition. H9c2 cell line studies on a transparent film prepared using ß-PPHT-f revealed that the elemental composition of the nanocomposite favored H9c2 cell adhesion and differentiation. All the characterization results indicate that the newly developed scalable novel ß-PPHT-f is hemocompatible and cardiomyocyte compatible, suggesting it as a useful material for direct blood contact and cardiac patch applications.

The HLA-G Genetic Contribution to Bipolar Disorder: A Trans-Ethnic Replication.

Bipolar disorder (BD) is frequently associated with immune dysfunctions. Studying the genetic diversity of the immuno-modulatory human leukocyte antigen (HLA)-G locus in a French BD cohort, we previously reported an association between a functionally relevant 14 bp Ins/Del polymorphism and BD risk. The present study investigated the genetic and expression diversities of HLA-G in a geographically distinct South Indian population-group BD patients, as well as the influence of exposure to the neurotropic Toxoplasma gondii pathogen. Three functionally relevant HLA-G polymorphisms, i.e. HLA-G 14 bp Ins/Del (rs66554220), +3142G>C (rs1063320) and +3187A>G (rs9380142) were genotyped by polymerase chain reaction (PCR) and real-time PCR. Sub-samples of BD patients and healthy controls (HC) were investigated for plasma levels of soluble HLA-G (sHLA-G) isoforms, as well as circulating stigma of T. gondii infection. Findings indicate: (i) the frequency of the HLA-G 14 bp Del/Del genotype was higher in BD cases, as compared to HC; (ii) the HLA-G + 3142 C allele and CC genotype were more prevalent in BD patients than in HC; (iii) sHLA-G levels were significantly higher in BD cases, especially in females and in the early onset sub-group; and (iv) the InsGA haplotype was more prevalent in HC. Our findings further support the genetic contribution of HLA-G to BD risk, as well as indicate relevant expression profiles. Such data may also indicate a potential developmental role in BD etiology, given that HLA-G is an important immune regulator from the intrauterine period and across development.

The significance of aryl acylamidase activity of acetylcholinesterase in osteoblast differentiation and mineralization.

Osteoblast differentiation is an essential event in the developmental process, which is favoured by the production of extra cellular matrix proteins and various enzymes including discrete ones like acetylcholinesterase (AChE). Despite the fact that AChE facilitates osteoblast differentiation, the significance of its catalytic functions [esterase and aryl acylamidase (AAA) activities] in the process is yet to be ascertained. In this context, SaOS-2 cell line was used in the present study to implicate the catalytic activities of AChE in process of osteoblast differentiation and mineralization. During differentiation, it was found that the activity of both esterase and AAA increased 1.13 and 1.46 folds respectively, signifying the involvement of catalytic activities of AChE in the process. Inhibition of both the catalytic activities of AChE with edrophonium significantly reduced the amount of mineralization by decreasing the alkaline phosphatase (ALP) activity and expression of differentiation-related genes such as RUNX-2, COL1A, ALP, OC, and OP significantly (p < 0.05). Inhibition of esterase activity without altering the AAA activity using gallamine significantly increased the level ALP activity and expression of differentiation-associated genes (p < 0.05), thus favouring mineralization. Therefore, this study concludes and confirms that the AAA activity of AChE is actively involved in the process of osteoblast differentiation and mineralization.

Understanding the molecular mechanism of aryl acylamidase activity of acetylcholinesterase - An in silico study.

Acetylcholinesterase (AChE) exhibits two different activities, namely esterase and aryl acylamidase (AAA). Unlike esterase, AAA activity of AChE is inhibited by the active site inhibitors while remaining unaffected by the peripheral anionic site inhibitors. This differential inhibitory pattern of active and peripheral anionic site inhibitors on the AAA activity remains unanswered. To answer this, we investigated the mechanism of binding and trafficking of AAA substrates using in silico tools. Molecular docking of serotonin and AAA substrates (o-nitroacetanilide, and o-nitrotrifluoroacetanilide,) onto AChE shows that these compounds bind at the side door of AChE. Thus, we conceived that the AAA substrates prefer the side door to reach the active site for their catalysis. Further, steered molecular dynamics simulations show that the force required for binding and trafficking of the AAA substrate through the side door is comparatively lesser than their dissociation (900kJ/mol/nm). Among the two substrates, o-nitrotrifluoroacetanilide required lesser force (380kJ/mol/nm) than o-nitroacetanilide the (550kJ/mol/nm) for its binding, thus validating o-nitrotrifluoroacetanilide as a better substrate. With these observations, we resolve that the AAA activity of AChE is mediated through its side door. Therefore, binding of PAS inhibitors at the main door of AChE remain ineffective against AAA activity.

A new role for the nonpathogenic nonsynonymous single-nucleotide polymorphisms of acetylcholinesterase in the treatment of Alzheimer's disease: a computational study.

Single-nucleotide polymorphisms (SNPs) are implicated in the complexity of understanding the genetics of diseases and their therapeutics. Here we have attempted to determine the impact of nonsynonymous SNPs (nsSNPs) on structure, dynamics, and ligand-binding properties of the human acetylcholinesterase (hAChE) protein, which has been targeted in the treatment of Alzheimer's disease. Of the reported 153 SNPs, 4 nsSNPs, namely, A415G, P104A, V302E, and Y119H, were prioritized to be functionally unfavorable by SIFT and PolyPhen algorithms. Molecular dynamics simulation revealed these nsSNP forms to be structurally stable, and they are also considered functionally active as they lie away from the catalytic triad. However, the aromatic amino acids lining the active-site gorge exhibited altered degrees of side chain dihedral angles. Such conformational alterations were evaluated for their ability to interfere with binding of hAChE inhibitors. The inhibitors (donepezil, galantamine, rivastigmine, and tacrine) were oriented differently in comparison to the native because of the steric hindrance offered by the altered dihedral angles. Interestingly, huperzine A alone exhibited higher efficiency in its binding to the AChE and retained similar orientation irrespective of the polymorphisms since the orientation of Asp74 involved in its binding and trafficking remained unaltered in all protein forms. Therefore, we conclude that nsSNPs confer changes to the dynamicity of proteins, which in turn affects their ligand-binding properties rather than their stability. Considering the diverse polymorphic nature of hAChE, while contemplating any structure-based drug design, the common, nonpathogenic nsSNPs should be considered for the utmost efficacy of drugs.

Why calcium channel blockers could be an elite choice in the treatment of Alzheimer's disease: a comprehensive review of evidences.

The universality and vitality of calcium ions are implicit from its diverse physiological functions, from regulation of enzymes to synaptic plasticity and memory. However, overloading of these ions could result in life-threatening degenerative disorders. Calcium channels, which are involved in the transport of calcium ions, are targeted and blocked to prevent its overload, favoring vascular relaxation. Besides this primary action, calcium channel blockers (CCBs) also genuinely exhibit cognitive-enhancing abilities and reduce the risk of dementia, especially of Alzheimer's type. Alzheimer's disease (AD) is triggered by the disruption of calcium homeostasis, which underlies the observed progressive cognitive decline that occurs in this neurodegenerative disorder. Fortunately, CCB is expected to offer neuroprotection and additionally demonstrate antiamyloid, antitau, antiphospholipase, antiplatelet, antioxidant, and anti-inflammatory activity, a solitary solution to all the subcellular physiological complications that are observed in AD. Therefore, the aim of this review was to unearth the prospective of CCB against cognitive frailty with a sole purpose of elucidating CCB as cognitive enhancers, which could find its use as a drug in prevention or treatment of AD.