Design, Synthesis, and Biological Evaluation of Ferulic Acid Template-Based Novel Multifunctional Ligands Targeting NLRP3 Inflammasome for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia, which arises due to low levels of acetyl and butyrylcholines, an increase in oxidative stress, inflammation, metal dyshomeostasis, Aß and tau aggregations. The currently available drugs for AD treatment can provide only symptomatic relief without interfering with pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multifunctional molecules for AD, systematic SAR studies on EJMC-4e were caried out to improve its multifunctional properties. The rigorous medicinal efforts led to the development of 12o, which displayed a 15-fold enhancement in antioxidant properties and a 2-fold increase in the activity against AChE and BChE over EJMC-4e. Molecular docking and dynamics studies revealed the binding sites and stability of the complex of 12o with AChE and BChE. The PAMPA-BBB assay clearly demonstrated that 12o can easily cross the blood-brain barrier. Interestingly, 12o also expresses promising metal chelation activity, while EJMC-4e was found to be devoid of this property. Further, 12o inhibited metal-induced or self Aß1-42 aggregation. Observing the neuroprotection ability of 12o against H2O2-induced oxidative stress in the PC-12 cell line is noteworthy. Furthermore, 12o also inhibited NLRP3 inflammasome activation and attenuated mitochondrial-induced ROS and MMP damage caused by LPS and ATP in HMC-3 cells. In addition, 12o is able to effectively reduce mitochondrial and cellular oxidative stress in the AD Drosophila model. Finally, 12o could reverse memory impairment in the scopolamine-induced AD mice model, as evident through in vivo and ex vivo studies. These findings suggest that this compound may act as a promising candidate for further improvement in the management of AD.

Ferroptosis and its modulators: A raising target for cancer and Alzheimer's disease.

The process of ferroptosis, a recently identified form of regulated cell death (RCD) is associated with the overloading of iron species and lipid-derived ROS accumulation. Ferroptosis is induced by various mechanisms such as inhibiting system Xc, glutathione depletion, targeting excess iron, and directly inhibiting GPX4 enzyme. Also, ferroptosis inhibition is achieved by blocking excessive lipid peroxidation by targeting different pathways. These mechanisms are often related to the pathophysiology and pathogenesis of diseases like cancer and Alzheimer's. Fundamentally distinct from other forms of cell death, such as necrosis and apoptosis, ferroptosis differs in terms of biochemistry, functions, and morphology. The mechanism by which ferroptosis acts as a regulatory factor in many diseases remains elusive. Studying the activation and inhibition of ferroptosis as a means to mitigate the progression of various diseases is a highly intriguing and actively researched topic. It has emerged as a focal point in etiological research and treatment strategies. This review systematically summarizes the different mechanisms involved in the inhibition and induction of ferroptosis. We have extensively explored different agents that can induce or inhibit ferroptosis. This review offers current perspectives on recent developments in ferroptosis research, highlighting the disease's etiology and presenting references to enhance its understanding. It also explores new targets for the treatment of cancer and Alzheimer's disease.

Repurposing the in-house generated Alzheimer's disease targeting molecules through computational and preliminary in-vitro studies for the management of SARS-coronavirus-2.

Covid-19 was declared a world pandemic. Recent studies demonstrated that Covid-19 impairs CNS activity by crossing the blood-brain barrier and ensuing cognitive impairment. In this study, we have utilized Covid-19 main protease (Mpro) as a biological target to repurpose our previously reported multifunctional compounds targeting Alzheimer's disease. Molecular docking, spatial orientation, molecular dynamics simulation, MM-GBSA energy calculation, and DFT studies were carried out with these molecules. Among all the compounds, F27, F44, and F56 exhibited higher binding energy (- 8.03, - 8.65, and - 8.68 kcal/mol, respectively) over the co-crystal ligand O6K (- 7.00 kcal/mol). In MD simulation, compounds F27, F44, and F56 could make a stable complex with Mpro target throughout the simulation. The compounds were synthesized following reported methods and subjected for cytotoxicity, and assessment of their capability to cross the blood-brain barrier in PAMPA assay, and antioxidant property evaluation through DPPH assay. The compounds F27, F44, and F56 exhibited cytocompatibility with the SiHA cell line and also displayed significant antioxidant properties with IC50 = 45.80 ± 0.27 µM, 44.42 ± 0.30 µM, and 42.74 ± 0.23 µM respectively. In the PAMPA assays, the permeability coefficient (Pe) value of F27, F44, and F56 lies in the acceptable range (Pe > 4). The results of the computational and preliminary in-vitro studies strongly corroborate the potential of F27, F44, and F56 as a lead for further optimization in treating the CNS complications associated with Covid-19.

Synthesis of phenylethanoid glycosides from acrylic esters of glucose and aryldiazonium salts via palladium-catalyzed cross-coupling reactions and evaluation of their anti-Alzheimer activity.

Cinnamic acid-containing sugar compounds such as phenylethanoid glycosides are widely present in nature and display various biological activities. In this work, the synthesis of trans-cinnamic acid containing phenylethanoid glycosides was achieved via palladium-catalyzed cross-coupling reactions between glycosyl acrylic esters and aryldiazonium salts. A wide range of functionalized aryldiazonium salts were successfully coupled with 6-O- and 4-O-acrylic esters of glucose under optimized conditions. The reactions proceeded at room temperature in the absence of additives and base. The desired products were obtained in good to excellent yields. Selected compounds from the library were screened for anti-Alzheimer activity, while compound 16 displayed significant inhibitory activities against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes.

Finite element method-based simulation on bone fracture fixation configuration factors for biodegradable embossed locking compression plate.

As an evolution, biodegradable implants need to maximize mechanical performance thereby may lead to confusion in selection of the biodegradable material and implant design to the fracture site. This requires selecting a unique fixation configuration to fit within the fractured bone, factors of which can be bone-plate clearance, interfragmentary gap, alteration in screw fixation position and variation in the number of screws whose configuration optimization can re-maximize the mechanical performance of the biodegradable implant. Therefore, these factors have been optimized based on the induced minimum stress using the finite element method-based simulation for which biodegradable embossed locking plates (BELCP) via screws made of Mg-alloy have been fitted over two fragments of femur body (as hollow cylindrical cortical bone). An average human weight of 62 kg is applied to one segment of the femur for all different configurations of each factor, where another segment is assumed to be fixed. By this simulation, the most optimal fixation configuration was found at a minimum induced stress value of 41.96 MPa which is approximately 85%, 18%, 6% and 48% respectively less than all maximum stress induced configurations in each of the factor. This optimized configuration was at the minimum clearance between bone and plate with a 3 mm interfragmentary gap using 8 screws where the locking screw begins to apply from the center of the BELCP. Overall, BELCP may be a better biodegradable implant plate for bone fracture fixation with these optimized fixation configurations as the improved mechanical performance after experimental validation.

Comparative transcriptomic and metabolite profiling reveals genotype-specific responses to Fe starvation in chickpea.

Iron deficiency is a major nutritional stress that severely impacts crop productivity worldwide. However, molecular intricacies and subsequent physiological and metabolic changes in response to Fe starvation, especially in leguminous crops like chickpea, remain elusive. In the present study, we investigated physiological, transcriptional, and metabolic reprogramming in two chickpea genotypes (H6013 and L4958) with contrasting seed iron concentrations upon Fe deficiency. Our findings revealed that iron starvation affected growth and physiological parameters of both chickpea genotypes. Comparative transcriptome analysis led to the identification of differentially expressed genes between the genotypes related to strategy I uptake, metal ions transporters, reactive oxygen species-associated genes, transcription factors, and protein kinases that could mitigate Fe deficiency. Our gene correlation network discovered several putative candidate genes like CIPK25, CKX3, WRKY50, NAC29, MYB4, and PAP18, which could facilitate the investigation of the molecular rationale underlying Fe tolerance in chickpea. Furthermore, the metabolite analysis also illustrated the differential accumulation of organic acids, amino acids and other metabolites associated with Fe mobilization in chickpea genotypes. Overall, our study demonstrated the comparative transcriptional dynamics upon Fe starvation. The outcomes of the current endeavor will enable the development of Fe deficiency tolerant chickpea cultivars.

Effectiveness of non-uniform thickness on a locking compression plate used as a biodegradable bone implant plate.

Conventional locking compression plate (LCP) made of non-biodegradable materials are well-known bone implants for internal fracture fixation because of their proven experimental success. LCP, however, is mechanically underpowered when made up of biodegradable materials (even with Mg-alloy). The biodegradable implant plate should not only exhibit adequate mechanical performance during implantation but also perform well after fracture, at least until complete healing of the fractured bone. With the aim of achieving enhanced mechanical performance, the design of the LCP has been modified to the design of Biodegradable Locking Compression Plate (BLCP) by adding a suitable thickness in the middle (only 4.6% of the total volume of the LCP), which may help retain some additional strength during implantation and after degradation. Both BLCP and LCP have been comparatively analyzed via FEM with the aid of axial compression and four-point bending tests. BLCP has a better mechanical capability of withstanding loads in its degraded form than in its non-degradable form. Furthermore, BLCP is up to 15.83% mechanically better in the non-degraded form as compared to LCP, which again becomes up to 100% more mechanically adequate in the degraded forms of BLCP than in LCP. BLCP is found safe for degradation up to 2 mm or 6 months with an estimated degradation rate of 4 mm/year, which may allow it to support fractured bone for at least the standard healing time. BLCP can be considered as a superior biodegradable bone implant plate after experimental assurance with the physiological environment and may replace LCP.

Exploration of Neuroprotective Properties of a Naturally Inspired Multifunctional Molecule (F24) against Oxidative Stress and Amyloid ß Induced Neurotoxicity in Alzheimer's Disease Models.

The pathological hallmarks of Alzheimer's disease (AD) are manifested as an increase in the level of oxidative stress and aggregation of the amyloid-ß protein. In vitro, in vivo, and in silico experiments were designed and carried out with multifunctional cholinergic inhibitor, F24 (EJMC-7a) to explore its neuroprotective effects in AD models. The neuroprotection ability of F24 was tested in SH-SY5Y cells, a widely used neuronal cell line. The pretreatment and subsequent co-treatment of SH-SY5Y cells with different doses of F24 was effective in rescuing the cells from H2O2 induced neurotoxicity. F24 treated cells were found to be effective in the reduction of cellular reactive oxygen species, DNA damage, and Aß1-42 induced neurotoxicity, which validated its neuroprotective effectiveness. F24 exhibited efficacy in an in vivoDrosophila model by rescuing eye phenotypes from degeneration caused by Aß toxicity. Further, computational studies were carried out to monitor the interaction between F24 and Aß1-42 aggregates. The computational studies corroborated our in vitro and in vivo studies suggesting Aß1-42 aggregation modulation ability of F24. The brain entry ability of F24 was studied in the parallel artificial membrane permeability assay. Finally, F24 was tested at doses of 1 and 2.5 mg/kg in the Morris water maze AD model. The neuroprotective properties shown by F24 strongly suggest that multifunctional features of this molecule provide symptomatic relief and act as a disease-modifying agent in the treatment of AD. The results from our experiments strongly indicated that natural template-based F24 could serve as a lead molecule for further investigation to explore multifunctional therapeutic agents for AD management.

Further SAR studies on natural template based neuroprotective molecules for the treatment of Alzheimer's disease.

In our earlier paper, we described ferulic acid (FA) template based novel series of multifunctional cholinesterase (ChE) inhibitors for the management of AD. This report has further extended the structure-activity relationship (SAR) studies of this series of molecules in a calibrated manner to improve upon the ChEs inhibition and antioxidant property to identify the novel potent multifunctional molecules. To investigate the effect of replacement of phenylpiperazine ring with benzylpiperazine, increase in the linker length between FA and substituted phenyl ring, and replacement of indole moiety with tryptamine on this molecular template, three series of novel molecules were developed. All synthesized compounds were tested for their acetyl and butyryl cholinestrases (AChE and BChE) inhibitory properties. Enzyme inhibition and PAS binding studies identified compound 13b as a lead molecule with potent inhibitor property towards AChE/BChE (AChE IC50 = 0.96 ± 0.14 µM, BChE IC50 = 1.23 ± 0.23 µM) compared to earlier identified lead molecule EJMC-G (AChE IC50 = 5.74 ± 0.13 µM, BChE IC50 = 14.05 ± 0.10 µM, respectively). Molecular docking and dynamics studies revealed that 13b fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Trp86, Ser125, Glu202, Trp 286, Phe295, Tyr 337 in AChE, and with Trp 82, Gly115, Tyr128, and Ser287 in BChE. The compound, 13b was found to be three times more potent antioxidant in a DPPH assay (IC50 = 20.25 ± 0.26 µM) over the earlier identified EJMC-B (IC50 = 61.98 ± 0.30 µM) and it also was able to chelate iron. Co-treatment of 13b with H2O2, significantly attenuated and reversed H2O2-induced toxicity in the SH-SY5Y cells. The parallel artificial membrane permeability assay-blood brain barrier (PAMPA-BBB) revealed that 13b could cross BBB efficiently. Finally, the in-vivo efficacy of 13b at dose of 10 mg/kg in scopolamine AD model has been demonstrated. The present study strongly suggests that the naturally inspired multifunctional molecule 13b may behave as a potential novel therapeutic agent for AD management.

A review on ferulic acid and analogs based scaffolds for the management of Alzheimer's disease.

Alzheimer's disease (AD) is an age-related multifactorial neurodegenerative disorder characterized by severe central cholinergic neuronal loss, gradually contributing to cognitive dysfunction and impaired motor activity, resulting in the brain's cell death at the later stages of AD. Although the etiology of AD is not well understood, however, several factors such as oxidative stress, deposition of amyloid-ß (Aß) peptides to form Aß plaques, intraneuronal accumulation of hyperphosphorylated tau protein, and low level of acetylcholine are thought to play a major role in the pathogenesis of AD. There is practically no drug for AD treatment that can address the basic factors responsible for the neurodegeneration and slow down the disease progression. The currently available therapies for AD in the market focus on providing only symptomatic relief without addressing the aforesaid basic factors responsible for the neurodegeneration. Ferulic acid (FA) is a phenol derivative from natural sources and serves as a potential pharmacophore that exerts multiple pharmacological properties such as antioxidant, neuroprotection, Aß aggregation modulation, and anti-inflammatory. Several FA based hybrid analogs are under investigation as a multi-target directed ligand (MTDLs) to develop novel hybrid compounds for the treatment of AD. In the present review article, we are focused on the critical pathogenic factors responsible for the onset of AD followed by the developments of FA pharmacophore-based hybrids compounds as a novel multifunctional therapeutic agent to address the limitations associated with available treatment for AD. The rationale behind the development of these compounds and their pharmacological activities in particular to their ChE inhibition (ChEI), neuroprotection, antioxidant property, Aß aggregation modulation, and metal chelation ability, are discussed in detail. We have also discussed the discovery of caffeic and cinnamic acids based MTDLs for AD. This review paper provides an in-depth insight into the research progress and current status of these novel therapeutics in AD and prospects for developing a druggable molecule with desired pharmacological affinity and reduced toxicity for the management of AD.

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19.

The importance of the main protease (Mpro) enzyme of SARS-CoV-2 in the digestion of viral polyproteins introduces Mpro as an attractive drug target for antiviral drug design. This study aims to carry out the molecular docking, molecular dynamics studies, and prediction of ADMET properties of selected potential antiviral molecules. The study provides an insight into biomolecular interactions to understand the inhibitory mechanism and the spatial orientation of the tested ligands and further, identification of key amino acid residues within the substrate-binding pocket that can be applied for structure-based drug design. In this regard, we carried out molecular docking studies of chloroquine (CQ), hydroxychloroquine (HCQ), remdesivir (RDV), GS441524, arbidol (ARB), and natural product glycyrrhizin (GA) using AutoDock 4.2 tool. To study the drug-receptor complex's stability, selected docking possesses were further subjected to molecular dynamics studies with Schrodinger software. The prediction of ADMET/toxicity properties was carried out on ADMET Prediction™. The docking studies suggested a potential role played by CYS145, HIS163, and GLU166 in the interaction of molecules within the active site of COVID-19 Mpro. In the docking studies, RDV and GA exhibited superiority in binding with the crystal structure of Mpro over the other selected molecules in this study. Spatial orientations of the molecules at the active site of Mpro exposed the significance of S1-S4 subsites and surrounding amino acid residues. Among GA and RDV, RDV showed better and stable interactions with the protein, which is the reason for the lesser RMSD values for RDV. Overall, the present in silico study indicated the direction to combat COVID-19 using FDA-approved drugs as promising agents, which do not need much toxicity studies and could also serve as starting points for lead optimization in drug discovery.

Association of common comorbidities with asthma in children: a cross-sectional study.

Asthma is a common chronic respiratory disease in children. The diagnosis of asthma in children may be associated with other comorbidities, which may influence the disease in several ways, including optimal asthma control. The main objective of this study was to determine the association of common comorbidities with asthma in children between 5 and 15 years. A cross-sectional study was carried out in a tertiary care hospital of western Rajasthan. A set of 23 questions were offered to the children with asthma and/or their parents and their responses were noted manually. A total of 95 children (74 male) were enrolled, allergic rhinitis (AR) was documented in 72 (75%) followed by psychological disturbance in 68 (71%), snoring in 47 (49.5%), gastro-esophageal reflux disease (GERD) in 44 (46.3%), atopic dermatitis in 26 (27.3%), and sinusitis in 19 (20%) children. There was no statistical significant association observed between asthma comorbidities and gender. Allergic rhinitis was the most common comorbidity in children with asthma followed by psychological disturbance, GER, and snoring. Both boys and girls had similar prevalence of asthma comorbidities.

Genetic analyses for deciphering the status and role of photoperiodic and maturity genes in major Indian soybean cultivars.

Allelic combinations of major photoperiodic (E1, E3, E4) and maturity (E2) genes have extended the adaptation of quantitative photoperiod sensitive soybean crop from its origin (China ∼35◦N latitude) to both north (up to ∼50◦N) and south (up to 40◦S) latitudes, but their allelic status and role in India (6-35◦N) are unknown. Loss of function and hypoactive alleles of these genes are known to confer photoinsensitivity to long days and early maturity. Early maturity has helped to adapt soybean to short growing season of India. We had earlier found that all the Indian cultivars are sensitive to incandescent long day (ILD) and could identify six insensitive accessions through screening 2071 accessions under ILD. Available models for ILD insensitivity suggested that identified insensitive genotypes should be either e3/e4 or e1 (e1-nl or e1-fs) with either e3 or e4. We found that one of the insensitive accessions (EC 390977) was of e3/e4 genotype and hybridized it with four ILD sensitive cultivars JS 335, JS 95-60, JS 93-05, NRC 37 and an accession EC 538828. Inheritance studies and marker-based cosegregation analyses confirmed the segregation of E3 and E4 genes and identified JS 93-05 and NRC 37 as E3E3E4E4 and EC 538828 as e3e3E4E4. Further, genotyping through sequencing, derived cleaved amplified polymorphic sequences (dCAPS) and cleaved amplified polymorphic sequences (CAPS) markers identified JS 95-60 with hypoactive e1-as and JS 335 with loss of function e3-fs alleles. Presence of photoperiodic recessive alleles in these two most popular Indian cultivars suggested for their role in conferring early flowering and maturity. This observation could be confirmed in F2 population derived from the cross JS 95-60 × EC 390977, where individuals with e1-as e1-as and e4e4 genotypes could flower 7 and 2.4 days earlier, respectively. Possibility of identification of new alleles ormechanism for ILD insensitivity and use of photoinsensitivity in Indian conditions have been discussed.

Molecular characterization and genetic diversity analysis of soybean (Glycine max (L.) Merr.) germplasm accessions in India.

Molecular characterization and genetic diversity among 82 soybean accessions was carried out by using 44 simple sequence repeat (SSR) markers. Of the 44 SSR markers used, 40 markers were found polymorphic among 82 soybean accessions. These 40 polymorphic markers produced a total of 119 alleles, of which five were unique alleles and four alleles were rare. The allele number for each SSR locus varied between two to four with an average of 2.97 alleles per marker. Polymorphic information content values of SSRs ranged from 0.101 to 0.742 with an average of 0.477. Jaccard's similarity coefficient was employed to study the molecular diversity of 82 soybean accessions. The pairwise genetic similarity among 82 soybean accessions varied from 0.28 to 0.90. The dendrogram constructed based on genetic similarities among 82 soybean accessions identified three major clusters. The majority of genotypes including four improved cultivars were grouped in a single subcluster IIIa of cluster III, indicating high genetic resemblance among soybean germplasm collection in India.