👤 Kushvinder Kumar

Alzheimer's disease (AD) is the leading cause of dementia worldwide with therapeutic lacunae till date. The beta-amyloid (Aβ) accumulation triggers AD pathogenesis, though clinical trials lowering Aβ have not altered disease outcomes suggesting other interacting factors to be identified for drug design of AD. Therefore, it is of interest to identify potential hub proteins interlinked with disease-driving pathways using a network-based approach for AD therapeutic designing. Literature mining was done to identify proteins implicated in AD etiology. Protein-protein interactions (PPIs) were retrieved from the STRING database and merged into a single network using Cytoscape 3.10.1. The hub proteins involved in AD etiology were predicted based on the topological algorithms of CytoHubba. Six major proteins, with STRING database identifiers - APP, BACE1, PSEN1, MAPT, APOE4 and TREM2, were identified to be involved in AD pathogenesis. The merged network of PPIs of these proteins contained 51 nodes and 211 edges, as predicted by Analyzer module of Cytoscape. The Amyloid precursor protein (APP) emerged as the highest-scoring hub protein across multiple centrality measures and topological algorithms. Thus, current data provides evidence to support the ongoing investigation of APP's multifaceted functions and therapeutic potential for AD. Show less

Alzheimer's disease (AD), a debilitating neurodegenerative condition, is characterized by progressive cognitive decline brought about by the deposition of amyloid beta (Aβ) plaques in the brain initiates downstream neuronal dysfunction and death in AD pathogenesis. The β-secretase (BACE-1) enzyme plays a crucial role in generating Aβ from amyloid precursor protein (APP). Hence, we report the virtual screening of marine phytochemicals as BACE-1 inhibitors. 2583 compounds, retrieved from Comprehensive Marine Natural Product Database (CMNPD), were primarily screened for drug-likeliness and blood-brain barrier permeability using admetSAR 2.0 and Show less

The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), β-secretase-1 (BACE-1), and inhibition of amyloid β (Aβ) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics. Show less

Dyggve-Melchior-Clausen (DMC) disease, also known as DMC syndrome, is a rare, progressive genetic disorder that is characterized by skeletal and intellectual abnormalities. The case report involves a four-year-old male child presenting with marked short stature, intellectual disability, coarse facies, and microcephaly. Initial investigations, including blood tests and radiological evaluations, prompted further genetic testing via whole-exome sequencing. This identified a homozygous mutation in the Dymeclin ( Show less

Astrocyte elevated gene-1 (AEG-1) is overexpressed in various malignancies. Exostosin-1 (EXT-1), a tumor suppressor, is an intermediate for malignant tumors. Understanding the mechanism behind the interaction between AEG-1 and EXT-1 may provide insights into colon cancer metastasis. AOM/DSS was used to induce tumor in BALB/c mice. Using an In BALB/c mice, the AOM+DSS treated mice developed necrotic, inflammatory and dysplastic changes in the colon with definite clinical symptoms such as loss of goblet cells, colon shortening, and collagen deposition. Administration of AEG-1 siRNA resulted in a substantial decrease in the disease activity index. Mice treated with EXT-1 siRNA showed diffusely reduced goblet cells. In vivo investigations revealed that PTCH-1 activity was influenced by upstream gene AEG-1, which in turn may affect EXT-1 activity. Data from The Cancer Genomic Atlas and GEO databases confirmed the upregulation of AEG-1 and downregulation of EXT-1 in cancer patients. This study revealed that AEG-1 silencing might alter EXT-1 expression indirectly through PTCH-1, influencing cell-ECM interactions, and decreasing dysplastic changes, proliferation and invasion. Show less

Tumor suppressors are well known drivers of cancer invasion and metastasis in metastatic castration sensitive prostate cancer (mCSPC). However, oncogenes are also known to be altered in this state, however the frequency and prognosis of these alterations are unclear. Thus, we aimed to study the spectrum of oncogene mutations in mCSPC and study the significance of these alteration on outcomes. Four hundred and seventy-seven patients with mCSPC were included who underwent next generation sequencing. Oncogene alterations were defined as mutations in A total of 477 patients were included with baseline characteristics with 117 patients (24.5%) harbored a mutation within an oncogene. A total of 172 oncogene mutations were found within the population with the most common being Oncogenes are frequency mutated in mCSPC and associated with aggressive features and inferior outcomes. Future work will need to validate these results to better assess its significance in allowing for personalization of care. Show less

The interaction between stromal and tumor cells in tumor microenvironment is a crucial factor in Mantle cell lymphoma (MCL) progression and therapy resistance. We have identified a long non-coding RNA, CERS6-AS1, upregulated in MCL and associated with poor overall survival. CERS6-AS1 expression was elevated in primary MCL within stromal microenvironment and in a subset of MCL cells adhered to stromal layer. These stromal-adhered MCL-subsets exhibited cancer stem cell signatures than suspension counterparts. Mechanistically, we found that downregulating CERS6-AS1 in MCL reduced Fibroblast Growth Factor Receptor-1 (FGFR1), expression attributed to loss of its interaction with RNA-binding protein nucleolin. In addition, using in-silico approach, we have discovered a direct interaction between nucleolin and 5'UTR of FGFR1, thereby regulating FGFR1 transcript stability. We discovered a positive association of CERS6-AS1 with cancer stem cell signatures, and Wnt signaling. Building on these, we explored potential therapeutic strategies where combining nucleolin-targeting agent with FGFR1 inhibition significantly contributed to reversing cancer stem cell signatures and abrogated primary MCL cell growth on stromal layer. These findings provide mechanistic insights into regulatory network involving CERS6-AS1, nucleolin, and FGFR1 axis-associated crosstalk between tumor cells and stromal cell interaction and highlights therapeutic potential of targeting a non-coding RNA in MCL. Show less

Hemigraphis alternata (H. alternata), commonly known as Red Flame Ivy, is widely recognized for its wound healing capabilities. However, the pharmacologically active plant components and their mechanisms of action in wound healing are yet to be determined. This study presents the mass spectrometry-based global metabolite profiling of aqueous and ethanolic extract of H. alternata leaves. The analysis identified 2285 metabolites from 24,203 spectra obtained in both positive and negative polarities. The identified metabolites were classified under ketones, carboxylic acids, primary aliphatic amines, steroids and steroid derivatives. We performed network pharmacology analysis to explore metabolite-protein interactions and identified 124 human proteins as targets for H. alternata metabolites. Among these, several of them were implicated in wound healing including prothrombin (F2), alpha-2A adrenergic receptor (ADRA2A) and fibroblast growth factor receptor 1 (FGFR1). Gene ontology analysis of target proteins enriched cellular functions related to glucose metabolic process, platelet activation, membrane organization and response to wounding. Additionally, pathway enrichment analysis revealed potential molecular network involved in wound healing. Moreover, in-silico docking analysis showed strong binding energy between H. alternata metabolites with identified protein targets (F2 and PTPN11). Furthermore, the key metabolites involved in wound healing were further validated by multiple reaction monitoring-based targeted analysis. Show less

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL. Show less

Introduction Recently, the expression of metallophosphoesterase-domain-containing protein 2 (MPPED2) was identified in cervical cancer. However, its precise role and correlation with other tumor suppressor proteins, such as p16INK4A, is not well studied in high-risk human papillomavirus (HPV) integrated human cervical carcinoma. Hence, in the present study, we try to see the expression of MPPED2 in human cervical carcinoma and its correlation with age and p16INK4A protein expression level. Methods The prospective study consists of 200 samples of 150 known cervical carcinoma and 50 controls. Histopathological evaluation, immunohistochemical staining, and semi-quantitative scoring of the intensity of proteins were performed. Statistical analysis was performed with the Shapiro-Wilk test, Spearman's rho correlation sig. (two-tailed), and Student's t-test. Results The data show that among the 150 cases, 136 (68.0%) cervical carcinoma tissues express the presence of high-risk HPV viral genome integration in the host cell. The expression of p16INK4A protein is higher in those tissues identified with high-risk HPV viral genomes. In contrast, the expression of MPPED2 protein is lesser or absent in those cervical tissues that have the higher expression of p16INK4A protein and vice versa. There is a significant correlation (p=0.000) between age and p16INK4A protein expression but not with MPPED2. A significant linear correlation (p=0.000) is found between the p16INK4A and MPPED2 proteins. Conclusion It may support the therapeutic application of MPPED2 protein to prevent cervical carcinoma progression in the near future. Show less

Type 2 diabetes mellitus (T2DM) is a metabolic disease and comorbidity associated with several conditions, including cardiac dysfunction leading to heart failure with preserved ejection fraction (HFpEF), in turn resulting in T2DM-induced cardiomyopathy (T2DM-CM). However, the molecular mechanisms underlying the development of T2DM-CM are poorly understood. It is hypothesized that molecular alterations in myopathic genes induced by diabetes promote the development of HFpEF, whereas cardiac myosin inhibitors can rescue the resultant T2DM-mediated cardiomyopathy. To test this hypothesis, a Leptin receptor-deficient Show less

Mycobacterium tuberculosis (MTB) is the causative organism of tuberculosis. Cholesterol is a crucial carbon source required for the survival of MTB in host cells. Transcription factor NR1H3 along with its important target genes ABCA1 and ApoE play important role in removal of extra cholesterol from cells. Changes in the gene expression of NR1H3, ABCA1 and ApoE can affect cholesterol homeostasis and thus the survival of MTB in host cells.Therefore, the present study was designed to analyze the mRNA expression of NR1H3, ABCA1 and ApoE in pulmonary TB (PTB) patients from the population of Punjab, India. In this study, mRNA expression of the transcription factor NR1H3 and its target genes ABCA1 and ApoE was analyzed in 89 subjects, including 41 PTB patients and 48 healthy controls (HCs) by real-time quantitative PCR. It was found that the mRNA expression of both NR1H3 and ABCA1 genes was significantly lower in TB patients than in HCs (p < 0.001). Even after sex-wise stratification of the subjects, mRNA expression of NR1H3 and ABCA1 was found to be down-regulated in both male and female TB patients. No significant difference was observed in expression of ApoE (p = 0.98). The present study found that the mRNA expression of NR1H3 and ABCA1 is down-regulated in TB patients from Punjab state of India. Show less

Impaired cholesterol efflux and/or uptake can influence arterial lipid accumulation leading to atherosclerosis. Here, we report that tripartite motif-containing protein 13 (TRIM13), a RING-type E3 ubiquitin ligase, plays a role in arterial lipid accumulation leading to atherosclerosis. Using molecular approaches and KO mouse model, we found that TRIM13 expression was induced both in the aorta and peritoneal macrophages (pMφ) of ApoE Show less

Circulating exosome-enriched extracellular vesicles (EVs) have drawn considerable importance in obesity-related insulin-resistance (IR). We sought to compare the proteomics profile of serum exosomes from normal individuals and those with obesity and IR. We isolated serum exosomes from male subjects with obesity and insulin resistance (Ob-IR, HOMA-IR > 2.0) and lean/overweight insulin-sensitive (Normal (N), HOMA-IR < 2.0) individuals. The differential protein expression between the two groups was detected by a label-free quantitative mass spectrometry analysis followed by GO annotation and ingenuity pathway analysis (IPA). We identified 23 upregulated and 46 downregulated proteins between Ob-IR and N groups. Some of these proteins are involved in altering insulin signaling (VPS13C, TBC1D32, TTR, and ADIPOQ), inflammation (NFκB and CRP), and B-cell proliferation/activation (IGLV4-69, IGKV1D-13, and IGHV4-28). GO analysis revealed that the differentially expressed proteins (DEPs) are mainly involved in regulating immune cell activation and are located in extracellular space. IPA analysis showed that top molecules mediating IR, inflammation and B-cell activation were upregulated in Ob-IR subjects compared to N subjects. Serum exosomal proteins can be used as biomarkers to identify the future risk of diabetes and a therapeutic target to prevent or slow down the progression of diabetes in high-risk individuals. Show less

The melanocortin-4 receptor (MC4R) plays a critical role in regulating energy homeostasis. Studies on obesogenic human MC4R (hMC4R) variants have not yet revealed how hMC4R maintains body weight. Here, we identified a signaling profile for obesogenic constitutively active H76R and L250Q hMC4R variants transfected in HEK293 cells that included constitutive activity for adenylyl cyclase (AC), cyclic adenosine monophosphate (cAMP) response element (CRE)-driven transcription, and calcium mobilization but not phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) activity. Importantly, the signaling profile included impaired α-melanocyte-stimulating hormone-induced CRE-driven transcription but not impaired α-melanocyte-stimulating hormone-induced AC, calcium, or pERK1/2. This profile was not observed for transfected H158R, a constitutively active hMC4R variant associated with overweight but not obesity. We concluded that there is potential for α-melanocyte-stimulating hormone-induced CRE-driven transcription in HEK293 cells transfected with obesogenic hMC4R variants to be the key predictive tool for determining whether they exhibit loss of function. Furthermore, in vivo, α-melanocyte-stimulating hormone-induced hMC4R CRE-driven transcription may be key for maintaining body weight. Show less

Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. To assess the role of ANGPTL4 in COVID-19-related outcomes. Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients. Show less

In this study, comparative analysis of skeletal muscle transcriptome was carried out for four biological replicates of Aseel, a fighter type breed and Punjab Brown, a meat type breed of India. The profusely expressed genes in both breeds were related to muscle contraction and motor activity. Differential expression analysis identified 961 up-regulated and 979 down-regulated genes in Aseel at a threshold of log Show less

Recent studies have demonstrated the association of APP and Aβ with cancer, suggesting that BACE1 may play an important role in carcinogenesis. In the present study, we assessed BACE1's usefulness as a therapeutic target in prostate cancer (PCa). BACE1 expression was observed in human PCa tissue samples, patient-derived xenografts (PDX), human PCa xenograft tissue in nude mice, and transgenic adenocarcinoma of the mouse prostate (TRAMP) tissues by immunohistochemistry (IHC) analysis. Additionally, the downstream product of BACE1 activity, i.e., Aβ1-42 expression, was also observed in these PCa tissues by IHC as well as by PET imaging in TRAMP mice. Furthermore, BACE1 gene expression and activity was confirmed in several established PCa cell lines (LNCaP, C4-2B-enzalutamide sensitive [S], C4-2B-enzalutamide resistant [R], 22Rv1-S, 22Rv1-R, PC3, DU145, and TRAMP-C1) by real-time PCR and fluorometric assay, respectively. Treatment with a pharmacological inhibitor of BACE1 (MK-8931) strongly reduced the proliferation of PCa cells in in vitro and in vivo models, analyzed by multiple assays (MTT, clonogenic, and trypan blue exclusion assays and IHC). Cell cycle analyses revealed an increase in the sub-G1 population and a significant modulation in other cell cycle stages (G1/S/G2/M) following MK-8931 treatment. Most importantly, in vivo administration of MK-8931 intraperitoneal (30 mg/kg) strongly inhibited TRAMP-C1 allograft growth in immunocompetent C57BL/6 mice (approximately 81% decrease, Show less

The risk of neurodegeneration was found to be increased among people with type 2 diabetes mellitus (T2DM). Brain disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and others are considered neurodegenerative diseases and can be characterized by progressive loss of neurons. The deficiency of insulin, impaired signaling, and its resistance lead to alteration in the neuronal functioning of the brain. Insulin degrading enzyme (IDE) plays a significant role in the amyloid β metabolism, aggregation, and deposition of misfolded proteins in the brain's hippocampal and cortical neuronal regions. The insulin signaling via IP3 activation upregulates the IDE and could be a promising approach to regulate neurodegeneration. The repurposing of existing antidiabetic drugs such as Metformin, DPP-4 inhibitors, thiazolidinediones, glucagon-like peptides (GLP-1), sodium-glucose co-transport-2 (SGCT-2) inhibitors, and insulin could be an alternative and effective strategy to treat neurodegeneration via modulating insulin signaling, insulin resistance, IDE activity, oxidative stress, mitochondrial dysfunction, serum lipid profile and neuroinflammation in the brain. Antidiabetic medications reduce the risk of neuroinflammation, oxidative stress, and Aβ deposition by enhancing their clearance rate. The downregulation of IDE alters the degradation of Aβ monomers in the Tg2576 APP mice. Also, the treatment with metformin activated the AMPK pathway and suppressed mTOR and BACE-1 protein expression in the APP/PS1-induced mice model. Thus, the primary intention of this review is to explore the link between T2DM and neurodegenerative disorders, and the possible role of various antidiabetic drugs in the management of neurodegenerative disorders. Show less

Our present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Aβ-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 µM concentration which was comparable to donepezil and also demonstrated anti-Aβ aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 µM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Aβ-phenotypic drosophila AD model and amelioration of behavioral deficits in the Aβ-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy. Show less

The naturally inspired multitarget-directed ligands (PC01-PC10 and PD01-PD26) were synthesized from piperine for the management of Alzheimer's disease (AD). The compound PD07 showed significant inhibitory activity on ChEs, BACE1, and Aβ Show less

Although over the last few decades, numerous attempts have been made to halt Alzheimer's disease (AD) progression and mitigate its symptoms, only a few have been proven beneficial. Most medications available, still only cater to the symptoms of the disease rather than fixing the cause at the root level. A novel approach involving the use of miRNAs, which work on the principle of gene silencing, is being explored by scientists. Naturally present miRNAs in the biological system help to regulate various genes than may be implicated in AD-like BACE-1 and APP. One miRNA thus, holds the power to keep a check on several genes, conferring it the ability to be used as a multi-target therapeutic. With aging and the onset of diseased pathology, dysregulation of these miRNAs is observed. This flawed miRNA expression is responsible for the unusual buildup of amyloid proteins, fibrillation of tau proteins in the brain, neuronal death and other hallmarks leading to AD. The use of miRNA mimics and miRNA inhibitors provides an attractive perspective for fixing the upregulation and downregulation of miRNAs that led to abnormal cellular activities. Furthermore, the detection of miRNAs in the CSF and serum of diseased patients might be considered an earlier biomarker for the disease. While most of the therapies designed around AD have not succeeded completely, the targeting of dysregulated miRNAs in AD patients might give a new direction to scholars to develop an effective treatment for Alzheimer's disease. Show less

Alzheimer's disease (AD), also called senile dementia, is the most common neurological disorder. Around 50 million people, mostly of advanced age, are suffering from dementia worldwide and this is expected to reach 100-130 million between 2040 and 2050. AD is characterized by impaired glutamatergic and cholinergic neurotransmission, which is associated with clinical and pathological symptoms. AD is characterized clinically by loss of cognition and memory impairment and pathologically by senile plaques formed by Amyloid β deposits or neurofibrillary tangles (NFT) consisting of aggregated tau proteins. Amyloid β deposits are responsible for glutamatergic dysfunction that develops NMDA dependent Ca Show less

BACE1 (beta-site amyloid precursor protein (APP) cleaving enzyme) is a key target for Alzheimer's disease research because it catalyses the rate-limiting step in the formation of amyloid protein (Aβ). Natural dietary flavonoids have gained a lot of interest as potential Alzheimer's therapy candidates because of their anti-amyloidogenic, antioxidative, and anti-inflammatory properties. More research is needed, however, to learn more about the specific routes through which flavonoids may have neuroprotective benefits in Alzheimer's disease. Here, we report an in silico molecular modeling study for natural compounds, particularly flavonoids, as BACE-1 inhibitors. The interactions of flavonoids with the BACE-1 catalytic core were disclosed by demonstrating the predicted docking pose of flavonoids with BACE-1. The stability of flavonoids BACE-1 complex was analyzed by molecular dynamic simulation (standard dynamic cascade). Our findings imply that these flavonoids, which have methoxy group instead of hydroxy may be promising BACE1 inhibitors that could reduce Aβ formation in Alzheimer's disease. The molecular docking study revealed that flavonoids e bind with the BACE1's wide active site along with the catalytic residues Asp32 and Asp228. Further molecular dynamic investigation revealed that the average RMSD for all complexes ranged from 2.05 to 2.32 Å, indicating that the molecules were relatively stable during MD simulation. The RMSD analyses demonstrate that the flavonoids were structurally stable during the MD simulation. The RMSF was utilised to study the time-dependent fluctuation of the complexes. The N-terminal (~2.5 Å) fluctuates less than the C-terminal (~6.5 Å). Rutin and Hesperidin were highly stable in the catalytic region as compared to other flavonoids like Rhoifolin, Hesperidin, Methylchalcone, Phlorizin and Naringin. We were able to justify the flavonoids' selectivity for BACE-1 and crossing BBB for the treatment of Alzheimer's disease by using a combination of molecular modelling tools. Show less

Alzheimer's disease (AD), a leading cause of dementia, has been a global concern. AD is associated with the involvement of the central nervous system that causes the characteristic impaired memory, cognitive deficits, and behavioral abnormalities. These abnormalities caused by AD is known to be attributed by extracellular aggregates of amyloid beta plaques and intracellular neurofibrillary tangles. Additionally, genetic factors such as abnormality in the expression of APOE, APP, BACE1, PSEN-1, and PSEN-2 play a role in the disease. As the current treatment aims to treat the symptoms and to slow the disease progression, there has been a continuous search for new nutraceutical agent or medicine to help prevent and cure AD pathology. In this quest, honey has emerged as a powerful nootropic agent. Numerous studies have demonstrated that the high flavonoids and phenolic acids content in honey exerts its antioxidant, anti-inflammatory, and neuroprotective properties. This review summarizes the effect of main flavonoid compounds found in honey on the physiological functioning of the central nervous system, and the effect of honey intake on memory and cognition in various animal model. This review provides a new insight on the potential of honey to prevent AD pathology, as well as to ameliorate the damage in the developed AD. Show less

The complex and multifaceted nature of Alzheimer's disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of Show less

Alzheimer's disease (AD) is an irreversible, progressive and very complex brain disorder. There is still uncertainty about the etiology of AD; however, a few hallmarks like an aggregation of tau proteins, amyloid-β plaques, oxidative stress, low level of choline in the brain etc., play significant roles. In the present work, we aim to evaluate the recent progress in the development of small organic molecules containing heterocycles like thiazole, pyridines, dihydropyridines, piperidines, pyrrolidines, pyrazoles, quinolines etc. as anti-Alzheimer's agents. Several databases, including SciFinder, ScienceDirect, Bentham Science, and PubMed, were searched for relevant articles and reviewed for the present work. Several research groups are actively working on these heterocycle-based compounds as potent single-target inhibitors. Most of the analogues have been evaluated for their cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibition potential. Several studies have also reported the inhibitory potential of the analogues against MAO-A, MAO-B, and BACE-1 enzymes. However, instead of targeting one enzyme or protein, more than one heterocycle ring is being joined to develop MTDLs (multi-target-directed ligands). Donepezil has become the focal point of anti-AD drug discovery projects. Several research groups have reported various donepezil-based analogues by replacing/ modifying its various ring systems like indanone, piperidine or the methylene linker. Small molecules with nitrogen-containing heterocycles have become the core of drug discovery efforts for AD. With the increasing prominence of the MTDL approach, several new ligands are being discovered as potent anti-AD agents. Show less