👤 Anubhav Mittal

Alzheimer's disease (AD) is the most prevalent cause of dementia, accounting for 60-80% of all cases and characterized by amyloid beta (Aβ) plaques and tau protein hyperphosphorylation. Among the signaling mechanisms implicated in AD, protein kinase C (PKC) isoforms and neuron-specific embryonic lethal abnormal vision-4 (ELAV4) have gained increasing attention due to their roles in synaptic plasticity, neuroinflammation, and mRNA stability. This review discusses the potential for targeting the PKC-ELAV4 axis to manage dementia. PKC isoforms, including PKC α, δ, and ε, are involved in amyloid-beta (Aβ) processing, tau phosphorylation, and regulation of mitochondrial activities, whereas ELAV4 stabilizes mRNAs that participate in both the degradation of Aβ (e.g., neprilysin) and the synthesis of Aβ (e.g., beta-site amyloid precursor protein cleaving enzyme 1, BACE1). We reviewed 75 papers published over the last 15 years using search terms such as neuroinflammation, synaptic plasticity, mRNA stability in dementia, ELAV, ELAV4, PKC, and PKC isoforms in databases including PubMed, WOS, and Google Scholar. Results were summarized, compared, and research gaps were identified during data collection and interpretation. ELAV4 can influence the processing of amyloid precursor protein (APP), the precursor of the amyloid-beta peptide, a hallmark of AD. Decreased expression of ELAV4 in the hippocampus is associated with dementia. PKC-δ activates c-Jun N-terminal kinase (JNK) expression, releases Beclin-1 from the Bcl2/Beclin-1 complex, and promotes autophagy. Oxidative stress and PKC η regulate the mitogenactivated protein kinase (MAPK) pathway, leading to tau phosphorylation and neuronal death. PKCε activators and ELAV4 inhibitors have positive effects on cognitive function and dementia management by inhibiting neuroinflammation and neuronal apoptosis, while PKC α, β, δ inhibitors may aid in managing different forms of dementia. This review highlights research gaps and proposes future directions for targeting the PKC-ELAV4 axis as a novel strategy in dementia management. Show less

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy that lacks reliable biomarkers to guide treatment decisions. Effective prognostic tools are needed to improve its clinical management. We conducted a comprehensive proteomic analysis on 115 PDA patient samples with matched adjacent normal tissue. A 20-protein diagnostic panel was identified (LGALS1, ANXA2, LGALS3BP, CTSD, S100P, COL12A1, SFN, THBS2, CTHRC1, THBS1, SERPINB5, LAMC2, POSTN, CEACAM6, CTSE, PLEC, PKM, S100A11, TAGLN2, ALDOA). Consensus clustering analysis identified four prognostic proteomic subtypes. Subtypes with poorer prognoses exhibited upregulation of neutrophil degranulation, extracellular matrix remodeling, focal adhesion, Mesenchymal Epithelial Transition, collagen formation, and PI3K-Akt-mTOR-related pathways, indicating a predominance of basal-like and activated stromal features. In tumors with homologous recombination deficiency or Catalogue of Somatic Mutations in Cancer Signature-3, several immune-related proteins were enriched. An 18-protein (PURB, SDCBP2, CD2BP2, GALM, SERPINA3, OAS3, FAN1, ZPR1, KRT2, NUDT2, SMNDC1, SERPINA4, CUTA, WDR36, POSTN, CLEC11A, PEX14, and PI4KA) risk score was developed and validated using multicox regression analyses with LASSO regularization. The risk score demonstrated independent prognostic significance for overall survival and recurrence, and was validated in an independent proteomic dataset generated using a different proteomic technology. This study thus introduces four novel prognostic PDA subtypes, and an 18-protein risk score validated in an independent dataset, which shows promise for improving survival prediction and could serve as a valuable tool for personalized treatment guidance. The findings from this study have significant implications for the future of pancreatic cancer management. By identifying a 20-protein panel with diagnostic and screening potential, this research provides a foundation for developing early detection tools for PDA, an aggressive cancer with limited treatment options. The classification of PDA into four proteomic subtypes with distinct prognostic outcomes paves the way for subtype-specific therapeutic approaches, allowing clinicians to better stratify patients based on their risk profiles. Additionally, the validated 18-protein risk score, which enhances survival prediction and operates independently of existing clinical variables, represents a promising tool for personalized prognostic assessments. Incorporating these proteomic-based biomarkers into clinical practice could improve diagnostic accuracy, guide individualized treatment decisions, and ultimately enhance patient outcomes in PDA. This study underscores the potential of proteomic profiling to improve cancer treatment by providing targeted, actionable insights into tumor biology. Show less

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is the leading cause of dementia in elderly individuals. Currently, there is no permanent treatment option available for this disorder, and the existing drug regimens are associated with limited effectiveness and side effects. To evaluate the neuroprotective effect of rosemary compounds, an extensive study was started with gas chromatography-mass spectrometry (GC-MS) analysis. GC-MS was performed to study the composition of rosemary essential oil and a total of 120 volatile compounds were identified. The 36 compounds from GC-MS data of rosemary essential oil having > 1% concentration in the oil were selected along with 3 already reported well-known non-volatile compounds of rosemary. se39 bioactive natural compounds of rosemary were docked against ACE, BACE1, GSK3, and TACE proteins, which are involved in AD progression. The top 3 compounds against each target protein were selected based on their binding energies and a total of 6 compounds were found as best candidates to target the AD; α Amyrin, Rosmanol, Androsta-1,4-dien-3-one,16,17-dihydroxy-(16.beta.,17.beta), Benzenesulfonamide,4-methyl-N-(5-nitro-2-pyridinyl), Methyl abietate, and Rosmarinic acid were the best compounds. The binding energy of α-Amyrin, Rosmanol, and Androsta-1,4-dien-3-one,16,17-dihydroxy-(16.beta.,17.beta) to ACE target is -10 kcal/mol, -9.3 kcal/mol, and - 9.3 kcal/mol, respectively. The best binding affinity was shown by complexes formed between GSK3-α-Amyrin (-9.1 kcal/mol), BACE1- α-Amyrin (-9.9 kcal/mol), and TACE- Benzenesulfonamide,4-methyl-N-(5-nitro-2-pyridinyl) (-9.1 kcal/mol). The comparative analysis between known inhibitors/ drugs of target proteins and the rosemary compound that shows the highest binding affinity against each protein also revealed the higher potential of rosemary natural compounds in terms of binding energy. The drug-likeliness properties like Lipinski's rule of five and the ADME/T analysis of top-selected compounds were screened through PkCSM and Deep-PK tools. The findings from this study suggested that rosemary compounds have the potential as a therapeutic lead for treating AD. This kind of experimental confirmation can lead to novel drug candidates against the pharmacological targets of AD. The online version contains supplementary material available at 10.1007/s40203-024-00238-9. Show less

The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca Show less

Numerous studies have investigated the relationship between various candidate gene polymorphisms and gallbladder stone disease (GSD) across ethnic populations; however, the results are often inconsistent. This meta-analysis aims to comprehensively evaluate the influence of common ABCG8 T400K, ABCG8 D19H, ABCG8 C54Y, ApoB100 EcoRI, ApoB100 XbaI, ApoE HhaI, CETP TaqI, CYP7A1 Bsa, LRPAP1 I/D and TNF-α A308G polymorphisms on the risk of gallbladder stone disease. 33 Full-text articles with 9250 cases and 12,029 healthy controls (total 21,279 subjects) were analyzed using the RevMan software (V5.1) and the Comprehensive Meta-analysis software (Version 2.0, BIOSTAT, Englewood, NJ) a Random-effects model was applied. Begg's funnel plots, Fail-safe number, Egger's regression intercept and Begg and Mazumdar rank correlation tests were performed for the potential publication bias and sensitivity analysis. The studies were also sub-grouped into European and non-European groups to find out role of ethnicity, if any, on GSD risk. Studies included in quantitative synthesis were ABCG8 T400K rs4148217 (cases/controls, n = 671/1416) (4 studies), ABCG8 D19H rs11887534 (n = 1633/2306) (8 studies), ABCG8 C54Y rs4148211 (n = 445/1194) (3 studies), ApoB100 EcoRI rs1042031 (n = 503/390) (4 studies), ApoB100 XbaI rs693 (n = 1214/1389) (9 studies), ApoE HhaI rs429358 (n = 1335/1482) (12 studies), CETP TaqI rs708272 (n = 1038/1025) (5 studies), CYP7A1 Bsa rs3808607 (n = 565/514) (3 studies), LRPAP1 I/D rs11267919 (n = 849/900) (3 studies), TNF-α A308G rs1800629 (n = 997/1413) (3 studies). The combined results displayed significant association of ABCG8 D19H (GC + CC) [OR with 95%CI = 2.2(1.7-2.8); Show less

We have previously shown that the zinc finger transcription repressor SNAI2 (SLUG) represses tumor suppressor BRCA2-expression in non-dividing cells by binding to the E2-box upstream of the transcription start site. However, it is unclear how proliferating breast cancer (BC) cells that has higher oxidation state, overcome this repression. In this study, we provide insight into the mechanism of de-silencing of BRCA2 gene expression by PRDX5A, which is the longest member of the peroxiredoxin5 family, in proliferating breast cancer cells. We used cell synchronization and DNA affinity pulldown to analyze PRDX5A binding to the BRCA2 silencer. We used oxidative stress and microRNA (miRNA) treatments to study nuclear localization of PRDX5A and its impact on BRCA2-expression. We validated our findings using mutational, reporter assay, and immunofluorescence analyses. Under oxidative stress, proliferating BC cells express PRDX5 isoform A (PRDX5A). In the nucleus, PRDX5A binds to the BRCA2 silencer near the E2-box, displacing SLUG and enhancing BRCA2-expression. Nuclear PRDX5A is translated from the second AUG codon in frame to the first AUG codon in the PRDX5A transcript that retains all exons. Mutation of the first AUG increases nuclear localization of PRDX5A in MDA-MB-231 cells, but mutation of the second AUG decreases it. Increased mitronic hsa-miRNA-6855-3p levels under oxidative stress renders translation from the second AUG preferable. Mutational analysis using reporter assay uncovered a miR-6855-3p binding site between the first and second AUG codon in the PRDX5A transcript. miR-6855-3p mimic increases accumulation of nuclear PRDX5A and inhibits reporter gene translation. Oxidative stress increases miR-6855-3p expression and binding to the inter-AUG sequence of the PRDX5A transcript, promoting translation of nuclear PRDX5A. Nuclear PRDX5A relieves SLUG-mediated BRCA2 silencing, resulting in increased BRCA2-expression. Show less

Mutations in sarcomeric genes are common genetic cause of cardiomyopathies. An intronic 25-bp deletion in cardiac myosin binding protein C (MYBPC3) at 3' region is associated with dilated and hypertrophic cardiomyopathies in Southeast Asia. However, the frequency of sarcomeric gene polymorphisms and associated clinical presentation have not been established with left ventricular dysfunction (LVD). Therefore, the aim of the present study was to explore the association of MYBPC3 25-bp deletion, titin (TTN) 18 bp I/D, troponin T type 2 (TNNT2) 5 bp I/D and myospryn K2906N polymorphisms with LVD. This study includes 988 consecutive patients with angiographically confirmed coronary artery disease (CAD) and 300 healthy controls. Among the 988 CAD patients, 253 with reduced left ventricle ejection fraction (LVEF≤45%) were categorized as LVD. MYBPC3 25-bp deletion, TTN 18 bp I/D and TNNT2 5 bp I/D polymorphisms were determined by direct polymerase chain reaction method, while myospryn K2906N polymorphism by TaqMan assay. Our results showed that MYBPC3 25-bp deletion polymorphism was significantly associated with elevated risk of LVD (LVEF <45) (healthy controls versus LVD: OR=3.85, P <0.001; and nonLVD versus LVD: OR=1.65, P = 0.035), while TTN 18 bp I/D, TNNT2 5 bp I/D and myospryn K2906N polymorphisms did not show any significant association with LVD. The results also showed that MYBPC3 25-bp deletion polymorphism was significantly associated with other parameters of LV remodelling, i.e. LV dimensions (LV end diastole dimension, LVEDD: P = 0.037 and LV end systolic dimension, LVESD: P = 0.032). Our data suggests that MYBPC3 25-bp deletion may play significant role in conferring LVD as well as CAD risk in north Indian population. Show less

Gallbladder cancer (GBC) is a violent neoplasm associated with late diagnosis, unsatisfactory treatment, and poor prognosis. The disease shows complex interplay between multiple genetic variants. We analyzed 15 polymorphisms in nine genes involved in various pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were matrix metalloproteinases (MMP-2, MMP-7, and MMP-9), tissue inhibitor of metalloproteinases (TIMP-2), cytochrome P450 (CYP)1A1, CYP1B1, phospholipase C epsilon 1 (PLCE1), liver X receptor (LXR)-alpha, and LXR-beta. Genotypes were determined by PCR-RFLP and TaqMan probes. Statistical analysis was done by SPSS version 16. Multilocus analysis was performed by Classification and Regression Tree (CART) analysis and multifactor dimensionality reduction (MDR) to gene-gene interactions in modifying GBC risk. In silico analysis was done using various bioinformatics tools (F-SNP, FAST-SNP). Single locus analysis showed association of MMP-2 (-735 C > T, -1306 C > T), MMP-7 - 181 A > G, MMP-9 (P574R, R668Q), TIMP-2 - 418 G > C, CYP1A1-MspI, CYP1A1-Ile462Val, PLCE1 (rs2274223 A > G, rs7922612 T > C) and LXR-beta T > C (rs3546355 G > A, rs2695121 T > C) polymorphisms with GBC risk (p < 0.05) whereas CYP1B1 and LXR-α variants were not associated with GBC risk. Multidimensional reduction analysis revealed LXR-β (rs3546355 G > A, rs2695121 T > C), MMP-2 (-1306 C > T), MMP-9 (R668Q), and PLCE1 rs2274223 A > G to be key players in GBC causation (p < 0.001, CVC = 7/10). The results were further supported by independent CART analysis (p < 0.001). In silico analysis of associated variants suggested change in splicing or transcriptional regulation. Interactome and STRING analysis showed network of associated genes. The study found PLCE1 and LXR-β network interactions as important contributory factors for genetic predisposition in gallbladder cancer. Show less

Liver X receptors (LXRs) α and β are ligand-activated transcription factors belonging to the family of nuclear receptors. LXRs play role in control of lipid homeostasis, glucose metabolism, inflammation, and proliferation. LXRs are expressed in gallbladder cholangiocytes and recent studies have shown that LXR-β (-/-) Mice exhibit an estrogen-dependent gallbladder carcinogenesis. However, there are no studies reported in humans. Therefore, using case-control design in the present study, we have evaluated the associations of LXR-α (rs7120118) and LXR-β (rs35463555 and rs2695121) genetic variants with gallbladder cancer (GBC) susceptibility in 400 cases and 200 controls. Genotypes were determined by TaqMan probes. Statistical analysis was done by SPSS and SNPstats. In silico analysis was performed using Bioinformatics tools (F-SNP, FAST-SNP). LXR-β genotypes (rs35463555) [GA + AA] and (rs2695121) [TC + CC] were associated with risk of GBC [OR = 1.46, p = 0.03; OR = 1.52, p = 0.01, respectively] as compared to healthy controls whereas LXR-α (rs7120118) was not associated with GBC risk. LXR-β haplotype [Ars35463555-Crs2695121] showed statistical significant association with GBC [OR = 5.0, p = 0.03]. On stratification based on gender, LXR-β [GA + AA] and [TC + CC] genotypes were found to be significantly associated in females GBC patients [OR = 1.5, p = 0.04; OR = 1.7, p = 0.005, respectively]. The LXR-β [TC + CC] associated with GBC patients with gallstones [OR; 1.8, p = 0.002]. The genetic risk by LXR-β was not modulated by tobacco consumption or age of onset. In silico analysis using FAST-SNP showed "Low-medium risk" by LXR-β (rs2695121) T > C variation. Our results suggest that LXR-β polymorphisms influence gallbladder cancer susceptibility through estrogen and gallstone-dependent pathways. Show less

Mutations in MYBPC3 encoding cardiac myosin binding protein C are common genetic cause of hereditary cardiac myopathies. An intronic 25-bp deletion in MYBPC3 at 3' region is associated with dilated (DCM) and hypertrophic (HCM) cardiomyopathies in Southeast Asia. However, the frequency of MYBPC3 25 bp deletion and associated clinical presentation has not been established in an unrelated cohort of left ventricular dysfunction (LVD) secondary to coronary artery disease (CAD) patients. We sought to determine the role of MYBPC3 25 bp polymorphism on LVD in two cohorts of CAD patients. The study included 265 consecutive patients with angiographically confirmed CAD and 220 controls. MYBPC3 25 bp polymorphism was determined by polymerase chain reaction. Our results showed that carrier status of MYBPC3 25 bp deletion was associated with significant compromised left ventricle ejection fraction (LVEF ≤45) in CAD patients (p value  =  <0.001; OR = 4.49). To validate our results, we performed a replication study in additional 140 cases with similar clinical characteristics and results again confirmed consistent findings (p = 0.029; OR = 3.3). Also, presence of the gene deletion did not have significant association in CAD patients with preserved ejection fraction (LVEF>45) (p value  = 0.1; OR  = 2.3). The frequency of MYBPC3 DW genotype and D allele was associated with compromised LVEF implying that genetic variants of MYBPC3 encoding mutant structural sarcomere protein could increase susceptibility to left ventricular dysfunction. Therefore, 25 bp deletion in MYBPC3 may represent a genetic marker for cardiac failure in CAD patients from Southeast Asia. Show less

Genetic polymorphisms in apolipoprotein genes may be associated with alteration in lipid profile and susceptibility to gallstone disease. To determine the association between apolipoprotein A1 (APOA1) -75 guanine [G] to adenine [A] and +83/84 M2(+/-), MspI) and apolipoprotein C3 (APOC3) (SstI) polymorphisms with gallstone disease. MspI polymorphisms of the APOA1 gene and SstI polymorphisms of APOC3 were analyzed in DNA samples of 214 gallstone patients and 322 age- and sex-matched healthy controls. All statistical analyses were performed using SPSS version 11.5 (SPSS, USA) and Arlequin version 2.0 (Arlequin, Switzerland). The APOA1 -75 G/A polymorphism was significantly associated with gallstone disease. Patients with the GG genotype (P=0.015) and G allele carriers (P=0.004) had a significantly higher risk of gallstone disease (1.087-fold and 1.561-fold, respectively), whereas patients with AA genotypes (P=0.011) and A allele carriers (P=0.004) were protected (OR 0.230 and 0.641, respectively) against gallstone disease. APOA1 +83 M2(+/-) and APOC3 SstI polymorphisms were not associated with gallstone disease. Case-control analysis of haplotypes showed a significant association in males only. G-M2(+)-S1 conferred risk for gallstone disease (P=0.036; OR 1.593, 95% CI 1.029 to 2.464), while A-M2(+)-S1 was protective (P=0.002; OR 0.370, 95% CI 0.197 to 0.695) against gallstone disease. In APOA1(-75)-APOA1(+83) bilocus haplotypes, G-M2(+) was associated (P=0.0001) with very high risk (OR 3.173, 95% CI 1.774 to 5.674) for gallstone disease in males only. APOA1(-75)-APOC3(SstI) haplotypes also showed significant association while APOA1(+83)-APOC3(SstI) haplotypes showed no association with gallstone disease. The APOA1 -75 G/A polymorphism is associated with gallstone disease and shows sex-specific differences. On the other hand, APOA1 M2(+/-) and APOC3 SstI polymorphisms may not be associated with gallstone disease. Haplotype analysis is a better predictor of risk for gallstone disease. Show less

DNA microarrays of promoter sequences have been developed in order to identify the profile of genes bound and activated by DNA regulatory proteins such as the transcription factors c-Jun and ATF2 as well as DNA-modifying methylases. The arrays contain 3083 unique human promoter sequences from +500 to -1000 nts from the transcription start site. Cisplatin-induced DNA damage rapidly leads to specific activation of the Jun kinase pathway leading to increased phosphorylation of c-Jun and ATF2-DNA complexes at hundreds of sites within 3 hours. Using three statistical criteria, approximately 269 most commonly phosphorylated c-Jun/ATF2-DNA complexes were identified and representative cases were verified by qPCR measurement of ChIP-captured DNA. Expression was correlated at the mRNA and protein levels. The largest functional cohort was 24 genes of known DNA repair function, most of which exhibited increased protein expression indicated coordinate gene regulation. In addition, cell lines of prostate cancer exhibit stable methylation or copy number changes that reflect the alterations of the corresponding primary tumors. 504 (18.5%) promoters showed differential hybridization between immortalized control prostate epithelial and cancer cell lines. Among candidate hypermethylated genes in cancer-derived lines, eight had previously been observed in prostate cancer, and 13 were previously determined methylation targets in other cancers. The vast majority of genes that appear to be both differentially methylated and differentially regulated between prostate epithelial and cancer cell lines are novel methylation targets, including PAK6, RAD50, TLX3, PIR51, MAP2K5, INSR, FBN1, GG2-1, representing a rich new source of candidate genes to study the role of DNA methylation in prostate tumors. Earlier studies using prototype promoter arrays examine approximately 7% of the proximal regulatory sequences while the current gene regulatory events surveyed here occur on a large scale and may rapidly effect the coordinated expression of a large number of genes. Show less