👤 Sanjay Tyagi

Advanced prostate cancer remains challenging, driven in part by Epidermal Growth Factor (EGF) signaling that promotes migration, invasion, and angiogenesis. We evaluated LA3IK ( The online version contains supplementary material available at 10.1038/s41598-026-41933-1. Show less

Alzheimer's disease (AD) is a progressive and complicated neurodegenerative disorder that mostly affects the elderly and is characterized by memory loss, cognitive dysfunction, accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, and cholinergic deficits. Current therapies used for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonist memantine, can only provide temporary or symptomatic relief, but they do not stop or reverse the progression of the disease. Numerous pathogenic hypotheses have been proposed to explain this mechanism; however, the amyloid cascade hypothesis remains the most widely accepted theory, as it suggests that β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays a critical role in the generation of Aβ peptides. Therefore, BACE1 may be a key therapeutic target. This review primarily focuses on the key role of BACE1 in AD pathogenesis and describes the development of its inhibitors over three generations, explaining their structure, design, and pharmacological properties. While the first generation lacked brain penetration, the second-generation improved potency but encountered clinical trial failures due to adverse effects. The third generation of these drugs was designed to achieve a balance between efficacy, selectivity, and safety. Additionally, we review the promising molecules currently under clinical investigation, highlighting both their therapeutic potential and the challenges that remain in developing effective disease-modifying therapies for AD treatment. Show less

We recently demonstrated the utility of the 'TB Concentration & Transport' kit for bio-safe, ambient-temperature transport of dried sputum samples on Trans-Filter, along with the 'TB DNA Extraction' kit for efficient DNA extraction from Trans-Filter for use in the Line Probe Assay (LPA) for diagnosing drug-resistant tuberculosis (TB). The present study aimed to develop and evaluate a new 'Quick TB DNA Extraction' kit ('Quick DNA' kit) for rapid DNA isolation from Trans-Filter samples and assess its compatibility with LPA for the detection of multidrug-resistant TB (MDR-TB). Consecutive presumptive TB/MDR-TB/XDR-TB patients (n = 1823) were screened using LED-FM and/or TBDetect microscopy at 2 Designated Microscopy Centres associated with the National Institute of Tuberculosis and Respiratory Diseases (NITRD), New Delhi. Smear-positive samples (n = 235) were processed in duplicate using the 'TB Concentration and Transport' kit. Dried sputum on bio-safe Trans-Filters was transported at ambient temperature, along with sputum samples, in a 3-layer packing in cooling conditions to NITRD Hospital (a National Reference Laboratory). DNA was extracted from Trans-Filters using 'Quick DNA' kit and the 'TB DNA Extraction' kit, and from sputum using Hain's GenoLyse® DNA Extraction kit for first-line LPA for MDR-TB detection. Quick Kit-LPA and Kit-LPA (LPA with DNA extracted from Trans-Filter using 'Quick DNA' kit and 'TB DNA Extraction' kit, respectively) showed similar sensitivity of 88.9% (95% CI: 65.3-98.6) and 88.5% (95% CI: 69.9-97.5) and specificity of 100% (95% CI: 98.2-100) and 99.5% (95% CI: 97.3-99.9) for rifampicin and isoniazid resistance detection, respectively against Direct-LPA (LPA with DNA extracted from sputum samples using GenoLyse kit). User feedback obtained from laboratory technicians corroborated that the one-step 'Quick DNA' kit procedure was rapid (5 minutes), easy to perform, seamlessly integrated with LPA testing, and was suitable as a replacement for Kit-LPA or Direct-LPA. The gap between drug-resistant TB detection and treatment initiation can be narrowed through Universal-Drug Susceptibility Testing by implementing (i) bio-safe and ambient temperature transport of sputum from primary healthcare centres to central laboratories, and (ii) by using Quick Kit-LPA over Direct-LPA in patients residing in remote areas. Show less

Metformin, a biguanide antihyperglycemic agent, prevents angiotensin II (AngII)-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient (ApoE-/-) mice. Low-density lipoprotein receptor-deficient (LDLR-/-) mice, a commonly used hypercholesterolemic model, closely mimics the lipoprotein distribution in humans. In addition, LDLR-/- mice exhibit characteristics of glucose metabolism that are distinct from ApoE-/- mice. However, it remains unknown whether metformin suppresses AngII-induced aortic aneurysm formation in LDLR-/- mice. Male LDLR-/- mice at 9 weeks of age were administered either vehicle or metformin in drinking water and fed a Western diet. Subsequently, AngII was infused into mice for 4 weeks. Mass spectrometry analysis determined plasma metformin concentrations in mice administered the drug. Metformin administration resulted in lower body weight compared to the vehicle group, indicating effective metformin administration. However, ex vivo measurements demonstrated that metformin failed to prevent AngII-induced ascending aortic dilatations, and did not reduce aortic diameters in the suprarenal abdominal region. In conclusion, metformin did not attenuate AngII-induced aortic aneurysm formation in either the ascending or suprarenal abdominal region of LDLR-/- mice. The online version contains supplementary material available at 10.1038/s41598-025-33367-y. Show less

Recent development of immune checkpoint inhibitors has revolutionized cancer immunotherapy. Although these drugs show dramatic effects on a subset of cancer patients, many other tumors are non-responsive and the pathological mechanism of the resistance is largely unknown. To identify genes underlying anti-PD-1 immunotherapy resistance using a systematic approach, we performed an in vivo genome wide CRISPR screening in lung cancer cells. We integrated our results with multi-omics clinical data and performed both in vitro and in vivo assays to evaluate the role of the top candidate in regulating cytotoxic T cell killing. We identified TUBB3 as a potential target to overcome the resistance and enhance the efficacy of anti-PD-1 immunotherapy. TUBB3 expression is upregulated in lung cancer patients, and its higher expression correlates with poorer patients' survival. We found that TUBB3 expression was significantly elevated in the non-responders compared to responders in our patient cohort that received immunotherapies. Importantly, the results of our preclinical experiments showed that inhibition of TUBB3 with a small molecule inhibitor synergized with anti-PD-1 treatment and enhanced tumor cell killing by cytotoxic T cells. Consistently, anti-PD-1 resistant cells showed significantly higher expression of TUBB3; however, TUBB3 inhibition rendered the resistant cells more susceptible to T cell killing. Mechanistic studies revealed that blocking TUBB3 suppressed the expression of PD-L1 through the EMT-related SNAI1 gene. Our results provide a rationale for a novel combination therapy consisting of the TUBB3 inhibition and anti-PD-1 immunotherapy for lung cancer. Show less

Atherosclerosis is a chronic condition characterized by impaired lipid homeostasis and chronic inflammatory pathology in large and mid-sized arteries. Myocardial infarction is caused by coronary artery thrombosis in a ruptured or unstable atherosclerotic plaque. Despite the emphasis on known triggering factors, such as hypertension and dyslipidemia, adverse events following MI, such as recurrence and mortality, are still high. Therefore, it is imperative to assess potential determinants of plaque instability. We evaluated markers of inflammation, extracellular matrix (ECM) remodeling, thrombosis, and lipids in first-time and recurrent MI (RMI). Two hundred patients diagnosed with MI within the first 24 h of the event were included in the study and categorized as first-time or recurrent MI. Serum levels of NF-κB, hs-CRP, TNF-α, IFN γ, IL-6, VCAM-1,MMP-9, stromelysin, TIMP-1, MCP-1, PAPP-A, vWF, D-dimer, PLA2, PON-1, Apo-B, Apo-A1, ox-LDL, and anti-oxidized LDL antibodies were analyzed by ELISA. We performed a multivariate logistic regression analysis for risk stratification. The mean age of first-time MI patients was 52.4 ± 25 years and that of recurrent MI patients was 55.9 ± 24.6 years. RMI patients showed significant ( Non-lipid factors provide substantial insights into plaque instability. Multiple markers of inflammation, thrombosis, extracellular matrix remodeling, and paroxonase-1 are reliable indicators of recurrent myocardial infarction. Show less

Migration and invasion enhancer 1 (MIEN1) overexpression characterizes several cancers and facilitates cancer cell migration and invasion. Leveraging conserved immunoreceptor tyrosine-based activation motif and prenylation motifs within MIEN1, we identified potent anticancer peptides. Among them, bioactive peptides LA3IK and RP-7 induced pronounced transcriptomic and protein expression changes at sub-IC50 concentrations. The peptides effectively inhibited genes and proteins driving cancer cell migration, invasion, and epithelial-mesenchymal transition pathways, concurrently suppressing epidermal growth factor-induced nuclear factor kappa B nuclear translocation in metastatic breast cancer cells. Specifically, peptides targeted the same signal transduction pathway initiated by MIEN1. Molecular docking and CD spectra indicated the formation of MIEN1-peptide complexes. The third-positioned isoleucine in LA3IK and CVIL motif in RP-7 were crucial for inhibiting breast cancer cell migration. This is evident from the limited migration inhibition observed when MDA-MB-231 cells were treated with scrambled peptides LA3IK SCR and RP-7 SCR. Additionally, LA3IK and RP-7 effectively suppressed tumor growth in an orthotopic breast cancer model. Notably, mice tolerated high intraperitoneal (ip) peptide doses of 90 mg/Kg well, surpassing significantly lower doses of 5 mg/Kg intravenously (iv) and 30 mg/Kg intraperitoneally (ip) used in both in vivo pharmacokinetic studies and orthotopic mouse model assays. D-isomers of LA3IK and RP-7 showed enhanced anticancer activity compared to their L-isomers. D-LA3IK remained stable in mouse plasma for 24 h with 75% remaining, exhibiting superior pharmacokinetic properties over D/L-RP-7. In summary, our findings mark the first report of short peptides based on MIEN1 protein sequence capable of inhibiting cancer signaling pathways, effectively impeding cancer progression both in vitro and in vivo. Show less

Immunophenotyping by flow cytometry (FCM) is a useful diagnostic tool for the evaluation of mature B-cell neoplasms (MBN). Here, CD200 expression may play a significant role and improve the distinction between various MBNs, but any potential as a prognostic marker is yet to be established. The present prospective study was conducted on all the suspected cases of MBNs. Immunophenotyping was done using a BD FACS Canto FCM using a panel of 4 to 6 color combinations of monoclonal antibodies; CD45, CD34, CD5, CD19, CD20, CD22, CD23, CD79b, FMC7, CD10, CD38, ZAP70, CD200, IgG, IgM, CD25, CD103, CD2, CD3, CD11c as well as κ and λ light chains. CD200 expression was compared in different subgroups. Of the total of 130 cases included in the study, CD200 was positive in 118 cases (90%). CD200 was expressed in 100% of the cases of CLL(86 cases), atypical CLL(06 cases), HCL(14 cases), FL(02 cases), SMZL(04 cases), LPL (01 case), and low-grade NHL (05 cases), with the highest intensity of fluorescence in HCL followed by CLL. All the cases of MCL and PLL were exclusively negative for CD200. In conclusion, the results of the present study support inclusion of this marker in the flow cytometric panels for the differential diagnosis of MBNs. Show less

SIRT3 deacetylates mitochondrial proteins, thereby enhancing their function. We have previously demonstrated that Sirt3 gene deletion leads to brain mitochondrial dysfunction and neuroinflammation. We also reported that silencing of Sirt3 gene in APP/PS1 mice results in exacerbation of insulin resistance, neuroinflammation and β amyloid plaque deposition. To further understand how metabolic syndrome and amyloid pathology interact, we performed RNA-seq analysis of the brain samples of APP/PS1/Sirt3 Show less

Earlier investigations on biological methods of wastewater treatment have revealed that algal based wastewater treatment could be a green, cost effective and efficient approach for the removal of heavy metals. So, this study aimed to assess the potential of microalga Chlorella pyrenoidosa for remediation of heavy metals (Cr, Cu, Pb, Zn, Cd, Mn, and Ni) from varying concentration (25%, 50%, 75 and 100%) of wastewater collected from Common Effluent Treatment Plant. Heavy metals such as Cr, Cu, Pb, Zn, Cd, Mn, and Ni have been removed significantly from the wastewater, with percentage removal ranging from 73%, 60%, 75%, 66%, 87%, 83%, and 74% with 50% test solution, 57%, 59%, 70%, 56%, 72%, 66%, and 62% with 75% test solution, and 47%, 55%, 56%, 71%, 61%, 77%, and 72% with 100% test solution respectively. Studies on biochemical assay (protein, carbohydrate, and pigment) of Chlorella pyrenoidosa were also an important part of the present investigation to understand the interaction of heavy metals with algal biochemical compounds using Pearson correlation co-efficient. Biomass grown in CETP wastewater can be used for synthesis of various fruitful value-added end products like bio-diesel, pharmaceutical products, cosmetic products, bio-adsorbent etc. Show less

Association of cholesteryl ester transfer protein (CETP) Gene -629C/A Polymorphism with angiographically proven atherosclerosis CETP gene has been linked to CAD risk via its role in HDL and LDL metabolism. There is no agreement of whether CETP is atherogenic or not. Furthermore, various genotypes of CETP gene have been associated with CETP levels and thus with atherosclerosis risk. Our aim was to study the association of CETP -629C/A gene polymorphism with CETP and HDL levels and their association if any with atherosclerosis. Study population consisted of angiographically documented 50 cases with coronary artery atherosclerosis and 50 controls negative for atherosclerosis of coronary artery. Serum lipid profile was measured on SYNCHRON CX-9 using standard kits. Serum CETP levels were measured by ELISA method. CETP -629C/A gene polymorphism was studied using PCR-RFLP method. There was no significant difference in lipid profile of the two groups. However, serum CETP level was significantly higher (46.44 ± 21.75 ng/ml) in cases than controls (37.10 ± 21.92 ng/ml) with Show less

Metallophosphoesterase-domain-containing protein 2 (MPPED2) is a highly evolutionarily conserved protein with orthologs found from worms to humans. The human MPPED2 gene is found in a region of chromosome 11 that is deleted in patients with WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, and MPPED2 may function as a tumor suppressor. However, the precise cellular roles of MPPED2 are unknown, and its low phosphodiesterase activity suggests that substrate hydrolysis may not be its prime function. We present here the structures of MPPED2 and two mutants, which show that the poor activity of MPPED2 is not only a consequence of the substitution of an active-site histidine residue by glycine but also due to binding of AMP or GMP to the active site. This feature, enhanced by structural elements of the protein, allows MPPED2 to utilize the conserved phosphoprotein-phosphatase-like fold in a unique manner, ensuring that its enzymatic activity can be combined with a possible role as a scaffolding or adaptor protein. Show less