Mass Spectrometry Advancements and Applications for Biomarker Discovery, Diagnostic Innovations, and Personalized Medicine

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(18), С. 9880 - 9880

Опубликована: Сен. 12, 2024

Mass spectrometry (MS) has revolutionized clinical chemistry, offering unparalleled capabilities for biomolecule analysis. This review explores the growing significance of mass (MS), particularly when coupled with liquid chromatography (LC), in identifying disease biomarkers and quantifying biomolecules diagnostic prognostic purposes. The unique advantages MS accurately diverse molecules have positioned it as a cornerstone personalized-medicine advancement. MS-based technologies transformed precision medicine, enabling comprehensive understanding mechanisms patient-specific treatment responses. LC-MS shown exceptional utility analyzing complex biological matrices, while high-resolution expanded analytical capabilities, allowing detection low-abundance elucidation pathways. integration other techniques, such ion mobility spectrometry, opened new avenues biomarker discovery validation. As we progress toward will be crucial addressing challenges individualized patient care, driving innovations diagnosis, prognosis, strategies.

Язык: Английский

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Nobiletin regulates intracellular Ca2+ levels via IP3R and ameliorates neuroinflammation in Aβ42-induced astrocytes

Redox Biology, Год журнала: 2024, Номер 73, С. 103197 - 103197

Опубликована: Май 16, 2024

Astrocytes are the major glial cells in human brain and provide crucial metabolic trophic support to neurons. The amyloid-β peptide (Aβ) alter morphological functional properties of astrocytes induce inflammation calcium dysregulation, contributing Alzheimer's disease (AD) pathology. Recent studies highlight role Toll-like receptor (TLR) 4/nuclear factor kappa-light-chain-enhancer activated B (NF-κB) signaling inflammation. Reactive oxygen species (ROS) generated due Aβ, apoptosis worsening AD progression. Astrocytic cell surface receptors, such as purinergic receptors (P2Y1 P2Y2), metabotropic glutamate (mGLUR)5, α7 nicotinic acetylcholine (α7nAChR), N-methyl-d-aspartate (NMDARs), have been suggested interact with inositol trisphosphate (IP3R) on endoplasmic reticulum (ER) Ca2+ movement from ER cytoplasm, causing dysregulation. We found that citrus flavonoid nobiletin (NOB) protected primary Aβ42-induced cytotoxicity inhibited TLR4/NF-κB rat astrocytes. NOB was regulate ROS levels through Keap1-Nrf2 pathway. P2Y1, P2Y2, mGLUR5, α7nAChR, NMDARs induced intracellular by activating IP3R regulated them, thereby regulating levels. Molecular docking analysis revealed a possible interaction between regulation. Furthermore, RNA sequencing various NOB-mediated biological pathways, AD-presenilin, AD-amyloid secretase, Wnt pathway, suggesting neuroprotective roles NOB. To conclude, is promising therapeutic agent for works modulating pathology at

Язык: Английский

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FLIM-Phasor Analysis (FLIM-ϕ) of Aβ-Induced Membrane Order Alterations: Towards a Cell-Based Biosensor for Early Alzheimer’s Disease Diagnosis

Micromachines, Год журнала: 2025, Номер 16(2), С. 234 - 234

Опубликована: Фев. 19, 2025

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and its early detection can be critical for prompt intervention that potentially slow down the progression improve patient's quality of life. However, diagnosis based solely on clinical symptoms challenging, especially in stages, while specific biomarkers such as amyloid-β peptide (Aβ) tau proteins provide objective evidence diagnosis. In this work, we explored effects Aβ cell membrane properties thanks to fluorescence lifetime imaging (FLIM) combined with phasor analysis (FLIM-ϕ). The results showed viscosity altered by presence cells experience effect even at nanomolar concentrations peptide. This considerable sensitivity opens up possibility envisioning cell-based biosensor able detect very low biological fluid, thus enabling timely intervention.

Язык: Английский

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Calcium modulating ligand confers risk for Parkinson's disease and impacts lysosomes

Annals of Clinical and Translational Neurology, Год журнала: 2025, Номер unknown

Опубликована: Март 7, 2025

Several genetic loci known to confer risk for Parkinson's disease (PD) function in lysosomal pathways. We systematically screened common variants linked PD by genome-wide association studies (GWAS) impact on cerebrospinal fluid (CSF) proteins reflecting function. Starting with 525 candidate gene-single nucleotide polymorphism (SNPs) pairs nominated Mendelian randomization from published GWAS, we filtered SNPs downstream evaluation, based strength of and brain gene expression. genotyped top 173 participants, adding three capturing variation at the TMEM106B, CTSB, RAB29 loci, encoding genes In same individuals, measured 15 CSF (nine six other implicated neurodegeneration) parallel reaction monitoring mass spectrometry. tested proteins. For our SNP associating multiple proteins, characterized expression its target CAMLG human tissue. Sixteen emerged analysis GWAS-nominated loci. Genotypes rs12657663 (CAMLG) associated levels markers (cathepsin F, cathepsin L, hexosaminidase B, tripeptidyl peptidase I) genotypes rs7910668 (ITGA8) B. The protein encoded CAMLG, calcium modulating ligand (CAML), is highly expressed neurons regions, higher Lewy body cases. Systematic nominates as a neuronally effects lysosomes.

Язык: Английский

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Promising clinical tools for specific Alzheimer disease diagnosis from plasma pTau217 and ApoE genotype in a cognitive disorder unit

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Май 10, 2025

Alzheimer's disease (AD) diagnosis relies on cerebrospinal fluid (CSF) biomarkers or amyloid PET. Alternatives for AD from blood samples are needed to develop a fully-automated early-diagnosis approach, potentially implemented in cognitive disorder unit. Plasma p-Tau217 was determined patients diagnosed with (n = 134) non-AD 132), CSF (Aβ42/Aβ40). A logistic regression model developed. The predictive performance assessed using training set (70% of data) and internally validated test (30% 1000 iterations. nomogram double cut-off strategy were proposed visualize the results, stratify (AD, non-AD, uncertain), respectively. (plasma p-Tau217, ApoE, age) showed satisfactory (AUC 0.94, sensitivity 0.85, specificity 0.89); so, together corresponding nomogram, it could be applied specialized clinical contexts. including only plasma 0.93, 0.72, 0.96) would useful approach less clinics. two-cut-off first as probability (< 0.41 > 0.57 AD). This study provided tools (nomogram, cut-off) identifying Aβ positivity at unit, which lead reduce analysis.

Язык: Английский

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Clinical Proteomics: A Promise Becoming Reality

Molecular & Cellular Proteomics, Год журнала: 2024, Номер 23(2), С. 100688 - 100688

Опубликована: Янв. 27, 2024

Methods to Discover and Validate Biofluid-Based Biomarkers in Neurodegenerative DementiasMolecular & Cellular ProteomicsVol. 22Issue 10PreviewIn Brief We review technologies used for body fluid protein biomarker discovery translation clinical practice. address their main characteristics, use research clinics, strengths limitations, a future perspective. Full-Text PDF Open AccessThe First Pituitary Proteome Landscape From Matched Anterior Posterior Lobes Better Understanding of the GlandMolecular 1PreviewIn Our study first pituitary proteome draft offers following novelty; time, we present an extensive proteomic database containing proteins from both anterior posterior lobes healthy pituitary, identifying various pituitary-enriched lobe specificities, followed by target verification hormones; are describing three uPE1 have demonstrated that S100 proteins, which known markers adenomas, showed presence significantly lobe. AccessSARS-CoV-2 Variants Show Different Host Cell Profiles With Delayed Immune Response Activation Omicron-Infected CellsMolecular 5PreviewIn SARS-CoV-2 has mutated over past years numerous variants concern (VOCs). Employing quantitative whole-cell proteomics, elucidate host cell immune responses upon infection with ancestral B.1, VOCs Delta, Omicron BA.1 strains. Molecular assays further illustrate reduced viral levels delayed pathway response when compared B.1 Delta. Overall, this insights into profiles distinct kinetics AccessProteomic Characterization Acute Myeloid Leukemia Precision MedicineMolecular 4PreviewIn Proteomic genomic studies identified new drug targets acute myeloid leukemia (AML), leading therapeutic options certain patient subpopulations. In addition, many other drugs advanced stages development proteomics keeps uncovering interest. Given large number therapies likely be available AML near future, identification signatures each will key select best treatment given patient. AccessSensitive, High-Throughput HLA-I HLA-II Immunopeptidomics Using Parallel Accumulation-Serial Fragmentation Mass SpectrometryMolecular 6PreviewIn In-depth mass spectrometry–based profiling human leukocyte antigen (HLA) peptides currently requires amounts sample, off-line fractionation is frequently improve coverage. However, primary tissues often input limited therefore not amenable such workflows. Here, developed optimized single-shot acquisition strategy on timsTOF single-cell sensitive high-throughput immunopeptidome analysis. demonstrate >2-fold increase identfied propose multiple collision energy slopes samples different peptide-binding motifs. AccessProspective Imaging Spectrometry Clinical DiagnosticsMolecular 9PreviewIn spectrometry emerging technology applications it provides spatial molecular data within tissue biopsy diagnoses prognoses. This article considers aspects imaging-based include analyte selection, quality control/assurance metrics, reproducibility, classification, scoring. AccessCross-Linking Uncovers Interactions Between High-Density Lipoproteins Spike GlycoproteinMolecular 8PreviewIn Here utilized cross-linking (XL-MS) investigate circulating interaction networks context SARS-CoV-2. The spike glycoprotein was determined interact high-density lipoprotein including ApoD. between ApoD confirmed cells through affinity purification-MS. XL-MS recombinant ApoD, coupled structural modeling, receptor-binding domain. overexpression cultured lines did influence replication or infection. AccessUncovering Protein Networks Cardiovascular ProteomicsMolecular article, critically assess existing methods reconstructing discuss method preferred cardiovascular research. necessity reconstruct separately type disease entity provide illustrative examples importance taking consideration relevant post-translational modifications. Finally, how findings could interpreted using RNA-sequencing data. AccessFunctional Impact Protein–RNA Variation Cancer AnalysesMolecular 7PreviewIn Proteogenomic cancer highlight broad protein–RNA discrepancies. Tumor Analysis Consortium (CPTAC) mRNA eight indications, show impact low RNA–protein correlations biological processes, signaling pathways, targets. lead suggesting protein-based subtyping may unravel features seen RNA measurements. These analyses critical role phenotypic tumor characterization. AccessMass Spectrometry–Based Proteomics Epithelial Ovarian Cancers: A PerspectiveMolecular systematically reviewed MS-based epithelial ovarian cancer, 2000 trials since 1990. None been adopted clinic, none firstly discovered phase 3 4. Stringent standards design required, more in-depth dysregulated essential. AccessClinical Solid Organ TissuesMolecular 11PreviewIn For years, immunohistochemistry tool pathology localization quantification solid tissues, but poorly standardized suffers practical limitations. field ripe novel complementary help diagnosis. perspective focuses issues hampering highlights liquid chromatography-tandem particular well-positioned complement testing. also where guidance needed ensure rigor environments. AccessIntegrated Understand Role Neuritin (NRN1) as Mediator Cognitive Resilience Alzheimer's DiseaseMolecular Mechanisms individuals (AD) avoid dementia well known. employed multiplex tandem tag (TMT-MS)–based identify linked cognitive resilience AD. Computational strategies NRN1 synaptic associated resilience. models AD, can facilitate dendritic spine against amyloid-β (Aβ) block Aβ-induced neuronal hyperexcitability. assessed alters TMT-MS, revealed overlapping synapse-related biology humans. Exploration Pancreatic CancerMolecular extremely lethal options. Identifying effective early-detection biomarkers urgently needed. review, describe recent advances functional pancreatic cancer. Regarding modifications–mediated intracellular signaling, ligands plasma membrane receptors–mediated intercellular signaling. terms bulk diagnostic studying heterogeneity. AccessMulti-Omics Profiling HealthMolecular Current medical care treating people after they become patients rather than preventing illness, high costs chronic late-stage diseases. Additionally, "one-size-fits all" approach healthcare does take account individual differences genetics, environment, lifestyle factors, decreasing benefiting interventions. Rapid multi-omics enabled deep phenotyping, empowers precision health approaches poised transform healthcare. AccessTen Years Extracellular Matrix Proteomics: Accomplishments, Challenges, Future PerspectivesMolecular extracellular matrix (ECM) complex assembly hundreds forming architectural organizer multicellular organisms. Over decade, bottom-up choice profile composition ECM. reviews state art ECM illustrates emerged powerful pipeline biomarkers. introduces resources proteomics. AccessUltrasensitive Detection Technologies Vesicle MeasurementsMolecular To harness full potential vesicles (EVs) applications, necessary find appropriate enable selective isolation rare subpopulations EVs. Many conventional detection sensitivity detect abundance EVs, limiting EV perspective, current ultrasensitive technologies, areas growth future. Glyco(proteo)mics increasingly mature toolbox glycomic- glycoproteomic applied biopharmaceuticals evaluation glycobiomarkers fields. glycoproteomics, parallel made earlier proposed tiers spectrometry. Multimarker readouts foreseen longitudinal sampling monitoring glycomic diagnosis monitoring. accurate multimarker panel discussed. AccessProteome Mapping Human Islet Microenvironment Reveals Endocrine–Exocrine Signaling Sphere InfluenceMolecular our Microdroplet Processing One pot Trace Samples (microPOTS) TMT platform islet microenvironment pancreas. were able quantify 6000 seven regions same enhancements computational extract hypotheses first-of-its-kind dataset. addition recapitulating functions islet, specific processing activities heterogeneity expression. AccessPlasma Kinetics ExerciseMolecular After measuring 4163 before, during, 1-h treadmill exercise 75 middle-aged adults, found 765 changed at peak exercise, majority these returned baseline after. Of 56 sustained change rest, there enrichment secreted association cardiometabolic traits independent cohort, promising candidates investigation. AccessDissecting Detergent-Insoluble Disease TMTc-Corrected Quantitative TMT-LC/LC–MS/MS TMTc-based correct ratio compression, analyzed detergent-insoluble 30 AD control brain samples. 84 enriched fraction, accumulated mostly low-complexity regions. pathological hallmarks resistant detergent extraction, providing list pathways exclusively proteome. AccessMS-Based Body Fluids: End BeginningMolecular its nature suited routine measurement held back technological conceptual constraints. improvements throughput, streamlining, robustness, progressively overcoming constraints recently success stories. Cutting-edge scan modes, multiplexing, sample preparation promise enhance technology, envision finally bring clinic. AccessAn Inflection Point Biomarkers: What What's NextMolecular highest value proposition medicine today. Despite progress sciences evolving regulatory frameworks biomarkers, about improving health. Achieving necessitates moving away reductionist thinking diseases adaptive systems defining representations system states. redefining communication, ultimately prove game changing who benefit. Atlas Knee Joint Proteins Their Osteoarthritis Defined Literature MiningMolecular Information gathered analysis knee joint essential management osteoarthritis, most prevalent rheumatic pathology. Pursuing one goals Project, systematic based literature mining define atlas organ, prioritization cited representative tissues. Pathway depicted processes contributing OA pathophysiology. AccessProteomics: Progress Promise Chronic Kidney Population genetics leverage large-scale accuracy tools kidney disease. Access "Clinical proteomics" understood encompass spectrum activity pre-clinical diagnostics: clinically materials; addressing question need; (MS)-based proteomics-derived tests reference laboratory informing decision-making. widely explore basis disease, targetable intervention, predict outcome response, probe resistance mechanisms. special issue presents wide range research, reviews, perspectives pertaining expanding scope reflected foci represented, neurodegenerative (1Teunissen C.E. Kimble L. Bayoumy S. Bolsewig K. Burtscher F. Coppens et al.MIRIADE consortium. discover validate biofluid-based dementias.Mol. Proteomics. 2023; 22100629Abstract Full Text Scopus (3) Google Scholar, 2Gobom J. Brinkmalm A. G. Blennow Zetterberg H. targeted spectrometry.Mol. 2024; 23 (100721)Google 3Hurst C. Pugh D.A. Abreha M.H. Duong D.M. Dammer E.B. Bennett al.Integrated understand neuritin mediator disease.Mol. 22100542Abstract (2) 4Zaman M. Fu Y. Chen P.C. Sun Yang Wu Z. al.Dissecting TMTc-corrected 22100608Abstract Scholar), infectious (5Burnap S.A. Ortega-Prieto A.M. Jimenez-Guardeño J.M. Ali Takov Fish al.Cross-linking uncovers interactions lipoproteins glycoprotein.Mol. 22100600Abstract (0) 6Metzler Tharyan R.G. Klann Grikscheit Bojkova D. Cinatl al.SARS-CoV-2 activation omicron-infected cells.Mol. 22100537Abstract (1) endocrinology (7Banerjee Biswas Barpanda Halder Sibal Kattimani R. al.The landscape matched better understanding gland.Mol. 22100478Abstract PubMed 8Gosline S.J.C. Veličković Pino J.C. Day L.Z. Attah I.K. Swensen A.C. al.Proteome mapping reveals endocrine-exocrine sphere influence.Mol. 22100592Abstract (9Hasman Mayr Theofilatos Uncovering proteomics.Mol. 22100607Abstract inflammatory (10Paz-González Lourido Calamia V. Fernández-Puente P. Quaranta Picchi al.An osteoarthritis defined mining.Mol. 22100606Abstract (11Schlosser Grams M.E. Rhee E.P. 22100550Abstract (12Huang Gao W. Tian Functional exploration cancer.Mol. 22100575Abstract 13Casado Cutillas P.R. characterization medicine.Mol. 22100517Abstract (4) 14Arad Geiger T. protein-RNA variation analyses.Mol. 22100587Abstract 15Qian Xue Guo spectrometry-based cancers: perspective.Mol. 22100578Abstract burgeoning (16Mi M.Y. Barber J.L. Rao Farrell L.A. Sarzynski M.A. Bouchard al.Plasma exercise.Mol. 22100601Abstract 17Babu Snyder Multi-omics health.Mol. 22100561Abstract (13) Scholar). part instrumentation, methodologies, capabilities. Methodological allowed detailed challenging materials like (18Naba Ten proteomics: accomplishments, challenges, perspectives.Mol. 22100528Abstract Scholar) CNS (4Zaman (EV) payloads driven robust (19Shami-Shah Norman Walt D.R. Ultrasensitive vesicle measurements.Mol. 22100557Abstract immunopeptidomics inform immunological guide vaccine expanded owing optimization (20Phulphagar K.M. Ctortecka Jacome A.S.V. Klaeger Verzani E.K. Hernandez G.M. al.Sensitive, accumulation-serial fragmentation 22100563Abstract remains workhorse contemporary scale array-based make them attractive alternative 16Mi Complex cross-sectional, multi-omic facilitated accelerating computer speeds, storage capabilities, promulgation focused (17Babu 18Naba Improved sample-handling instrument contributed expansion spatially-resolved (8Gosline Prior limitations prevented numbers being greatly highly multiplexed (3Hurst far MS systems, scanning acquisition. Targeted reaction application modifications assessing stage effects drugs. largely purposes candidate preclinical measure peptide PTM-modified related imaging explored augment replace histopathologic suite (21Moore Patterson N.H. Norris Caprioli R.M. Prospective diagnostics.Mol. 22100576Abstract 22Phipps W.S. Kilgore M.R. Kennedy J.J. Whiteaker J.R. Hoofnagle A.N. Paulovich A.G. organ tissues.Mol. 22100648Abstract especially important deepening perturbations posttranslational phosphorylation, ubiquitylation, acetylation, sumoylation, glycosylation. now PTMs scale, individually serial yielding global exactly thereby facilitating integration while sparing precious material. Such comprehensive portraits much alone. Bottlenecks lack access annotation follow-up information integrated slowly proteogenomics enhancing becomes ever clearer (23Mani Krug Zhang B. Satpathy Clauser K.R. Ding al.Cancer proteogenomics: prospects.Nat. Rev. Cancer. 2022; 22: 298-313Crossref (56) While initially overhyped, considerable evidence techniques depth, reproducibility required aid diagnosis, prognosis, clinically-actionable prediction 24Bader Albrecht Mann fluids: end beginning.Mol. 22100577Abstract (5) 25Barker A.D. Alba M.M. Mallick Agus D.B. Lee J.S.H. An inflection point biomarkers: what what's next.Mol. 22100569Abstract 26van der Burgt Wuhrer glyco(proteo)mics 22100565Abstract needs additional validation, assay refinement, economics assessment, viable reimbursement remain challenges deployment problems clinic works progress, papers demonstrate, greater ever, likelihood having direct, positive interventions precise therapies. member scientific advisory boards Kymera, PTM BioLabs, Seer. G members board PrognomIQ. work supported grants P01CA206978 S.A.C. NIH, U24CA270823 U01CA271402 C U24-CA271075 National Institute (NCI) program, Swiss Science Foundation (SNF) grant CRSII5_186405 C., Dr Miriam Sheldon Adelson Medical Research thank entire Broad group valuable discussions.

Язык: Английский

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Comparative Analysis of Diagnostic Techniques in Alzheimer’s Disease: The Role of AI, Biomarkers, and Brain Mapping Methods

The Neuroscience Journal of Shefaye Khatam, Год журнала: 2024, Номер 12(3), С. 91 - 102

Опубликована: Июнь 1, 2024

Язык: Английский

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Glial reactivity is linked to synaptic dysfunction across the aging and Alzheimer’s disease spectrum

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Авг. 12, 2024

Previous studies have shown that glial and neuronal changes may trigger synaptic dysfunction in Alzheimer’s disease(AD). However, the link between markers abnormalities living brain is poorly understood. Here, we investigated association biomarkers of astrocyte microglial reactivity 478 individuals across aging AD spectrum from two cohorts with available CSF measures amyloid-β(Aβ), phosphorylated tau(pTau181), reactivity(GFAP), activation(sTREM2), biomarkers(GAP43 neurogranin). Elevated GFAP levels were linked to presynaptic postsynaptic dysfunction, regardless cognitive status or Aβ presence. sTREM2 associated cognitively unimpaired impaired + individuals. Notably, pTau181 mediated all associations biomarkers. These results suggest neuronal-related could be used clinical trials targeting AD.

Язык: Английский

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Investigation of the expression of Cis P‐tau and Pin1 proteins following air pollution induction in the brain tissue of C57BL/6 mice

Biotechnology and Applied Biochemistry, Год журнала: 2024, Номер unknown

Опубликована: Авг. 27, 2024

Abstract Alzheimer's disease (AD) is a multifactorial in which environmental factors play role. Among factors, air pollution vital issue modern life. Despite extensive considerations, it remains uncertain how mediates neurodegeneration AD. Beta‐amyloids and hyperphosphorylated tau proteins are the two main pathological markers that have been studied AD so far. Tau protein basically phosphoprotein whose functions controlled by phosphorylation. The function of to be located on surface microtubules stabilize them. Studies shown phosphorylated (p‐tau) exists cis trans conformations at Thr231, among highly neurotoxic. Pin1 enzyme performs conversion or vice versa. In this study, an experimental mouse model was designed investigate formation p‐tau inducing pollution. way, mice were randomly exposed 2‐week, 1‐month, 2‐month intervals. We investigated form during brains using Western blots immunofluorescence. fluorescent imaging results blotting analysis revealed significant accumulation pollution‐treated models compared healthy control mice. According blot results, induction caused decrease protein. clearly show tauopathy observed mediated through tau. Our findings unravel mysteries upon would help find possible therapeutic target fight devastating disorder

Язык: Английский

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Network Pharmacology and Molecular Docking Perspectives into Lignans for Alzheimer's Disease Treatment

Kahramanmaraş Sütçü İmam Üniversitesi Tarım ve Doğa Dergisi, Год журнала: 2024, Номер unknown

Опубликована: Авг. 14, 2024

Alzheimer’s Disease (AD) is a debilitating neurodegenerative condition with limited treatment options. Lignans, class of naturally occurring polyphenols found in various plants, have been shown to the potential modulate pathways associated AD pathology. In this study, we used network pharmacology and molecular docking investigate therapeutic lignans against by targeting specific proteins involved disease progression. Our established interaction includes key such as EGFR, HSP90AA1, BCL2, HSP90AB1, IL6, JUN, ESR1, PIK3CA, ERBB2, PIK3R1. Molecular studies revealed how interact these highlighted their influence through mechanisms inflammation modulation, apoptosis regulation, signal transduction pathways. The results suggest that significant binding abilities targets, potentially inhibiting activity thus alleviating symptoms reducing amyloid-beta accumulation tau phosphorylation. These findings support viability basis for development new therapies call further vivo confirm efficacy safety. This integrated approach underscores value combining search agents complex diseases AD.

Язык: Английский

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