Genetic Insights Into the Role of Cathepsins in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis: Evidence From Mendelian Randomization Study DOI Creative Commons
Yan‐Hong Jiang, Wenhui Fan, Yaxin Li

et al.

Brain and Behavior, Journal Year: 2024, Volume and Issue: 15(1)

Published: Dec. 31, 2024

Abstract Background Previous studies have confirmed the significant role of cathepsins in development neurodegenerative diseases. We aimed to determine whether genetically predicted 10 may a causal effect on Alzheimer's disease (AD), Parkinson's (PD), and amyotrophic lateral sclerosis (ALS). Methods conducted two‐sample bidirectional Mendelian randomization (MR) study using publicly available data from genome‐wide association (GWAS) assess associations between three diseases, including AD, PD, ALS. employed following methods, inverse variance weighting (IVW), MR‐Egger, weighted median (WM). The results were further validated sensitivity analysis. Results forward MR analysis indicate that elevated cathepsin H levels increase risk AD ( p = 0.005, odds ratio [OR] 1.040, 95% confidence interval [CI] 1.011–1.069), B decrease PD < 0.001, OR 0.890, CI 0.831–0.954), no was found Reverse suggests there is Conclusion Our provides new genetic insights into PD. However, our findings need be wider population, future research should explore potential mechanisms these diseases order provide basis for therapeutic strategies.

Language: Английский

Mendelian randomization analyses explore the relationship between cathepsins and lung cancer DOI Creative Commons
Jialin Li, Mingbo Tang, Xinliang Gao

et al.

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: Oct. 7, 2023

Lung cancer, a major contributor to cancer-related fatalities worldwide, involves complex pathogenesis. Cathepsins, lysosomal cysteine proteases, play roles in various physiological and pathological processes, including tumorigenesis. Observational studies have suggested an association between cathepsins lung cancer. However, the causal link cathepsin family cancer remains undetermined. This study employed Mendelian randomization analyses investigate this association. The univariable analysis results indicate that elevated H levels increase overall risk of adenocarcinoma, among smokers. Conversely, reverse suggest squamous carcinoma may lead increased B levels. A multivariable using nine as covariates reveals In conclusion, serve marker for potentially inspiring directions diagnosis treatment.

Language: Английский

Citations

29
Alterations in Blood Methylome as Potential Epigenetic Biomarker in Sporadic Parkinson's Disease DOI Creative Commons
Paulina González-Latapí, Bernabé I. Bustos, Siyuan Dong

et al.

Annals of Neurology, Journal Year: 2024, Volume and Issue: 95(6), P. 1162 - 1172

Published: April 2, 2024

Objective To characterize DNA methylation (DNAm) differences between sporadic Parkinson's disease (PD) and healthy control (HC) individuals enrolled in the Progression Markers Initiative (PPMI). Methods Using whole blood, we characterized longitudinal DNAm PD patients (n = 196) HCs 86) PPMI. RNA sequencing (RNAseq) was used to conduct gene expression analyses for genes mapped differentially methylated cytosine‐guanine sites (CpGs). Results At time of patient enrollment, 5,178 CpGs were (2,683 hypermethylated 2,495 hypomethylated) compared HC. Of these, 579 underwent significant changes over 3 years. Several found near cytochrome P450 family 2 subfamily E member 1 ( CYP2E1 ) gene. Additionally, multiple associated with N‐myc downregulated 4 NDRG4 RNA‐Seq showed 75 expressed controls. An integrative analysis both revealed 20 that exhibited hypomethylation concomitant overexpression. gene, cathepsin H CTSH ), displayed hypermethylation its decreased expression. Interpretation We provide initial evidence alterations blood may serve as potential epigenetic biomarker disease. evaluate significance these throughout progression PD, additional profiling at longer intervals during prodromal stages will be necessary. ANN NEUROL 2024;95:1162–1172

Language: Английский

Citations

9
Identification of potential therapeutic targets for Alzheimer's disease from the proteomes of plasma and cerebrospinal fluid in a multicenter Mendelian randomization study DOI
Shengnan Wang,

Jianxin Xi,

Mengyuan Zhang

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 294, P. 139394 - 139394

Published: Jan. 5, 2025

Language: Английский

Citations

1
Compensational role between cathepsins DOI Creative Commons

Urša Pečar Fonović,

Janko Kos, Ana Mitrović

et al.

Biochimie, Journal Year: 2024, Volume and Issue: 226, P. 62 - 76

Published: April 23, 2024

Cathepsins, a family of lysosomal peptidases, play crucial role in maintaining cellular homeostasis by regulating protein turnover and degradation as well many specific regulatory actions that are important for proper cell function human health. Alterations the activity expression cathepsins have been observed diseases such cancer, inflammation, neurodegenerative disorders, bone remodelling-related conditions others. These changes not exclusively harmful, but rather appear to be compensatory response on lack one cathepsin order maintain tissue integrity. The upregulation inhibition or dysfunction other suggests fine-tuned system proteolytic balance understanding may improve therapeutic potential cathepsin's inhibitors. Selectively targeting modulating their could offer new treatment strategies number diseases. This review emphasises need comprehensive research into biology context disease. identification involved responses, elucidation underlying molecular mechanisms development targeted interventions lead innovative approaches.

Language: Английский

Citations

8
Therapeutic cysteine protease inhibitors: a patent review (2018–present) DOI

Giulia Barchielli,

Antonella Capperucci, Damiano Tanini

et al.

Expert Opinion on Therapeutic Patents, Journal Year: 2024, Volume and Issue: 34(1-2), P. 17 - 49

Published: Feb. 1, 2024

Cysteine proteases are involved in a broad range of biological functions, ranging from extracellular matrix turnover to immunity. Playing an important role the onset and progression several diseases, including cancer, immune-related neurodegenerative disease, viral parasitic infections, cysteine represent attractive drug target for development therapeutic tools.

Language: Английский

Citations

6
From past to future: 50 years of pharmacological interventions to treat narcolepsy DOI Creative Commons
Éric Konofal

Pharmacology Biochemistry and Behavior, Journal Year: 2024, Volume and Issue: 241, P. 173804 - 173804

Published: June 7, 2024

The history of narcolepsy research began with the pioneering work Jean-Baptiste-Édouard Gélineau in late 19th century. In 1880s, introduced term "narcolepsy" to describe a condition characterized by sudden and uncontrollable episodes sleep. His clinical descriptions laid foundation for our understanding this complex disorder. Over last half-century, pharmacological landscape treatment has evolved remarkably, shifting from merely managing symptoms increasingly targeting its underlying pathophysiology. By 1930s, treatments such as ephedrine amphetamine were alleviate excessive daytime sleepiness, marking significant advancements management. These stimulants provided temporary relief, helping patients maintain wakefulness during day. As progressed, focus shifted towards disorder's mechanisms. discovery orexin (also known hypocretin) 1990s revolutionized field. This breakthrough underscored importance regulating sleep-wake cycles new targets intervention. Looking ahead, future pharmacotherapy is poised further innovation. ongoing exploration receptor agonists potential development neuroprotective therapeutic underscore promising horizon. Emerging into genetic immunological underpinnings opens avenues personalized medicine approaches identification biomarkers more precise strategies. Additionally, refinement existing through improved delivery systems investigation combination therapies offer opportunities enhanced efficacy quality life narcolepsy.

Language: Английский

Citations

6
Cathepsins and cancer risk: a Mendelian randomization study DOI Creative Commons
Tingting Deng, Xixue Lu,

Xuemin Jia

et al.

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15

Published: May 31, 2024

Background Previous observational epidemiological studies reported an association between cathepsins and cancer, however, a causal relationship is uncertain. This study evaluated the cancer using Mendelian randomization (MR) analysis. Methods We used publicly available genome-wide (GWAS) data for bidirectional MR Inverse variance weighting (IVW) was as primary method of Results After correction False Discovery Rate (FDR), two were found to be significantly associated with risk: cathepsin H (CTSH) levels increased risk lung (OR = 1.070, 95% CI 1.027–1.114, P 0.001, FDR 0.009), CTSH decreased basal cell carcinoma 0.947, 0.919–0.975, 0.0002, 0.002). In addition, there no statistically significant effect 20 cancers on nine cathepsins. Some unadjusted low P-value phenotypes are worth mentioning, including positive correlation O (CTSO) breast 1.012, 1.001–1.025, 0.041), S (CTSS) pharyngeal 1.017, 1.001–1.034, 0.043), CTSS endometrial 1.055, 1.012–1.101, 0.012); negative Z ovarian (CTSZ) 0.970, 0.949–0.991, 0.006), prostate 0.902–0.944, 0.028), E (CTSE) pancreatic 0.963, 0.938–0.990, 0.006). Conclusion Our analyses showed may help provide new insights further mechanistic clinical cathepsin-mediated cancer.

Language: Английский

Citations

5
Molecular Profiling of Odontoclasts during Physiological Tooth Replacement DOI Creative Commons

Joaquín Ignacio Henríquez,

Stéphane Flibotte,

Katherine Fu

et al.

Journal of Dental Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

The odontoclast is a rarely studied cell type that overly active in many dental pathologies, leading to tooth loss. It difficult find diphyodont mammals which either physiological or pathological root resorption can be studied. Here we use the adult leopard gecko, has repeated cycles of and shedding. RNA-seq was carried out compare gene expression profiles functional teeth developing teeth. Genes more highly expressed bell-stage were related morphogenesis ( PTHLH, SFRP2, SHH, EDAR). Some genes osteoclasts ACP5, CTSK, CSF1R) relatively abundant compared with There was, however, no differential RANK RANKL 2 types. In addition, proteolysis not found ADAMTS2, 3, 4, 14; CTSA, CTSH, CTSS). We used tartrate acid resistant phosphatase cathepsin K (CTSK) staining identify odontoclasts around gecko dentition. 3 populations CTSK cells: (1) large, multinucleated crown ruffled border inside pits; (2) smaller, precursor cells pulp fewer nuclei; (3) flattened external next bone attachment. positive relationship between population CTSK+ on surface. tested candidate signal may involved presence. An antagonist CSF1R delivered vivo, resulted significant decrease DMSO controls. Thus, CSF1 signaling pathway upstream This first work detail molecular characteristics during shedding demonstrate local drug delivery possible model.

Language: Английский

Citations

0
Cellular pharmacology of tenofovir alafenamide and emtricitabine in neutrophils and platelets in people with and without HIV DOI

Vincent Mainella,

Brian R. Branchford, Travis Nemkov

et al.

Journal of Antimicrobial Chemotherapy, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

Previous studies have primarily focused on nucleos(t)ide reverse transcriptase inhibitor pharmacology in peripheral blood mononuclear cells (PBMCs) and erythrocytes via dried spots (DBS), but not other major cells. Our objectives were to describe compare the concentrations of tenofovir-diphosphate (TFV-DP) emtricitabine-triphosphate (FTC-TP) DBS, PBMCs, neutrophils, platelets people with HIV (PWH) without (PWOH). isolated from whole drawn PWH PWOH receiving tenofovir alafenamide emtricitabine. TFV-DP FTC-TP quantified using LC-MS/MS each cell type. Linear regression models controlled for time drug, adherence, since last dose, where applicable, determine geometric mean percent differences (95% confidence interval) by status estimated half-lives. Data available 13 (96% male) 30 (53% male). Compared PWOH, DBS was 48.9% (15.6%, 91.9%) higher 36.3% (4.5%, 77.7%) higher; also trended [43.5% (-3.24%, 113%)]. No types significantly differed status. demonstrated longest half-lives followed PBMCs then platelets. After normalizing volume, both drugs accumulated greatest least platelets, across PWOH. findings highlight differential drug disposition that vary serostatus The mechanisms implications these require additional research.

Language: Английский

Citations

0
Neurofilament accumulation disrupts autophagy in giant axonal neuropathy DOI Creative Commons

Jean‐Michel Paumier,

James P. Zewe, Chiranjit Panja

et al.

JCI Insight, Journal Year: 2025, Volume and Issue: 10(5)

Published: March 9, 2025

Neurofilament accumulation is associated with many neurodegenerative diseases, but it the primary pathology in giant axonal neuropathy (GAN). This childhood-onset autosomal recessive disease caused by loss-of-function mutations gigaxonin, E3 adaptor protein that enables neurofilament degradation. Using a combination of genetic and RNA interference approaches, we found dorsal root ganglia from mice lacking gigaxonin have impaired autophagy lysosomal degradation through 2 mechanisms. First, accumulations interfere distribution autophagic organelles, impairing their maturation fusion lysosomes. Second, attract chaperone 14-3-3, which responsible for proper localization key regulator transcription factor EB (TFEB). We propose this dual disruption contributes to pathogenesis other diseases involving accumulations.

Language: Английский

Citations

0