The lateral habenula (LHb) attracts a growing interest as a regulator of monoaminergic activity which were frequently reported to be defective in depression. Here we found that chronic social defeat stress (CSDS) increased production of pro-inflammatory cytokines in LHb associated with mobilization of monocytes and remodeling of extracellular matrix by increased matrix metalloproteinase (MMP) activity. RNA-seq analysis identified proprotein convertase Pcsk5 as an upstream regulator of MMP activation, with upregulation in LHb neurons of mice with susceptibility to CSDS. PCSK5 facilitated motility of microglia in vitro by converting inactive pro-MMP14 and pro-MMP2 to their active forms, highlighting its role in mobilization of microglia and monocytes in neuroinflammation. Suppression of Pcsk5 expression via small interfering RNA (siRNA) ameliorated depressive-like behaviors and pathological mobilization of monocytes in mice with susceptibility to CSDS. PCSK5-MMPs signaling pathway could be a target for development of the antidepressants targeting the inflammatory response in specific brain regions implicated in depression.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852607 | PMC |
| http://dx.doi.org/10.1038/s41386-020-00843-0 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
CCN1 is a matricellular protein highly expressed in esophageal squamous cell carcinoma (ESCC) but hardly detectable in esophageal adenocarcinoma (EAC). Expression of CCN1 in EAC cells leads to TRAIL-mediated apoptosis. Unlike TRAIL, which primarily triggers cell death, APRIL and BAFF promote cell growth via NFκB signaling.
View Article and Find Full Text PDFEmerging oral therapeutic strategies for inhibiting PCSK9.
Atheroscler Plus
March 2025
Department of Pharmaceutical and Pharmacological Sciences, Padova, Italy.
Pharmacological inhibition of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) have been firmly established to be an effective approach to reduce low-density lipoprotein (LDL) cholesterol levels and cardiovascular events. Subcutaneous administration of monoclonal antibodies (evolocumab and alirocumab) every 2 or 4 weeks determined a 60 % reduction of LDL cholesterol levels, while the GalNac-siRNA anti PCSK9 (inclisiran) provided an effective lipid lowering activity (-50 %) after an initial subcutaneous dose, repeated after 3 months and followed by a maintenance dose every 6 months. Although these two approaches have the potentiality to bring the majority of patients at high and very-high cardiovascular risk to the appropriate LDL cholesterol targets, their cost and subcutaneous administration represent a strong limitation for their large-scale use.
View Article and Find Full Text PDFCombined action of dietary-based approaches and therapeutic agents on cholesterol metabolism and main related diseases.
Clin Nutr ESPEN
January 2025
Centro de Investigação de Montanha (CIMO), Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal; Laboratório Associado para a Sustentabilidade e Tecnologia em Regiões de Montanha (SusTEC), Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal. Electronic address:
Background: Dyslipidaemia is among the major causes of severe diseases and, despite being well-established, the hypocholesterolaemic therapies still face significant concerns about potential side effects (such as myopathy, myalgia, liver injury digestive problems, or mental fuzziness in some people taking statins), interaction with other drugs or specific foods. Accordingly, this review describes the latest developments in the most effective therapies to control and regulate dyslipidaemia.
Scope And Approach: Herein, the metabolic dynamics of cholesterol and their integration with the current therapies: statins, bile acid sequestrants, fibrates, niacin, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, reconstituted high-density lipoprotein (rHDL), or anti-inflammatory and immune-modulating therapies), were compared focusing their effectiveness, patients' adhesion and typical side-effects.
The pleiotropic effects of PCSK9 in cardiovascular diseases beyond cholesterol metabolism.
Acta Physiol (Oxf)
February 2025
Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China.
Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality globally, with elevated low-density lipoprotein cholesterol (LDL-C) levels being a major risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in regulating LDL-C levels by promoting the degradation of hepatic low-density lipoprotein receptors (LDLR) responsible for clearing LDL-C from the circulation. PCSK9 inhibitors are novel lipid-modifying agents that have demonstrated remarkable efficacy in reducing plasma LDL-C levels and decreasing the incidence of CVD.
View Article and Find Full Text PDFHistone deacetylase 6 inhibition prevents hypercholesterolemia-induced erectile dysfunction independent of changes in markers of autophagy.
Sex Med
December 2024
Department of Health, Nutrition, and Food Sciences, Florida State University, Tallahassee, FL 32306, United States.
Background: Erectile dysfunction is a condition with a rapidly increasing prevalence globally with a strong correlation to the increase in obesity and cardiovascular disease rates.
Aim: The aim of the current study is to investigate the potential role of tubacin, a histone deacetylase 6 (HDAC6) inhibitor, in restoring erectile function in a hypercholesterolemia-induced endothelial dysfunction model.
Methods: Thirty-nine male C57Bl/6 J mice were divided into 3 groups.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!