scholarly journals PKCδ Mediates NF-κB Inflammatory Response and Downregulates SIRT1 Expression in Liver Fibrosis

2019 ◽  
Vol 20 (18) ◽  
pp. 4607 ◽  
Author(s):  
Lee ◽  
Kim ◽  
Lee ◽  
Kwon
Keyword(s):  
Inflammatory Response ◽  
Hepatic Cirrhosis ◽  
Regulatory Mechanism ◽  
Sirtuin 1 ◽  
Sirt1 Expression ◽  
Kinase C ◽  
Promising Target ◽  
Ccl4 Treatment ◽  
Fibrotic Diseases

The precise mechanism of hepatic cirrhosis remains largely unclear. In particular, a potential regulatory mechanism by which protein kinase C-delta (PKCδ ) affects profibrogenic gene expression involved in hepatic cirrhosis has never been explored. In the present study, we investigated whether PKCδ activation is involved in liver inflammatory fibrosis in both lipopolysaccharide (LPS)-treated RAW 264.7 and CCl4-treated mice. PKCδ was strongly activated by LPS or CCl4 treatment and consequently stimulated nuclear factor (NF)-κB inflammatory response. Interestingly, the activation of PKCδ negatively regulated sirtuin-1 (SIRT1) expression, whereas PKCδ suppression by PKCδ peptide inhibitor V1-1 or siRNA dramatically increased SIRT1 expression. Furthermore, we showed that the negative regulation of PKCδ leads to a decrease in SIRT1 expression. To our knowledge, these results are the first demonstration of the involvement of PKCδ in modulating NF-κB through SIRT1 signaling in fibrosis in mice, suggesting a novel role of PKCδ in inflammatory fibrosis. The level of NF-κB p65 in the nucleus was also negatively regulated by SIRT1 activity. We showed that the inhibition of PKCδ promoted SIRT1 expression and decreased p65 levels in the nucleus through deacetylation. Moreover, the inactivation of PKCδ with V1-1 dramatically suppressed the inflammatory fibrosis, indicating that PKCδ represents a promising target for treating fibrotic diseases like hepatic cirrhosis.

scholarly journals Role of SIRT1 in HIV-associated kidney disease

2020 ◽  
Vol 319 (2) ◽  
pp. F335-F344 ◽  
Author(s):  
Xuan Wang ◽  
Ruijie Liu ◽  
Weijia Zhang ◽  
Deborah P. Hyink ◽  
Gokul C. Das ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Drug Targets ◽  
Cell Injury ◽  
Kidney Diseases ◽  
Sirtuin 1 ◽  
Kidney Cells ◽  
Sirt1 Expression ◽  
Hiv 1

Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We have previously shown that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3, were increased in HIVAN kidneys. Here, we demonstrate the key role of sirtuin 1 (SIRT1) deacetylase in the regulation of NF-κB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-κB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of negative regulatory factor in podocytes stably expressing HIV-1 proviral genes, which was associated with inactivation of NF-κB p65 and a reduction in HIV-1 long terminal repeat promoter activity. In vivo, the administration of the small-molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we showed that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1-infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.

scholarly journals SIRT1 Expression and Regulation in the Primate Testis

2021 ◽  
Vol 22 (6) ◽  
pp. 3207
Author(s):  
Fazal Wahab ◽  
Ignacio Rodriguez Polo ◽  
Rüdiger Behr
Keyword(s):  
Germ Cells ◽  
Rhesus Macaques ◽  
Sirtuin 1 ◽  
Primate Species ◽  
Seminiferous Tubules ◽  
Sirt1 Expression ◽  
Protein Substrates ◽  
Development And Differentiation ◽  
Endocrine Factor

The epigenetic mechanisms controlling germ cell development and differentiation are still not well understood. Sirtuin-1 (SIRT1) is a nicotinamide adenosine dinucleotide (NAD)-dependent histone deacetylase and belongs to the sirtuin family of deacetylases. It catalyzes the removal of acetyl groups from a number of protein substrates. Some studies reported a role of SIRT1 in the central and peripheral regulation of reproduction in various non-primate species. However, testicular SIRT1 expression and its possible role in the testis have not been analyzed in primates. Here, we document expression of SIRT1 in testes of different primates and some non-primate species. SIRT1 is expressed mainly in the cells of seminiferous tubules, particularly in germ cells. The majority of SIRT1-positive germ cells were in the meiotic and postmeiotic phase of differentiation. However, SIRT1 expression was also observed in selected premeiotic germ cells, i.e., spermatogonia. SIRT1 co-localized in spermatogonia with irisin, an endocrine factor specifically expressed in primate spermatogonia. In marmoset testicular explant cultures, SIRT1 transcript levels are upregulated by the addition of irisin as compared to untreated controls explants. Rhesus macaques are seasonal breeders with high testicular activity in winter and low testicular activity in summer. Of note, SIRT1 mRNA and SIRT1 protein expression are changed between nonbreeding (low spermatogenesis) and breeding (high spermatogenesis) season. Our data suggest that SIRT1 is a relevant factor for the regulation of spermatogenesis in primates. Further mechanistic studies are required to better understand the role of SIRT1 during spermatogenesis.

scholarly journals MicroRNA-181a-5p regulates inflammatory response of macrophages in sepsis

Open Medicine ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. 899-908 ◽  
Author(s):  
Zheng Huang ◽  
Hang Xu
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Sirtuin 1 ◽  
Raw 264.7 Cells ◽  
Inflammatory Factors ◽  
Raw 264.7 ◽  
Raw264.7 Macrophages ◽  
Pathway Activation

AbstractThe aim of this study was to evaluate the role of miR-181a-5p in sepsis, and to further explore the molecular mechanism. RAW 264.7 cells were stimulated with 1 μg/ml LPS for 4 hours. Firstly, qRT-PCR and ELISA was adopted to evaluate the expression of miR-181a-5p and p ro-inflammatory cytokines in RAW 264.7 macrophages a fter LPS stimulation. Results showed that pro-inflammatory cytokines and miR-181a-5p were significantly increased after LPS treatment. Then, we identified that sirtuin-1 (SIRT1) was a direct target of miR-181a-5p and it was down-regulated in LPS treated RAW264.7 macrophages. Furthermore, the data suggested that the miR-181a-5p inhibitor significantly inhibited LPS enhanced inflammatory cytokines expression and NF-κB pathway activation, and these changes were eliminated by SIRT1 silencing. Moreover, the role of the miR-181a-5p inhibitor on sepsis was studied in vivo. We found that the miR-181a-5p inhibitor significantly decreased the secretion of inflammatory factors, and the levels of creatine (Cr), blood urea nitrogen (BUN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in a serum for mice with sepsis. However, all the effects were reversed by SIRT1-siRNA. In summary, these results indicated that miR-181a-5p was involved in sepsis through regulating the inflammatory response by targeting SIRT1, suggesting that miR-181a-5p may be a potential target for the treatment of sepsis.

scholarly journals The Prognostic Role of SIRT1-Autophagy Axis in Gastric Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Guanglin Qiu ◽  
Xuqi Li ◽  
Chao Wei ◽  
Xiangming Che ◽  
Shicai He ◽  
...  
Keyword(s):  
Prognostic Indicator ◽  
Beclin 1 ◽  
Sirtuin 1 ◽  
Clinicopathological Parameters ◽  
Poor Survival ◽  
Free Survival ◽  
Sirt1 Expression ◽  
Transmission Electron ◽  
The Relationship

Aim. Sirtuin 1 (SIRT1) can induce autophagy through deacetylation of Beclin-1 and other autophagy mediators. However, the relationship between SIRT1 and autophagy in GC has not been defined. Therefore, the aim of this study was to confirm the prognostic value of SIRT1 and Beclin-1 and their relationship in GC patients. Methods. Transmission electron microscopy (TEM) was performed to examine the autophagy in GC patients. Immunohistochemistry was used to examine the expression of SIRT1, Beclin-1 in GC, and adjacent nonneoplastic mucosa. Results. In 7 out of 8 GC patients’ samples examined by TEM, more autophagic vesicles were observed in GC tissues compared to adjacent nonneoplastic mucosa tissue. A positive correlation between SIRT1 and Beclin-1 expression was observed. Furthermore, Beclin-1 or SIRT1 expression alone or their combined expression were significantly correlated with advanced clinicopathological parameters. High Beclin-1 and SIRT1 expression alone and their combined high expression predicted shorter overall survival and relapse-free survival. Both high Beclin-1 and SIRT1 expressions were independent prognostic factors for poor survival of GC. Conclusions. Based on our results we can conclude that SIRT1 and Beclin-1 expression alone or in combination can be used as prognostic indicator and may represent new therapeutic targets in GC.

scholarly journals SIRT1 inhibits rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and inflammatory response via suppressing NF-κB pathway

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Guoqing Li ◽  
Zhongbing Xia ◽  
Ying Liu ◽  
Fanru Meng ◽  
Xia Wu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Sirtuin 1 ◽  
Migration And Invasion ◽  
Synovial Hyperplasia ◽  
Sirt1 Expression ◽  
Tnf Α ◽  
Synovial Tissues ◽  
Inflammatory Phenotypes

Rheumatoid arthritis (RA) is an autoimmune disease of the joints characterized by synovial hyperplasia and chronic inflammation. Fibroblast-like synoviocytes (FLS) play a central role in RA initiation, progression, and perpetuation. Prior studies showed that sirtuin 1 (SIRT1), a deacetylase participating in a broad range of transcriptional and metabolic regulations, may impact cell proliferation and inflammatory responses. However, the role of SIRT1 in RA–FLS was unclear. Here, we explored the effects of SIRT1 on the aggressiveness and inflammatory responses of cultured RA-FLS. SIRT1 expression was significantly lower in synovial tissues and FLS from RA patients than from healthy controls. Overexpression of SIRT1 significantly inhibited RA-FLS proliferation, migration, and invasion. SIRT1 overexpression also significantly increased RA-FLS apoptosis and caspase-3 and -8 activity. Focusing on inflammatory phenotypes, we found SIRT1 significantly reduced RA-FLS secretion of TNF-α, IL-6, IL-8, and IL-1β. Mechanistic studies further revealed SIRT1 suppressed NF-κB pathway by reducing p65 protein expression, phosphorylation, and acetylation in RA-FLS. Our results suggest SIRT1 is a key regulator in RA pathogenesis by suppressing aggressive phenotypes and inflammatory response of FLS. Enhancing SIRT1 expression or function in FLS could be therapeutic beneficial for RA by inhibiting synovial hyperplasia and inflammation.

A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis

Blood ◽  
2009 ◽  
Vol 114 (25) ◽  
pp. 5236-5244 ◽  
Author(s):  
Martina Tremmel ◽  
Alexandra Matzke ◽  
Imke Albrecht ◽  
Anna M. Laib ◽  
Vivienne Olaku ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Surface Protein ◽  
Receptor Activation ◽  
Tubule Formation ◽  
Kinase C ◽  
Promising Target ◽  
Hepatocyte Growth

Abstract A specific splice variant of the CD44 cell- surface protein family, CD44v6, has been shown to act as a coreceptor for the receptor tyrosine kinase c-Met on epithelial cells. Here we show that also on endothelial cells (ECs), the activity of c-Met is dependent on CD44v6. Furthermore, another receptor tyrosine kinase, VEGFR-2, is also regulated by CD44v6. The CD44v6 ectodomain and a small peptide mimicking a specific extracellular motif of CD44v6 or a CD44v6-specific antibody prevent CD44v6-mediated receptor activation. This indicates that the extracellular part of CD44v6 is required for interaction with c-Met or VEGFR-2. In the cytoplasm, signaling by activated c-Met and VEGFR-2 requires association of the CD44 carboxy-terminus with ezrin that couples CD44v6 to the cytoskeleton. CD44v6 controls EC migration, sprouting, and tubule formation induced by hepatocyte growth factor (HGF) or VEGF-A. In vivo the development of blood vessels from grafted EC spheroids and angiogenesis in tumors is impaired by CD44v6 blocking reagents, suggesting that the coreceptor function of CD44v6 for c-Met and VEGFR-2 is a promising target to block angiogenesis in pathologic conditions.

Downregulation of IRAK3 by miR-33b-3p relieves chondrocyte inflammation and apoptosis in an in vitro osteoarthritis model

2020 ◽  
Vol 85 (3) ◽  
pp. 545-552
Author(s):  
Tao Tao ◽  
Yunkun Zhang ◽  
Hui Wei ◽  
Ke Heng
Keyword(s):  
Functional Role ◽  
Regulatory Mechanism ◽  
Interleukin 1 ◽  
Inverse Correlation ◽  
Promising Target ◽  
Tnf Α ◽  
Direct Target ◽  
Distinctive Role

ABSTRACT Interleukin-1 receptor-associated kinase-3 (IRAK3) has a distinctive role in regulating inflammation. However, the functional role of IRAK3 and regulatory mechanism underlying the pathogenesis of osteoarthritis (OA) remain unclear. Here, we first found that IRAK3 was upregulated, while miR-33b-3p was downregulated in the cartilage of OA patients and IL-1β-induced CHON-001 cells. IRAK3 was confirmed as the direct target of miR-33b-3p and negatively regulated by miR-33b-3p. There was an inverse correlation between IRAK3 mRNA expression and miR-33b-3p expression in OA cartilage tissues. The in vitro functional experiments showed that miR-33b-3p overexpression caused a remarkable increase in viability, a significant decrease in inflammatory mediators (IL-1β and TNF-α), and apoptosis in IL-1β-induced CHON-001 cells. Importantly, IRAK3 knockdown imitated, while overexpression reversed the effects of miR-33b-3p on IL-1β-induced inflammation and apoptosis in CHON-001 cells. Collectively, miR-33b-3p significantly alleviated IL-1β-induced inflammation and apoptosis by downregulating IRAK3, which may serve as a promising target for OA.

scholarly journals The Role of Tyrosine Phosphorylation of Protein Kinase C Delta in Infection and Inflammation

2019 ◽  
Vol 20 (6) ◽  
pp. 1498 ◽  
Author(s):  
Qingliang Yang ◽  
Jordan Langston ◽  
Yuan Tang ◽  
Mohammad Kiani ◽  
Laurie Kilpatrick
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Inflammatory Response ◽  
Tyrosine Phosphorylation ◽  
Critical Role ◽  
In Vivo Models ◽  
Kinase C ◽  
Microfluidic Assays

Protein Kinase C (PKC) is a family composed of phospholipid-dependent serine/threonine kinases that are master regulators of inflammatory signaling. The activity of different PKCs is context-sensitive and these kinases can be positive or negative regulators of signaling pathways. The delta isoform (PKCδ) is a critical regulator of the inflammatory response in cancer, diabetes, ischemic heart disease, and neurodegenerative diseases. Recent studies implicate PKCδ as an important regulator of the inflammatory response in sepsis. PKCδ, unlike other members of the PKC family, is unique in its regulation by tyrosine phosphorylation, activation mechanisms, and multiple subcellular targets. Inhibition of PKCδ may offer a unique therapeutic approach in sepsis by targeting neutrophil-endothelial cell interactions. In this review, we will describe the overall structure and function of PKCs, with a focus on the specific phosphorylation sites of PKCδ that determine its critical role in cell signaling in inflammatory diseases such as sepsis. Current genetic and pharmacological tools, as well as in vivo models, that are used to examine the role of PKCδ in inflammation and sepsis are presented and the current state of emerging tools such as microfluidic assays in these studies is described.

scholarly journals Long-term modulation of mitochondrial Ca2+ signals by protein kinase C isozymes

2004 ◽  
Vol 165 (2) ◽  
pp. 223-232 ◽  
Author(s):  
Paolo Pinton ◽  
Sara Leo ◽  
Mariusz R. Wieckowski ◽  
Giulietta Di Benedetto ◽  
Rosario Rizzuto
Keyword(s):  
Protein Kinase C ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Regulatory Mechanism ◽  
Cellular Responses ◽  
Kinase C ◽  
A Cell ◽  
Dynamic Interplay

The modulation of Ca2+ signaling patterns during repetitive stimulations represents an important mechanism for integrating through time the inputs received by a cell. By either overexpressing the isoforms of protein kinase C (PKC) or inhibiting them with specific blockers, we investigated the role of this family of proteins in regulating the dynamic interplay of the intracellular Ca2+ pools. The effects of the different isoforms spanned from the reduction of ER Ca2+ release (PKCα) to the increase or reduction of mitochondrial Ca2+ uptake (PKCζ and PKCβ/PKCδ, respectively). This PKC-dependent regulatory mechanism underlies the process of mitochondrial Ca2+ desensitization, which in turn modulates cellular responses (e.g., insulin secretion). These results demonstrate that organelle Ca2+ homeostasis (and in particular mitochondrial processing of Ca2+ signals) is tuned through the wide molecular repertoire of intracellular Ca2+ transducers.

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