scholarly journals SOCS1 Regulates Apoptosis and Inflammation by Inhibiting IL-4 Signaling in IL-1β-Stimulated Human Osteoarthritic Chondrocytes

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Qiang He ◽  
Caihong Sun ◽  
Wei Lei ◽  
Jianbing Ma
Keyword(s):  
Cell Viability ◽  
Therapeutic Target ◽  
Cell Apoptosis ◽  
Inflammatory Factors ◽  
Cytokine Signaling ◽  
Potential Therapeutic Target ◽  
Osteoarthritic Chondrocytes ◽  
Total Knee ◽  
Apoptosis And Inflammation ◽  
Regulatory Functions

Recently, Suppressor of Cytokine Signaling 1 (SOCS1) was identified as a potential therapeutic target for osteoarthritis (OA) treatment. However, the mechanisms and signaling pathways of SOCS1 in the regulation of OA development are unclear. The purpose of the current study was to investigate whether interleukin- (IL-) 4 was involved in regulatory mechanism of SOCS1 in human osteoarthritic chondrocytes. First, IL-1βwas used to stimulate human osteoarthritic chondrocytes isolated from the articular cartilage of OA patients undergoing total knee replacement. The protein and mRNA expression levels of SOCS1 were upregulated in IL-1β-stimulated human osteoarthritic chondrocytes compared with control cells. The knockdown of SOCS1 increased cell viability and inhibited cell apoptosis. It was also found that IL-4 expression was increased by SOCS1 silencing. Additionally, knockdown of IL-4 reduced cell viability and increased cell apoptosis of osteoarthritic chondrocytes transfected with SOCS1 siRNA. Moreover, the decreased expression of inflammatory factors induced by SOCS1 was enhanced by IL-4 knockdown. In conclusion, IL-4 signaling plays a crucial role in the regulatory functions of SOCS1 in apoptosis and inflammation in human osteoarthritic chondrocytes. These findings provide a potential therapeutic target for the clinical treatment of OA.

scholarly journals Immunoregulatory Role of MicroRNA-21 in Macrophages in Response to Bacillus Calmette-Guerin Infection Involves Modulation of the TLR4/MyD88 Signaling Pathway

2017 ◽  
Vol 42 (1) ◽  
pp. 91-102 ◽  
Author(s):  
Xin Xue ◽  
Yi Qiu ◽  
Hong-Li Yang
Keyword(s):  
Cell Viability ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Bacillus Calmette Guerin ◽  
Myd88 Signaling ◽  
Apoptosis And Necrosis

Background/Aims: The purpose of this study is to explore the immunoregulatory role of microRNA-21 (miR-21) targeting of the TLR4/MyD88 signaling pathway in macrophages in response to Bacillus Calmette-Guerin (BCG) infection. Methods: After infection with BCG, mouse RAW246.7 cells were assigned into control, BCG, miR-21 mimic + BCG, mimic-negative control (NC) + BCG, miR-21 inhibitor + BCG, inhibitor-NC + BCG, BCG + TAK242 (an inhibitor of the TLR4 signaling pathway), and miR-21 inhibitor + TAK242 + BCG groups. Western blotting and qRT-PCR were used to detect the expression of miR-21, TLR4 and MyD88. The levels of TNF-a, IL-6 and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). Cell viability was measured using an MTT assay. Cell apoptosis and necrosis rates were detected using flow cytometry. Results: Compared with the control group, miR-21 expression and levels of TNF-a, IL-6 and IL-10, as well as cell apoptosis and necrosis rates, were elevated, while expression of TLR4 and MyD88, as well as cell viability, were reduced in BCG infection groups. Compared with the BCG group, miR-21 expression was increased in the miR-21 mimic + BCG group but decreased in the miR-21 inhibitor + BCG and miR-21 inhibitor + TAK242 + BCG groups. The expression of TLR4 and MyD88, as well as the cell viability, were decreased, while levels of TNF-a, IL-6 and IL-10, as well as cell apoptosis and necrosis rates, were increased in the miR-21 mimic + BCG and TAK242 + BCG groups. The opposite trends were found in the miR-21 inhibitor + BCG group. Compared with the TAK242 + BCG group, the miR-21 inhibitor + TAK242 + BCG group had higher expression of TLR4 and MyD88 as well as higher cell viability and lower levels of TNF-a, IL-6, IL-10, cell apoptosis and necrosis rates. However, the miR-21 inhibitor + TAK242 + BCG group exhibited the opposite trends when compared with the miR-21 inhibitor + BCG group. Conclusion: Our results suggest that miR-21 can negatively modulate the TLR4/MyD88 signaling pathway, resulting in decreased cell viability, increased cell apoptosis and increased levels of inflammatory factors following BCG infection in macrophages.

scholarly journals FAM3C: an emerging biomarker and potential therapeutic target for cancer

2021 ◽  
Author(s):  
Yuanyuan Zhu ◽  
Zhangya Pu ◽  
Guoqiang Wang ◽  
Yubin Li ◽  
Yinmiao Wang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Subcellular Localization ◽  
Therapeutic Target ◽  
Current Knowledge ◽  
Expression Patterns ◽  
Tumor Formation ◽  
Cancer Development ◽  
Poor Survival ◽  
Potential Therapeutic Target ◽  
Regulatory Functions

FAM3C is a member of the FAM3 family. Recently, overexpression of FAM3C has been reported in numerous types of cancer, including breast and colon cancer. Increasing evidence suggests that elevated FAM3C and its altered subcellular localization are closely associated with tumor formation, invasion, metastasis and poor survival. Moreover, FAM3C has been found to be the regulator of various proteins that associate with cancer, including Ras, STAT3, TGF-β and LIFR. This review summarizes the current knowledge regarding FAM3C, including its structure, expression patterns, regulation, physiological roles and regulatory functions in various malignancies. These findings highlight the importance of FAM3C in cancer development and provide evidence that FAM3C is a novel biomarker and potential therapeutic target for various cancers.

Circ_0091702 relieves lipopolysaccharide (LPS)-induced cell injury by regulating the miR-182/PDE7A axis in sepsis

2021 ◽  
Author(s):  
Xinliang Zhang ◽  
Shimin Dong
Keyword(s):  
Cell Viability ◽  
Cell Apoptosis ◽  
Cell Injury ◽  
Circular Rna ◽  
Suppressive Effect ◽  
Important Regulator ◽  
Apoptosis And Inflammation ◽  
Hk2 Cells

Abstract Circular RNA (circRNA) plays an important role in the progression of sepsis. Circ_0091702 has been found to be an important regulator of sepsis progression, so its role and mechanism in sepsis progression deserve to be further explored. LPS could suppress cell viability, while enhance cell apoptosis and inflammation to induce cell injury. Circ_0091702 was downregulated in LPS-induced HK2 cells, and its overexpression alleviated LPS-induced cell injury. MiR-182 could be sponged by circ_0091702. Moreover, miR-182 inhibitor could relieve LPS-induced cell injury, and its overexpression also reversed the inhibition of circ_0091702 on LPS-induced cell injury. PDE7A was a target of miR-182, and its expression was reduced in LPS-induced HK2 cells. Additionally, silencing of PDE7A reversed the suppressive effect of circ_0091702 on LPS-induced cell injury. Our data suggested that circ_0091702 sponged miR-182 to regulate PDE7A, thereby alleviating LPS-induced cell injury in sepsis.

BNIP3-mediated Autophagy Induced Inflammatory Response and Inhibited VEGF Expression in Cultured Retinal Pigment Epithelium Cells Under Hypoxia

2019 ◽  
Vol 19 (6) ◽  
pp. 395-404 ◽  
Author(s):  
Yuhong Chen ◽  
Quan Yan ◽  
Yihua Xu ◽  
Fuxiang Ye ◽  
Xiaodong Sun ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Retinal Pigment Epithelial ◽  
Retinal Pigment ◽  
Inflammatory Factors ◽  
Vegf Expression ◽  
Rpe Cells ◽  
Pigment Epithelial ◽  
Mtorc1 Pathway

Background: Bcl-2/adenovirus E1B-19kDa-interacting protein (BNIP3), an important target of hypoxia-inducible factors-1 alpha (HIF-1α), was reported to be overexpressed under hypoxic condition. Our previous study demonstrated the protective effect on detached retina by BNIP3-mediated autophagy. The study investigated the role of BNIP3-mediated autophagy in retinal pigment epithelial (RPE) cells under hypoxia, and observed the relationship between BNIP3, vascular endothelial growth factor (VEGF) and inflammatory response in hypoxic RPE cells. Methods: BNIP3 knock down in retinal pigment epithelial cells was performed by small interfering RNA (siRNA) technology in ARPE-19 cells, a human RPE cell line. Both control and BNIP3-knockdown ARPE-19 cells were then subjected to a hypoxic challenge using cobalt (II) chloride (CoCl2). The expression of autophagy-related genes, VEGF and inflammatory factors (IL-18, IL-8, MMP-2, MMP-9, NLRP3, TNF-α) in RPE cells was examined using quantitative Polymerase Chain Reaction (qPCR). The protein levels of HIF-1α, BNIP3, the maker proteins (ATG5, LC3,p62, Beclin-1) of autophagy and the component proteins (p-p70S6K, p70S6K, mTOR, p-mTOR) of the mTORC1 pathway were analyzed by Western blot. BNIP3 subcellualr localization was detected by immunofluorescence. Cell viability was measured with Cell Counting kit-8. Cell apoptosis was examined by TUNEL staining and caspase-3 activity assay. Results: The expression levels of BNIP3, HIF-1α and marker genes of autophagy were upregulated in ARPE-19 cells in response to hypoxia. Importantly, hypoxia-induced autophagy was mediated by the mTORC1 pathway, and was blocked upon BNIP3 knockdown. Additionally, hypoxia reduced cell viability, which was relieved by an mTORC1 inhibitor. Also, autophagy protected ARPE-19 cells from CoCl2-induced cell apoptosis. Moreover, inhibition of autophagy upregulated the expression of VEGF and IL-18, and downregulated the expression of other inflammatory factors in the hypoxic ARPE-19 cells. Conclusion: BNIP3-mediated autophagy under hypoxia is involved in regulating inflammatory response and VEGF expression, which consequently affects the cell viability of RPE cells.

scholarly journals Overexpression of miR-874-3p alleviates LPS-induced apoptosis and inflammation in alveolar epithelial cell by targeting EGR3/NF-κB

2021 ◽  
Author(s):  
Huirun Yang ◽  
Yang Dong ◽  
Yan Zhou ◽  
Huajun Li
Keyword(s):  
Cell Viability ◽  
Cell Apoptosis ◽  
Promoter Activity ◽  
Pediatric Patients ◽  
Inflammatory Factors ◽  
Serum Samples ◽  
Expression Levels ◽  
Over Expression ◽  
Tnf Α ◽  
Lps Treatment

Objective: MicroRNA (miRNA) is implicated in the pathogenic mechanism of pneumonia. Role of miR-874-3p in pediatric pneumonia was therefore evaluated in this study. Methods: Expression levels of miR-874-3p in the serum samples from pediatric patients with pneumonia and LPS-treated HPAEpiC were determined by RT-qPCR (reverse transcription quantitative real-time PCR). Secretion of inflammatory factors in LPS-treated HPAEpiC were determined by qRT-PCR and ELISA. Cell viability and apoptosis were evaluated by CCK8 and flow cytometry, respectively. HPAEpiC was used for the validation of binding target of miR-874-3p. Mechanism was determined by NF-κB promoter activity assay. Results: MiR-874-3p was reduced in serum samples of pediatric patients with pneumonia, and LPS treatment dose-dependently decreased miR-874-3p expression in HPAEpiC. TNF-α and IL-1β expression levels were increased in HPAEpiC post LPS treatment. Over-expression of miR-874-3p attenuated LPS-induced increase of TNF-α and IL-1β and reversed LPS-induced decrease of cell viability and increase of cell apoptosis in HPAEpiC. EGR3 (early growth response 3), increased in LPS-induced HPAEpiC, was a target gene of miR-874-3p. EGR3 over-expression reversed miR-874-3p over-expression-induced increase of cell viability, decrease of cell apoptosis, TNF-α and IL-1β in LPS-induced HPAEpiC. Over-expression of miR-874-3p reduced p65 expression and NF-κB promoter activity in LPS-induced HPAEpiC, while EGR3 over-expression reversed these suppressive effects. Conclusion: MiR-874-3p negatively regulates EGR3 expression to promote cell viability and inhibit apoptosis as well as inflammation in LPS-treated HPAEpiC via suppression of NF-κB pathway, suggesting a potential therapeutic strategy for pneumonia.

scholarly journals Melatonin Represses Mitophagy to Protect Mouse Granulosa Cells from Oxidative Damage

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 968
Author(s):  
Yi Jiang ◽  
Ming Shen ◽  
Yuanyuan Chen ◽  
Yinghui Wei ◽  
Jingli Tao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Circadian Rhythms ◽  
Oxidative Damage ◽  
Cell Viability ◽  
Granulosa Cells ◽  
Therapeutic Target ◽  
Potential Therapeutic Target ◽  
Protective Mechanisms

Various environmental stimuli, including oxidative stress, could lead to granulosa cell (GC) death through mitophagy. Recently, it was reported that melatonin (MEL) has a significant effect on GC survival during oxidative damage. Here, we found that MEL inhibited oxidative stress-induced mitophagy to promote GC survival. The loss of cell viability upon H2O2 exposure was significantly restored after MEL treatment. Concomitantly, MEL inhibited the activation of mitophagy during oxidative stress. Notably, blocking mitophagy repressed GC death caused by oxidative stress. However, MEL cannot further restore viability of cells treated with mitophagy inhibitor. Moreover, PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase, was inhibited by MEL during oxidative stress. As a result, the E3 ligase Parkin failed to translocate to mitochondria, leading to impaired mitochondria clearance. Using RNAi to knock down PINK1 expression, we further verified the role of the MEL-PINK1-Parkin (MPP) pathway in maintaining GC survival by suppressing mitophagy. Our findings not only clarify the protective mechanisms of MEL against oxidative damage in GCs, but also extend the understanding about how circadian rhythms might influence follicles development in the ovary. These findings reveal a new mechanism of melatonin in defense against oxidative damage to GCs by repressing mitophagy, which may be a potential therapeutic target for anovulatory disorders.

scholarly journals Cholesterol Biosynthesis Is Required for Cell Death in Response to G9A Inhibitor in Lung Cancer (P05-010-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Ha Eun Kim ◽  
Seo Yoon Choi ◽  
Yoon Jung Park
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Viability ◽  
Rna Sequencing ◽  
Therapeutic Target ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Autophagic Cell Death ◽  
Potential Therapeutic Target ◽  
Western Blots

Abstract Objectives G9A is a eukaryotic histone methyltransferase that contributes to transcriptional silencing of tumor suppressor genes by modulating histone 3 lysine 9 methylation (H3K9m). It has been recently suggested as a promising therapeutic target for breast cancer and neuroblastoma. This study was aimed to investigate the effect of G9A inhibition and its cellular metabolic mechanisms. Methods Using OncomineTM, G9A overexpression in lung cancer was assessed. Cell viability upon treatment of G9A inhibitor (BIX01294, BIX) and siG9A was measured by MTT and IncuCyteR assays. Additionally, apoptosis and autophagy were analyzed through western blots. In order to identify targets, transcriptomes using RNA sequencing was conducted upon BIX treatment. Further functional relevance of targets was validated using Chromatin IP and recovery tests. Results BIX-mediated inhibition of G9A reduced cell viability of lung cancer cells via induction of autophagy. Through RNA sequencing, we found that G9A inhibition mainly affected cholesterol biosynthesis pathway. BIX directly induced the expression of SREBF2 gene, by lowering H3K9me1 and H3K9me2 at the promoter. A cholesterol biosynthesis inhibitor, 25-HC, partially recovered BIX-induced cell death by attenuating autophagy. Our data suggests that cholesterol metabolism can be a potential therapeutic target by G9A inhibition and its induction of autophagic cell death. Conclusions Our data suggests that cholesterol metabolism can be a potential therapeutic target by G9A inhibition and its induction of autophagic cell death. Funding Sources NRF of Korea grant (2018R1D1A1B07051274); BK21 Plus Project (22A20130012143).

Targeting the Otub1/c-Maf axis for the treatment of multiple myeloma

Blood ◽  
2020 ◽  
Author(s):  
Yujia Xu ◽  
Min Xu ◽  
Jiefei Tong ◽  
Xiaowen Tang ◽  
Jinhao Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Therapeutic Target ◽  
Cell Apoptosis ◽  
Transcriptional Activity ◽  
Potential Therapeutic Target ◽  
Recognition Element ◽  
Approved Drugs ◽  
Factor C ◽  
Fda Approved Drugs ◽  
Oncogenic Transcription Factor

The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM) but how to achieve it is still elusive. In the present study we found the Otub1/c-Maf axis could be a potential target. Otub1, an OTU family deubiquitinase, was found to interact with c-Maf by mass spectrometry. Otub1 abrogates c-Maf K48-linked polyubiquitination thus preventing its degradation and enhancing its transcriptional activity. Specifically, this deubiquitinating activity depends on its Lys71 and the N-terminus but independent UBE2O, a known E2 of c-Maf. Otub1 promotes MM cell survival and MM tumor growth. In contrast, silence of Otub1 leads to c-Maf degradation and c-Maf-expressing MM cell apoptosis. Therefore, the Otub1/c-Maf axis could be a therapeutic target of MM. In order to explore this concept, we performed a c-Maf-recognition element-driven luciferase-based screen against FDA-approved drugs and natural products, from which the generic cardiac glycoside lanatoside C (LanC) is found to prevent c-Maf de-ubiquitination and induces its degradation by disrupting the interaction of Otub1 and c-Maf. Consequently, LanC inhibits c-Maf transcriptional activity, induces c-Maf-expressing MM cell apoptosis, and suppresses MM growth and prolongs overall survival of model mice but without apparent toxicity. Therefore, the present study identifies Otub1 as a novel deubiquitinase of c-Maf and establishes that the Otub1/c-Maf axis is a potential therapeutic target for MM.

scholarly journals Regulation of the miR-19b-mediated SOCS6-JAK2/STAT3 pathway by lncRNA MEG3 is involved in high glucose-induced apoptosis in hRMECs

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Fan Xiao ◽  
Lan Li ◽  
Jing-Song Fu ◽  
Yu-Xiang Hu ◽  
Rong Luo
Keyword(s):  
Cell Viability ◽  
High Glucose ◽  
Caspase 3 ◽  
Signalling Pathway ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Protein Levels ◽  
Induced Apoptosis ◽  
Apoptosis And Inflammation ◽  
Stat3 Signalling

Abstract Objective: Diabetic retinopathy (DR) is one of the most severe and common complications of diabetes mellitus. The present study aimed to investigate the molecular mechanism of MEG3, miR-19b and SOCS6 in human retinal microvascular endothelial cells (hRMECs) under high glucose conditions. Methods: HRMECs were cultured in 5 or 30 mM D-glucose medium. qRT-PCR and Western blotting were used to determine the mRNA expression and protein levels. MTT assay and flow cytometry analysis were performed to detect the viability and apoptosis of hRMECs, respectively. TNF-α, IL-6 and IL-1β levels in cell supernatants were detected by ELISA. The activity of caspase-3/7 was also determined. A luciferase reporter assay was performed to confirm the targeting relationship between miR-19b and SOCS6, as well as MEG3 and miR-19b. Results: Our study demonstrated that miR-19b was increased and SOCS6 was decreased in HG-induced hRMECs. Knockdown of SOCS6 inhibited cell viability and reversed the promotion of cell viability induced by knockdown of miR-19b. Additionally, miR-19b directly targeted and negatively regulated SOCS6. Moreover, miR-19b promoted the cell apoptosis rate and caspase-3/7 activity and increased inflammatory factors through the SOCS6-mediated JAK2/STAT3 signalling pathway. In addition, MEG3 attenuated HG-induced apoptosis of hRMECs by targeting the miR-19b/SOCS6 axis. Conclusion: These findings indicate that MEG3 inhibited HG-induced apoptosis and inflammation by regulating the miR-19b/SOCS6 axis through the JAK2/STAT3 signalling pathway in hRMECs. Thus, these findings might provide a new target for the treatment of DR.

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