scholarly journals Saikosaponin D Attenuates Pancreatic Injury Through Suppressing the Apoptosis of Acinar Cell via Modulation of the MAPK Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Caixia Li ◽  
Lihua Cui ◽  
Lanqiu Zhang ◽  
Lei Yang ◽  
Yuzhen Zhuo ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
Acinar Cells ◽  
Pancreatic Injury ◽  
Mapk Signaling ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Acinar Cells ◽  
Drug Induced ◽  
Chinese Medicinal Herb ◽  
Ar42j Cells

Chronic pancreatitis (CP) is a progressive fibro-inflammatory syndrome. The damage of acinar cells is the main cause of inflammation and the activation of pancreatic stellate cells (PSCs), which can thereby possibly further aggravate the apoptosis of more acinar cells. Saikosaponind (SSd), a major active ingredient derived from Chinese medicinal herb bupleurum falcatum, which exerted multiple pharmacological effects. However, it is not clear whether SSd protects pancreatic injury of CP via regulating the apoptosis of pancreatic acinar cells. This study systematically investigated the effect of SSd on pancreatic injury of CP in vivo and in vitro. The results revealed that SSd attenuate pancreatic damage, decrease the apoptosis and suppress the phosphorylation level of MAPK family proteins (JNK1/2, ERK1/2, and p38 MAPK) significantly in the pancreas of CP rats. In addition, SSd markedly reduced the apoptosis and inflammation of pancreatic acinar AR42J cells induced by cerulein, a drug induced CP, or Conditioned Medium from PSCs (PSCs-CM) or the combination of PSCs-CM and cerulein. Moreover, SSd significantly inhibited the activated phosphorylation of JNK1/2, ERK1/2, and p38 MAPK induced by cerulein or the combination of PSCs-CM and cerulein in AR42J cells. Furthermore, SSd treatment markedly decreased the protein levels of p-JNK and p-p38 MAPK caused by PSCs-CM alone. In conclusion, SSd ameliorated pancreatic injury, suppressed AR42J inflammation and apoptosis induced by cerulein, interrupted the effect of PSCs-CM on AR42J cells inflammation and apoptosis, possibly through MAPK pathway.

PSD-95 protects the pancreas against pathological damage through p38 MAPK signaling pathway in acute pancreatitis

2021 ◽  
pp. 153537022110032
Author(s):  
Yinan Guo ◽  
Weikai Hu ◽  
Xueyan Wang ◽  
Chunyun Li ◽  
Tianyu Cui ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
P38 Mapk ◽  
Cell Model ◽  
Control Cell ◽  
Acinar Cells ◽  
Mapk Signaling ◽  
Pancreatic Tissue ◽  
Pancreatic Acinar Cells ◽  
Ar42j Cells ◽  
Inhibition Group

Acute pancreatitis is one of the leading causes of gastrointestinal disorder-related hospitalizations, yet its pathogenesis remains to be fully elucidated. Postsynaptic density protein-95 (PSD-95) is closely associated with tissue inflammation and injury. We aimed to investigate the expression of PSD-95 in pancreatic acinar cells, and its function in regulating the inflammatory response and pancreatic pathological damage in acute pancreatitis. A mouse model of edematous acute pancreatitis was induced with caerulein and lipopolysaccharide in C57BL/6 mice. Tat-N-dimer was injected to inhibit the PSD-95 activity separately, or simultaneously with SB203580, inhibitor of p38 MAPK phosphorylation. Rat pancreatic acinar cells AR42J were cultured with 1 μM caerulein to build a cell model of acute pancreatitis. PSD-95-knockdown and negative control cell lines were constructed by lentiviral transfection of AR42J cells. Paraffin-embedded pancreatic tissue samples were processed for routine HE staining to evaluate the pathological changes of human and mouse pancreatic tissues. Serum amylase and inflammatory cytokine levels were detected with specific ELISA kits. Immunofluorescence, immunohistochemical, Western-blot, and qRT-PCR were used to detect the expression levels of PSD-95, p38, and phosphorylated p38. Our findings showed that PSD-95 is expressed in the pancreatic tissues of humans, C57BL/6 mice, and AR42J cells, primarily in the cytoplasm. PSD-95 expression increased at 2 h, reaching the peak at 6 h in mice and 12 h in AR42J cells. IL-6, IL-8, and TNF-α increased within 2 h of disease induction. The pancreatic histopathologic score was greater in the PSD-95 inhibition group compared with the control ( P < 0.05), while it was lesser when phosphorylation of p38 MAPK was inhibited compared with the PSD-95 inhibition group ( P < 0.05). Moreover, phosphorylation of p38 MAPK increased statistically after PSD-95 knocked-down. In conclusion, PSD-95 effectively influences the pathological damage of the pancreas in acute pancreatitis by affecting the phosphorylation of p38 MAPK.

scholarly journals Pancreatogenic Diabetes: Triggering Effects of Alcohol and HIV

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 108
Author(s):  
Moses New-Aaron ◽  
Murali Ganesan ◽  
Raghubendra Singh Dagur ◽  
Kusum K. Kharbanda ◽  
Larisa Y. Poluektova ◽  
...  
Keyword(s):  
Multiorgan Failure ◽  
Acinar Cells ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Acinar Cells ◽  
Alcoholic Pancreatitis ◽  
People Living With Hiv ◽  
Zymogen Activation ◽  
Pancreatogenic Diabetes ◽  
Hiv Entry ◽  
Living With Hiv

Multiorgan failure may not be completely resolved among people living with HIV despite HAART use. Although the chances of organ dysfunction may be relatively low, alcohol may potentiate HIV-induced toxic effects in the organs of alcohol-abusing, HIV-infected individuals. The pancreas is one of the most implicated organs, which is manifested as diabetes mellitus or pancreatic cancer. Both alcohol and HIV may trigger pancreatitis, but the combined effects have not been explored. The aim of this review is to explore the literature for understanding the mechanisms of HIV and alcohol-induced pancreatotoxicity. We found that while premature alcohol-inducing zymogen activation is a known trigger of alcoholic pancreatitis, HIV entry through C-C chemokine receptor type 5 (CCR5) into pancreatic acinar cells may also contribute to pancreatitis in people living with HIV (PLWH). HIV proteins induce oxidative and ER stresses, causing necrosis. Furthermore, infiltrative immune cells induce necrosis on HIV-containing acinar cells. When necrotic products interact with pancreatic stellate cells, they become activated, leading to the release of both inflammatory and profibrotic cytokines and resulting in pancreatitis. Effective therapeutic strategies should block CCR5 and ameliorate alcohol’s effects on acinar cells.

The defense response of Caenorhabditis elegans to Cutibacterium acnes SK137 via the TIR-1-p38 MAPK signaling pathway

2021 ◽  
Author(s):  
Ayano Tsuru ◽  
Yumi Hamazaki ◽  
Shuta Tomida ◽  
Mohammad Shaokat Ali ◽  
Eriko Kage-Nakadai
Keyword(s):  
Caenorhabditis Elegans ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Defense Response ◽  
Mapk Pathway ◽  
Defense Responses ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Healthy Skin ◽  
Cutibacterium Acnes

Abstract Cutibacterium acnes plays roles in both acne disease and healthy skin ecosystem. We observed that mutations in the tir-1/SARM1 and p38 MAPK cascade genes significantly shortened Caenorhabditis elegans lifespan upon Cutibacterium acnes SK137 infection. Antimicrobial molecules were induced by SK137 in a TIR-1-dependent manner. These results suggest that defense responses against SK137 involve the TIR-1-p38 MAPK pathway in Caenorhabditis elegans.

Long non-coding RNA H19 acts as a microRNA-194 sponge to inhibit the apoptosis and promote the proliferation of hypertrophic scar fibroblasts

2021 ◽  
Author(s):  
Bo Liu ◽  
Lijuan Lin ◽  
Shengjin Yu ◽  
Rongjun Xia ◽  
Linlin Zheng
Keyword(s):  
P38 Mapk ◽  
Hypertrophic Scar ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Hypertrophic Scars ◽  
Downstream Effector ◽  
Non Coding Rna ◽  
Proliferation And Apoptosis ◽  
Signaling Axis ◽  
Underlying Mechanisms

The effects of long non-coding RNAs (lncRNAs) on the proliferation of hypertrophic scars have been described. However, the underlying mechanisms are not well characterized. The present study aimed to investigate the mechanisms of lncRNA H19 in hypertrophic scars. The effects of the lncRNA H19 on the proliferation and apoptosis of hypertrophic scar fibroblasts (HSFs) were analyzed using 5’-Ethynyl-2’-deoxyuridine staining, flow cytometry, and MTT. The results revealed H19 promoted the proliferation and inhibited the apoptosis in HSF. In addition, the binding associations between H19 and microRNA-194 (miR-194), and miR-194 and insulin-like growth factor-I receptor (IGF1R) were identified using bioinformatics screening and verified using dual-luciferase assays. Furthermore, the effects of the IGF1R knockdown on H19-induced HSF phenotypes and regulation over the p38 MAPK pathway were determined. Mechanistically, miR-194 was identified as the downstream effector of the H19-mediated phenotypes of HSFs through its ability to directly target IGF1R, thus modulating the p38 MAPK signaling pathway. In conclusion, the findings suggested that H19 may inhibit the apoptosis and promote the proliferation of HSFs through the miR-194/IGF1R/p38 MAPK signaling axis, thereby contributing to the progression of hypertrophic scars. These findings may provide novel targets for the treatment of hypertrophic scars.

Activated Pancreatic Stellate Cells Promote Acinar Duct Metaplasia by Disrupting Mitochondrial Respiration and Releasing Reactive Oxygen Species

2021 ◽  
Vol 01 ◽  
Author(s):  
Hong Xiang ◽  
Fangyue Guo ◽  
Qi Zhou ◽  
Xufeng Tao ◽  
Deshi Dong
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Respiration ◽  
Reactive Oxygen ◽  
Acinar Cells ◽  
Stellate Cells ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Acinar Cells ◽  
Oxygen Species

Background: Chronic pancreatitis (CP) is a long-term risk factor for pancreatic ductal adenocarcinoma (PDAC), and both diseases share a common etiology. The activation of Pancreatic stellate cells (PaSCs) caused by inflammation of the chronic pancreas plays a pivotal role in the pathology of pancreatic fibrosis and the malignant phenotype of PDAC. However, the central role of activated PaSCs in acinar-to-ductal metaplasia (ADM) remains unknown. Objective: In the present study, we investigated the link between pancreatic fibrosis and ADM and the possible underlying mechanism. Methods: A caerulein-treated mouse CP model was established, and Masson trichrome histochemical stain and transmission electron microscope (TEM) were used to observe stromal fibrosis and cell ultrastructure, respectively. The expression of amylase and cytokeratin 19 (CK19), mitochondria respiration, and reactive oxygen species (ROS) were detected in vitro in the co-culture model of primary pancreatic acinar cells and PaSCs. Results: The activation of PaSCs and pancreatic fibrosis were accompanied by ADM in pancreatic parenchyma in caerulein-treated mice, which was verified by the co-cultivation experiment in vitro. Furthermore, we showed that activated PaSCs promote ADM by disrupting mitochondrial respiration and releasing ROS. The expression of inflammation-and ADM-related genes, including S100A8, S100A9, and CK19, was observed to be up-regulated in pancreatic acinar cells in the presence of activated PaSCs. The expression of S100A9 and CK19 proteins was also up-regulated in acinar cells co-cultured with activated PaSCs. Conclusion: The manipulation of mitochondrial respiration and ROS release is a promising preventive and/or therapeutic strategy for PDAC, and S100A9 is expected to be a therapeutic target to block the ADM process induced by the activation of PaSCs.

scholarly journals Transgenic expression of cyclooxygenase-2 in pancreatic acinar cells induces chronic pancreatitis

2019 ◽  
Vol 316 (1) ◽  
pp. G179-G186
Author(s):  
Haojie Huang ◽  
Jiaxiang Chen ◽  
Lisi Peng ◽  
Yao Yao ◽  
Defeng Deng ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Transgenic Mice ◽  
Fibrous Tissue ◽  
Acinar Cells ◽  
Cyclooxygenase 2 ◽  
Therapeutic Interventions ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Acinar Cells ◽  
Transgenic Expression ◽  
Cox 2

Replacement of the exocrine parenchyma by fibrous tissue is a main characteristic of chronic pancreatitis. Understanding the mechanisms of pancreatic fibrogenesis is critical for the development of preventive and therapeutic interventions. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin synthesis, is expressed in patients with chronic pancreatitis. However, it is unknown whether COX-2 can cause chronic pancreatitis. To investigate the roles of pancreatic acinar COX-2 in fibrogenesis and the development of chronic pancreatitis, COX-2 was ectopically expressed specifically in pancreatic acinar cells in transgenic mice. Histopathological changes and expression levels of several profibrogenic factors related to chronic pancreatitis were evaluated. COX-2 was expressed in the pancreas of the transgenic mice, as detected by Western blot analysis. Immunohistochemical staining showed COX-2 was specifically expressed in pancreatic acinar cells. COX-2 expression led to progressive changes in the pancreas, including pancreas megaly, persistent inflammation, collagen deposition, and acinar-to-ductal metaplasia. Quantitative RT-PCR and immunostaining showed that profibrogenic factors were upregulated and pancreatic stellate cells were activated in the COX-2 transgenic mice. Expression of COX-2 in pancreatic acinar cells is sufficient to induce chronic pancreatitis. Targeting this pathway may be valuable in the prevention of chronic pancreatitis. NEW & NOTEWORTHY COX-2 expression is observed in pancreatic tissues of human chronic pancreatitis. In this study, we showed that COX-2 expression caused the development of chronic pancreatitis in transgenic mice, supporting the idea that COX-2 inhibition may be an effective preventive and therapeutic strategy.

scholarly journals APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

2011 ◽  
Vol 300 (1) ◽  
pp. E103-E110 ◽  
Author(s):  
Xiaoban Xin ◽  
Lijun Zhou ◽  
Caleb M. Reyes ◽  
Feng Liu ◽  
Lily Q. Dong
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Adaptor Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Scaffolding Protein ◽  
Mapk Activation ◽  
P38 Mapk Pathway ◽  
Mitogen Activated Protein

The adaptor protein APPL1 mediates the stimulatory effect of adiponectin on p38 mitogen-activated protein kinase (MAPK) signaling, yet the underlying mechanism remains unclear. Here we show that, in C2C12 cells, overexpression or suppression of APPL1 enhanced or suppressed, respectively, adiponectin-stimulated p38 MAPK upstream kinase cascade, consisting of transforming growth factor-β-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase 3 (MKK3). In vitro affinity binding and coimmunoprecipitation experiments revealed that TAK1 and MKK3 bind to different regions of APPL1, suggesting that APPL1 functions as a scaffolding protein to facilitate adiponectin-stimulated p38 MAPK activation. Interestingly, suppressing APPL1 had no effect on TNFα-stimulated p38 MAPK phosphorylation in C2C12 myotubes, indicating that the stimulatory effect of APPL1 on p38 MAPK activation is selective. Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation.

MiR-155 aggravates impaired autophagy of pancreatic acinar cells through targeting Rictor

2020 ◽  
Vol 52 (2) ◽  
pp. 192-199 ◽  
Author(s):  
Xueming Zhang ◽  
Jiangtao Chu ◽  
Haijun Sun ◽  
Dali Zhao ◽  
Biao Ma ◽  
...  
Keyword(s):  
Acinar Cells ◽  
Immunofluorescence Assay ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Luciferase Reporter ◽  
Cellular Model ◽  
Protein Levels ◽  
Ar42j Cells ◽  
Direct Target ◽  
Dual Luciferase Reporter Assay

Abstract The aim of this study was to investigate the role and mechanism of miR-155 in regulating autophagy in a caerulein-induced acute pancreatitis (AP) cellular model. GFP-LC3 immunofluorescence assay was performed to detect autophagy vesicle formation in pancreatic acinar cell line AR42J. AR42J cells were transfected with miR-155 mimic, inhibitor, and corresponding controls to explore the effect of miR-155 on autophagy. The protein levels of LC3-I, LC3-II, Beclin-1, and p62 were analyzed by western blot analysis. Dual-luciferase reporter assay was performed to verify the interaction between miR-155 and Rictor (RPTOR independent companion of MTOR complex 2). The results showed that caerulein treatment induced impaired autophagy as evidenced by an increase in the accumulation of p62 together with LC3-II in AR42J cells, accompanied by miR-155 upregulation. Furthermore, miR-155 overexpression aggravated, whereas miR-155 silencing reduced the caerulein-induced impairment of autophagy. Mechanistically, Rictor was confirmed to be a direct target of miR-155, which could rescue the miR-155 overexpression-mediated aggravation of impaired autophagy. Collectively, these findings indicate that miR-155 aggravates impaired autophagy in caerulein-treated pancreatic acinar cells by targeting Rictor.

scholarly journals Estrogen Enhances Matrix Synthesis in Nucleus Pulposus Cell through the Estrogen Receptor β-p38 MAPK Pathway

2016 ◽  
Vol 39 (6) ◽  
pp. 2216-2226 ◽  
Author(s):  
Pei Li ◽  
Yuan Xu ◽  
Yibo Gan ◽  
Liyuan Wang ◽  
Bin Ouyang ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Matrix Synthesis ◽  
P38 Mapk Pathway ◽  
Collagen Ii

Background/Aims: Matrix homeostasis within the disc nucleus pulposus (NP) tissue is important for disc function. Increasing evidence indicates that sex hormone can influence the severity of disc degeneration. This study was aimed to study the role of 17β-estradiol (E2) in NP matrix synthesis and its underlying mechanism. Methods: Rat NP cells were cultured with (10-5, 10-7 and 10-9 M) or without (control) E2 for48 hours. The estrogen receptor (ER)-β antagonist PHTPP and ERβ agonist ERB 041 were used to investigate the role mediated by ERβ. The p38 MAPK inhibitor SB203580 was used to investigate the role of p38 MAPK signaling pathway. Gene and protein expression of SOX9, aggrecan and collagen II, glycosaminoglycan (GAG) content, and immunostaining assay for aggrecan and collagen II were analyzed to evaluate matrix production in rat NP cells. Results: E2 enhanced NP matrix synthesis in a concentration-dependent manner regarding gene and proetin expression of SOX9, aggrecan and collagen II, protein deposition of aggrecan and collagen II, and GAG content. Moreover, activation of p38 MAPK signaling pathway was increased with elevating E2 concentration. Further analysis indicated that ERB 041 and PHTPP could respectively enhance and suppress effects of E2 on matrix synthesis in NP cells, as well as activation of p38 MAPK pathway. Additionally, inhibition of p38 MAPK signaling pathway significantly abolished the effects of E2 on matrix synthesis. Conclusion: E2 can enhance matrix synthesis of NP cells and the ERβ/p38 MAPK pathway is involved in this regulatory process.

scholarly journals Rhein Induces a Necrosis-Apoptosis Switch in Pancreatic Acinar Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Xianlin Zhao ◽  
Juan Li ◽  
Shifeng Zhu ◽  
Yiling Liu ◽  
Jianlei Zhao ◽  
...  
Keyword(s):  
Annexin V ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Necrotic Cell ◽  
Ar42j Cells ◽  
Associated Proteins ◽  
Apoptosis And Necrosis ◽  
Dose Dependent

Objectives. The Chinese herbal medicine Da-Cheng-Qi decoction can regulate a necrosis-apoptosis switch in injured pancreatic acinar cells. This study investigated the effects of rhein, a component of this medicine, on a necrosis-apoptosis switch in pancreatic rat AR42J cells.Methods. Cerulein-treated AR42J cells were used. After pretreatment with 479, 119.8, or 29.9 μg/L rhein, cells were cocultured with rhein and cerulein (10−8 M) for 4, 8, or 16 h. Apoptosis and necrosis were examined using annexin V and propidium iodide costaining. Mitochondria-dependent apoptosis-associated proteins were examined using enzyme-linked immunosorbent assays and western blotting.Results. Few cells died in untreated samples. The number was significantly higher in 16-h-cerulein-treated samples and treatment with 479 μg/L rhein most effectively increased the apoptotic-to-necrotic cell ratio (P<0.05). In cerulein-treated cells, rhein increased the concentrations of p53, cytochrome C, and caspase-3, and increased the Bax/Bcl-2 ratio in a time- and dose-dependent manner, with the maximum effect in cells treated with 479 μg/L rhein for 16 h (P<0.05).Conclusions. Rhein induces the necrosis-apoptosis switch in injured pancreatic acinar cells in a time- and dose-dependent manner. Mitochondria-dependent apoptosis signaling pathways might play an important role in this effect.

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