Bone marrow-derived mesenchymal stem cells alleviates renal injury in severe acute pancreatitis via RhoA/Rho kinase. Chen Xian-Qiang,Yao Yi,Huang He-Guang International journal of clinical and experimental pathology Acute pancreatitis (AP) is a common acute abdominal disease, 10%-20% of which can evolve into severe acute pancreatitis (SAP). SAP causes significant morbidity and mortality. RhoA/Rho kinase is activated in SAP. Bone marrow-derived mesenchymal stem cells (BMSCs) have been demonstrated to be a therapeutic role in SAP, but the underlying molecular mechanism is still unclear. This study was designed to determine whether RhoA/Rho kinase involved in APS, and the specific mechanism of BMSCs in APS. We validated that BMSCs could promote renal repair, reduce the ratio of wet to dry kidney weight, renal EB concentration, pancreatic edema and serum amylase, Cr, BUN and systemic TNF-α, IL-6 levels. BMSCs also reduce ROCK I and increase ZO-1 protein levels in APS, but the effects are inhibited by RhoA/Rho promoter CNF1. These results indicated that BMSCs can alleviate SAP rat kidney injury by inhibiting the RhoA/Rho kinase signaling pathways, increase the ZO-1 expression, reduce capillary permeability, blood capillary leakage and improve renal function.

Serotonin-RhoA/ROCK axis promotes acinar-to-ductal metaplasia in caerulein-induced chronic pancreatitis. Tao Xufeng,Chen Qing,Li Ning,Xiang Hong,Pan Yue,Qu Yueyang,Shang Dong,Go Vay Liang W,Xue Jing,Sun Yongwei,Zhang Zhigang,Guo Junchao,Xiao Gary Guishan Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie The underlying molecular mechanisms of chronic pancreatitis (CP) developing into pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. Here we show that the level of serotonin in mouse pancreatic tissues is upregulated in caerulein-induced CP mice. In vitro study demonstrates that serotonin promotes the formation of acinar-to-ductal metaplasia (ADM) and the activation of pancreatic stellate cells (PSCs), which results from the activation of RhoA/ROCK signaling cascade. Activation of this signaling cascade increases NF-κB nuclear translocation and α-SMA expression, which further enhance the inflammatory responses and fibrosis in pancreatic tissues. Intriguingly, quercetin inhibits both ADM lesion and PSCs activation in vitro and in vivo via its inhibitory effect on serotonin release. Our findings underscore the instrumental role of serotonin-mediated activation of RhoA/ROCK signaling pathway in development of PDAC from CP and highlight a potential to impede PDAC development by disrupting tumor-promoting functions of serotonin. 10.1016/j.biopha.2020.109999

Effect of bone marrow mesenchymal stem cells on RhoA/ROCK signal pathway in severe acute pancreatitis. Cai Jianping,Zhou Xianghong,Yu Haibo,Xue Huanzhou,Li Deyu American journal of translational research The effect of bone marrow mesenchymal stem cells (BMSCs) on RhoA/ROCK signal pathway expression in severe acute pancreatitis (SAP) was investigate in the present study. SAP model was established by retrograde injection of 5% sodium taurocholate into biliopancreatic duct. SD rats were then randomly divided into four groups: normal control, untreated SAP, BMSCs transplant + SAP and ROCK inhibitor + SAP groups (N = 30 each). All rats were sacrificed at 6, 12 and 24 h followed by analysis of serum amylase, TNF-α and IL-6 levels by ELISA, RhoA and ROCK I expression in pancreatic tissues by Western blot, morphological change by HE staining. CM-Dil labelled BMSC can be observed in transplant group. Compared to control group, untreated SAP group had significantly elevated serum amylase, ascites, and levels of TNF-α and IL-6 (P<0.05) in a time-dependent manner, with enhanced pancreatic RhoA and ROCK I protein expression (P<0.05). However, BMSCs transplant group showed decreased serum amylase, ascites, TNF-α and IL-6, plus lower RhoA or ROCK I protein expression (P<0.05). Meanwhile, Y-27632 intervention group also showed lower serum amylase or ascites, plus lower RhoA or ROCK I (P<0.05). HE staining showed improved pathological score in BMSCs transplant or Y-27632 intervention group (only at 6 h time point) compared to untreated SAP group (P<0.05). Pancreatic expression of RhoA and ROCK I is up-regulated in SAP, with severe pancreatic tissue damage. BMSCs can alleviate pancreatic injury possibly through decreasing serum inflammatory factor level and inhibiting RhoA/ROCK signal pathway.

Captopril pretreatment protects the lung against severe acute pancreatitis induced injury via inhibiting angiotensin II production and suppressing Rho/ROCK pathway. Yu Qi-Hong,Guo Jie-Fang,Chen Yan,Guo Xiao-Rong,Du Yi-Qi,Li Zhao-Shen The Kaohsiung journal of medical sciences Acute pancreatitis (AP) usually causes acute lung injury, which is also known as acute pancreatitis associated lung injury (APALI). This study aimed to investigate whether captopril pretreatment was able to protect lung against APALI via inhibiting angiotensin II (Ang II) production and suppressing Rho/ROCK (Rho kinase) pathway in rats. Severe AP (SAP) was introduced to rats by bile-pancreatic duct retrograde injection of 5% sodium taurocholate. Rats were randomly divided into three groups. In the sham group, sham operation was performed; in the SAP group, SAP was introduced; in the pre-cpl + SAP group, rats were intragastrically injected with 5 mg/kg captopril 1 hour prior to SAP induction. Pathological examination of the lung and pancreas, evaluation of pulmonary vascular permeability by wet/dry ratio and Evans Blue staining, detection of serum amylase, Western blot assay for Ang II receptor type 1 (AT1), RhoA, ROCK (Rho kinase), and MLCK (myosin light chain kinase) were performed after the animals were sacrificed at 24 hours. After the surgery, characteristic findings of pancreatitis were observed, accompanied by lung injury. The serum amylase, Ang II, and lung expression of AT1, RhoA, ROCK, and MLCK increased dramatically in SAP rats. However, captopril pretreatment improved the histological changes, reduced the pathological score of the pancreas and lung, inhibited serum amylase and Ang II production, and decreased expression of AT1, RhoA, ROCK, and MLCK in the lung. These findings suggest that captopril pretreatment is able to protect the lung against APALI, which is, at least partially, related to the inhibition of Ang II production and the suppression of the Rho/ROCK pathway. 10.1016/j.kjms.2016.07.008