MicroRNA-708 represses hepatic stellate cells activation and proliferation by targeting ZEB1 through Wnt/β-catenin pathway

Yang, Jun; Tao, Qing; Zhou, Yiwen; Chen, Yi‐Ping Phoebe; Li, Liang-yun; Hu, Shuang; Liu, Yumin; Shu, Jinling; Zhang, Xian‐Zheng; Zhang, Lei; Zhang, Lingling

doi:10.1016/j.ejphar.2020.172927

Cited by 19 publications

(12 citation statements)

References 63 publications

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“…Due to their stability in the circulation, 31 either protein‐bound or exosome‐encapsulated microRNAs have shown promise in evaluation of fibrosis in NASH 44 . In our mouse models, 30 we found a significant portion of miRNAs that were upregulated by proglumide in tissues and blood (e.g., miR‐185‐5p, 25 miR‐378a‐3p, 22 miR708‐5p, 24 and miR‐346‐5p, 45 ) had previously been shown to inhibit fibrosis, inflammation, or both from activated hepatic stellate cells. A significant fold increase in the expression of these miRNAs would imply there was fibrinolysis or cessation of fibrogenesis in the livers of our study participants while administered proglumide.…”

Section: Discussionmentioning

confidence: 80%

Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non‐alcoholic Steatohepatitis

Rabiee¹,

Gay

Shivapurkar

et al. 2022

Clin Pharma and Therapeutics

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High saturated fat diets have been shown to raise blood levels of cholecystokinin (CCK) and induce nonalcoholic steatohepatitis (NASH). CCK receptors are expressed on stellate cells and are responsible for hepatic fibrosis when activated. The purpose of this study was to test the safety and dose of a CCK receptor antagonist, proglumide, in human participants with NASH. An open‐label single ascending dose study was conducted in 18 participants with clinical NASH based upon steatosis by liver ultrasound, elevated hepatic transaminases, and a component of the metabolic syndrome. Three separate cohorts (N = 6 each) were treated with oral proglumide for 12 weeks in a sequential ascending fashion with 800 (Cohort 1), 1,200 (Cohort 2), and 1,600 (Cohort 3) mg/day, respectively. Blood hematology, chemistries, proglumide levels, a biomarker panel for fibrosis, and symptom surveys were determined at baseline and every 4 weeks. Abdominal ultrasounds and transient elastography utilizing FibroScan were obtained at baseline and at Week 12. Proglumide was well tolerated at all doses without any serious adverse events. There was no change in body weight from baseline to Week 12. For Cohorts 1, 2, and 3, the median percent change in alanine aminotransferase was 8.42, −5.05, and −22.23 and median percent change in fibrosis score by FibroScan was 8.13, −5.44, and −28.87 (kPa), respectively. Hepatic steatosis as measured by controlled attenuation parameter score significantly decreased with proglumide, (P < 0.05). Blood microRNA biomarkers and serum 4‐hydroxyproline were consistent with decreased fibrosis at Week 12 compared with baseline. These findings suggest proglumide exhibits anti‐inflammatory and anti‐fibrotic properties and this compound is well tolerated in participants with NASH.

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Section: Discussionmentioning

confidence: 80%

Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non‐alcoholic Steatohepatitis

Rabiee¹,

Gay

Shivapurkar

et al. 2022

Clin Pharma and Therapeutics

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“…The microRNAs (miR) miR-185-5p, miR-346-5p, miR-378-3p, miR-708-5p are known to inhibit fibrosis from stellate cells [ 46 , 47 , 48 , 49 ]. These were significantly upregulated in the peripheral blood of mice treated with the combination therapy in the mT3-2D immunocompetent PDAC model ( Figure 6 B).…”

Section: Resultsmentioning

confidence: 99%

“…Strikingly, a significant portion of miRNAs from the panel have been reported for their implication in regulation of inflammation, fibrosis and oncogenesis. Among others, miR-185-5p, miR-346-5p, miR-378a-3p, miR-708-5p [ 46 , 47 , 48 , 49 ] are upregulated by proglumide and have been clearly shown to inhibit fibrosis. In the case of miR-185-5p, miR-378a-3p, miR-708-5p this effect is through inhibition of stellate cell activation.…”

Section: Discussionmentioning

confidence: 99%

Cholecystokinin Receptor Antagonist Improves Efficacy of Chemotherapy in Murine Models of Pancreatic Cancer by Altering the Tumor Microenvironment

Malchiodi

Cao

Safronenka

et al. 2021

Cancers

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Pancreatic cancer is resistant to chemotherapy in part due to the dense desmoplastic fibrosis surrounding the tumor, the immunosuppressive cells in the tumor microenvironment (TME), and the early rate of metastases. In this study, we examined the effects of a CCK receptor antagonist, proglumide, alone and in combination with gemcitabine in murine models of pancreatic cancer. Tumor growth rate, metastases, and survival were assessed in mice bearing syngeneic murine or human pancreatic tumors treated with PBS (control), gemcitabine, proglumide, or the combination of gemcitabine and proglumide. Excised tumors were evaluated histologically for fibrosis, immune cells, molecular markers, and uptake of chemotherapy by mass spectroscopy. Peripheral blood was analyzed with a microRNAs biomarker panel associated with fibrosis and oncogenesis. Differentially expressed genes between tumors of mice treated with gemcitabine monotherapy and combination therapy were compared by RNAseq. When given in combination the two compounds exhibited inhibitory effects by decreasing tumor growth rate by 70%, metastases, and prolonging survival. Proglumide monotherapy altered the TME by decreasing fibrosis, increasing intratumoral CD8+ T-cells, and decreasing arginase-positive cells, thus rendering the tumor sensitive to chemotherapy. Proglumide altered the expression of genes involved in fibrosis, epithelial–mesenchymal transition, and invasion. CCK-receptor antagonism with proglumide renders pancreatic cancer susceptible to chemotherapy.

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“…Zinc finger E-box binding homeobox 1 (ZEB1) is a transcription factor which has critical roles in epithelial-mesenchymal transition (EMT), senescence, and angiogenesis (19)(20)(21). It has been reported that ZEB1 induces inflammatory response in periodontal disease and liver fibrosis (22,23). In addition, the p38 MAPK signaling pathway is associated with septic lung injury (24)(25)(26).…”

Section: Mir-374a-5p Alleviates Sepsis-induced Acute Lung Injury By T...mentioning

confidence: 99%

miR‑374a‑5p alleviates sepsis‑induced acute lung injury by targeting ZEB1 via the p38 MAPK pathway

Shen

2022

Exp Ther Med

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The aim of the present study was to investigate the effects of microRNA (miR)-374a-5p on sepsis-induced acute lung injury (ALI) and the associated mechanism. Lipopolysaccharide (LPS)-induced human pulmonary microvascular endothelial cells (HPMVECs) were used to construct the cellular model of sepsis. A luciferase reporter assay was performed to confirm the association between miR-374a-5p and zinc finger E-box binding homeobox 1 (ZEB1). Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to assess the relative expression of miR-374a-5p, ZEB1 and apoptosis-related proteins. Cell viability and apoptosis were determined by Cell Counting Kit-8 assay and flow cytometry, respectively. Enzyme-linked immunosorbent assays were used to evaluate inflammatory cytokines. The results revealed that miR-374a-5p was downregulated in sepsis patients and LPS-treated HPMVECs. Upregulation of miR-374a-5p alleviated LPS-triggered cell injury in HPMVECs, as evidenced by restoration of cell viability, and inhibition of apoptosis and the production of proinflammatory cytokines. In addition, ZEB1 was revealed to be a downstream target of miR-374a-5p, and overexpression of ZEB1 could reverse the anti-apoptotic and anti-inflammatory effects of miR-374a-5p on an LPS-induced sepsis cell model. Moreover, miR-374a-5p-induced protective effects involved the p38 MAPK signaling pathway. Collectively, miR-374a-5p exerted a protective role in sepsis-induced ALI by regulating the ZEB1-mediated p38 MAPK signaling pathway, providing a potential target for the diagnosis and treatment of sepsis.

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MicroRNA-708 represses hepatic stellate cells activation and proliferation by targeting ZEB1 through Wnt/β-catenin pathway

Cited by 19 publications

References 63 publications

Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non‐alcoholic Steatohepatitis

Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non‐alcoholic Steatohepatitis

Cholecystokinin Receptor Antagonist Improves Efficacy of Chemotherapy in Murine Models of Pancreatic Cancer by Altering the Tumor Microenvironment

miR‑374a‑5p alleviates sepsis‑induced acute lung injury by targeting ZEB1 via the p38 MAPK pathway

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