Publications by authors named "Hengyue Zhu"

16 Publications

  • Page 1 of 1

Multifunctional T cell response in active pulmonary tuberculosis patients.

Int Immunopharmacol 2021 Oct 29;99:107898. Epub 2021 Jul 29.

Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address:

Background: Tuberculosis still threatens human health. We aimed to investigate the T cell immune status and the role of multifunctional T cells in pulmonary tuberculosis patients.

Methods: Thirty active pulmonary tuberculosis (APTB) patients, 30 latent tuberculosis infection (LTBI) patients, 25 cured pulmonary tuberculosis (CPTB) patients and 25 healthy controls (HCs) enrolled in this study. Flow cytometer for detecting T cell phenotype and function. CBA Flex Set was used to measure chemokine.

Results: Compared with HCs and LTBI patients, APTB patients had fewer CD4 T and CD8 T cells, but the expression of granzyme A, granzyme B and perforin on CD8 T cells increased. Compared to LTBI and CPTB patients, Mycobacterium tuberculosis-specific CD8 T cells in APTB patients appeared to be more differentiated CD45RACCR7 cells, and there were more multifunctional CD4 T and CD8 T cells. Importantly, the frequency of multifunctional CD4 T cells in the pleural fluid of APTB patients was higher than that of peripheral blood. And the proportion of multifunctional CD4 T cells expressing the migration receptor CXCR3 in the peripheral blood of APTB patients decreased, while the concentrations of its ligands, chemokine MIG, IP-10 and I-TAC increased significantly in plasma, especially in pleural fluid.

Conclusions: Decreased T lymphocytes in APTB patients may cause compensatory activation of CD8 T cells. Multifunctional CD4 T cells in peripheral blood could migrate to the lungs under the action of CXCR3 and associated chemokine. Multifunctional CD4 T cells and Multifunctional CD8 T cells were of great significance in monitoring disease treatment.
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http://dx.doi.org/10.1016/j.intimp.2021.107898DOI Listing
October 2021

NUDCD1 knockdown inhibits the proliferation, migration, and invasion of pancreatic cancer via the EMT process.

Aging (Albany NY) 2021 07 29;13(14):18298-18309. Epub 2021 Jul 29.

School of Stomatology, Wenzhou Medical University, Wenzhou 110013, China.

NudC domain containing 1 (NUDCD1) is an oncoprotein frequently activated or upregulated in various human cancers, but its role in pancreatic cancer (PC) remains unknown. Thus, we aimed to determine the function and mechanism of NUDCD1 in PC. We employed Western blot and quantitative real-time polymerase chain reaction to assess NUDCD1 expression in cells and PC tissues. NUDCD1 was knocked down in Patu8988 and PANC-1 cells. We conducted real-time cell analysis, wound healing assay, transwell assay and colony formation assay to evaluate the metastatic and proliferative abilities of PC cells. Western blot was conducted to assess the expression of markers associated with apoptosis and epithelial-mesenchymal transition (EMT). Also, we established a tumor xenograft model to determine the role of NUDCD1 . NUDCD1 was overexpressed in PC tissues and cells. NUDCD1 knockdown suppressed the invasion, migration, and proliferative abilities of the cells and induced PC cell apoptosis. The specific mechanism of NUDCD1 was related to the modulation of the EMT process. Data obtained from experiments revealed that NUDCD1 knockdown inhibited the tumor growth, proliferation, and metastasis by modulating the EMT and inducing the apoptosis of PC cells.
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http://dx.doi.org/10.18632/aging.203276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351729PMC
July 2021

The anti-dysenteric drug fraxetin enhances anti-tumor efficacy of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation.

Aging (Albany NY) 2021 07 28;13(14):18545-18563. Epub 2021 Jul 28.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Fraxetin, a natural product isolated and purified from the bark of , has anti-inflammatory, analgesic, and anti-dysenteric activities. This study aimed to investigate the anti-tumor effects of fraxetin in pancreatic ductal adenocarcinoma (PDA). The effects of fraxetin on the malignant biological behavior of PDA were evaluated. Besides, the effects of fraxetin on the sensitivity of PCCs to gemcitabine, angiogenesis, the epithelial-mesenchymal transition (EMT), glucose metabolism, reactive oxygen species (ROS), and STAT3 activity were analyzed. By reversing the EMT, fraxetin suppressed proliferation, invasion, and migration, and induced mitochondrial-dependent apoptosis in PCCs. Also, treatment with fraxetin inhibited PDA growth and metastasis in nude mouse models. Furthermore, fraxetin made PCCs more sensitive to the chemotherapy drug gemcitabine. Mechanically, fraxetin treatment suppressed oncogenic KRAS-triggered STAT3 activation in PCCs and PDA tissues. Fraxetin shows significant interactions with STAT3 Src Homology 2 (SH2) domain residues, thereby preventing its homo-dimer formation, which then blocks the activation of downstream signal pathways. The anti-tumor activity of fraxetin in PDA was functionally rescued by a STAT3 activator colivelin. As a result, fraxetin hindered hypoxia-induced angiogenesis by decreasing HIF-1α and VEGFA expression, controlled glucose metabolism by reducing GLUT1 expression, inhibited the EMT by blocking the Slug-E-cadherin axis, and drove ROS-mediated apoptosis by regulating the STAT3-Ref1 axis. In conclusion, fraxetin enhances the anti-tumor activity of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation.
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http://dx.doi.org/10.18632/aging.203301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351699PMC
July 2021

Correction to: Chemopreventive effect of Betulinic acid via mTOR -Caspases/Bcl2/Bax apoptotic signaling in pancreatic cancer.

BMC Complement Med Ther 2021 Apr 26;21(1):131. Epub 2021 Apr 26.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, Wenzhou Medical University First Affiliated Hospital, Wenzhou, Zhejiang, China.

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http://dx.doi.org/10.1186/s12906-021-03254-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074483PMC
April 2021

Highly activated TRAIL CD56 NK cells are associated with the liver damage in HBV-LC patients.

Immunol Lett 2021 Apr 27;232:9-19. Epub 2021 Jan 27.

Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. Electronic address:

Background: Chronic hepatitis B-related liver cirrhosis(HBV-LC)is the most common cirrhosis in China, which is characterized as liver damage and high mortality. We aim to investigate the characteristics of TRAILNK cells in patients with HBV-LC and their relationship with liver damage in patients with HBV-LC.

Methods: Thirty cases each of chronic hepatitis B (CHB), HBV-related compensated liver cirrhosis (HBV-CLC) and HBV-related decompensated liver cirrhosis (HBV-DLC) patients were recruited in this study. Thirty age-and sex-matched healthy individuals were recruited as healthy controls (HCs). NK cell phenotypes were determined using flow cytometry. Serum chemokine concentrations were ascertained using the CBA Flex set. Cell apoptosis was analyzed using the Annexin V-PE/7-AAD apoptosis Kit.

Results: CD56 NK cells increased, but CD56 NK cells reduced in HBV-LC patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was mainly expressed on CD56 NK cells. As the degree of liver damage increased, the frequency and activation of total TRAILNK cells and TRAILNK cell subsets continued to increase, especially in the HBV-LC patients. Furthermore, the difference in frequency and activation of total TRAILNK cells between the HBV-CLC and HBV-DLC groups was mainly due to the highly activation and increase of TRAILCD56 NK cells. With the increasing degree of liver damage, CXCR3-associated chemokines (including CXCL9, CXCL10 and CXCL11) were constantly increased, particularly in the HBV-DLC group. The expression of CXCR3 on CD56 NK cells was almost 100 % in all enrolled cohorts. CXCR3-associated chemokines were negatively correlated with liver function and positively correlated with fibrosis degree. TRAILCD56 NK cells were negatively correlated with liver function, and positively correlated with fibrosis degree and CXCR3-associated chemokines. The apoptosis of K562 cells and hepatocytes was suppressed partially by the TRAIL-neutralizing antibodies.

Conclusions: The increase of CXCR3-related chemokines (including CXCL9, CXCL10 and CXCL11) might be related to the migration of TRAIL CD56 NK cells to the liver. Highly activated TRAIL CD56 NK cells were associated with the liver damage in HBV-LC patients. These findings may provide new perspectives and theoretical basis for future immunotherapy of HBV-LC patients.
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http://dx.doi.org/10.1016/j.imlet.2020.12.008DOI Listing
April 2021

CC-223, NSC781406, and BGT226 Exerts a Cytotoxic Effect Against Pancreatic Cancer Cells via mTOR Signaling.

Front Pharmacol 2020 11;11:580407. Epub 2020 Nov 11.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, Wenzhou Medical University First Affiliated Hospital, Wenzhou, China.

The mTOR signaling pathway is abnormally activated in pancreatic cancer and is related to tumor glucose metabolism. However, its specific regulation mechanism is still unclear. Therefore, this study aims to investigate whether Sestrin2 affects the glucose metabolism of pancreatic cancer by modulating mTOR signal and then affects its biological behavior. We have observed that l-leucine can promote the proliferation of pancreatic cancer cells and increase the expression of Sestrin2 and p-mTOR proteins. In order to further study the role of Sestrin2 and mTOR signaling in pancreatic cancer, we conducted Sestrin2 overexpression and mTOR pharmacological inhibition experiments. We found that Sestrin2 overexpression can increase glycolysis of pancreatic cancer cells and promote their proliferation. This effect can be eliminated by mTOR inhibitors. Finally, we found that Sestrin2 knockdown could inhibit the growth of pancreatic cancer . In conclusion, these findings suggest that Sestrin2 may promote the occurrence and development of pancreatic cancer through mTOR signaling.
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http://dx.doi.org/10.3389/fphar.2020.580407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7741184PMC
November 2020

Inhibition of proliferation-linked signaling cascades with atractylenolide I reduces myofibroblastic phenotype and renal fibrosis.

Biochem Pharmacol 2021 01 19;183:114344. Epub 2020 Nov 19.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Institute of Chronic Kidney Disease, Wenzhou Medical University, Wenzhou 325000, China; Center for Health Assessment, Wenzhou Medical University, Wenzhou 325000, China. Electronic address:

Renal fibrosis is a frequent axis contributing to the occurrence of end-stage nephropathy. Previously, it has been reported that atractylenolide Ⅰ (ATL-1), a natural compound extracted from Atractylodes macrocephala, has anti-cancer and antioxidant effects. However, the renal anti-fibrotic effects of action remain unclear. In this study, the anti-fibrotic effects of ATL-1 were examined in fibroblasts, tubular epithelial cells (TECs) triggered by TGF-β1 in vitro, and using a unilateral ureteral obstruction (UUO) mouse model in vivo. We found that ATL-1 represses the myofibroblastic phenotype and fibrosis development in UUO kidneys by targeting the fibroblast-myofibroblast differentiation (FMD), as well as epithelial-mesenchymal transition (EMT). The anti-fibrotic effects of ATL-1 were associated with reduced cell growth in the interstitium and tubules, leading to suppression of the proliferation-linked cascades activity consisting of JAK2/STAT3, PI3K/Akt, p38 MAPK, and Wnt/β-catenin pathways. Besides, ATL-1 treatment repressed TGF-β1-triggered FMD and the myofibroblastic phenotype in fibroblasts by antagonizing the activation of proliferation-linked cascades. Likewise, TGF-β1-triggered excessive activation of the proliferation-linked signaling in TECs triggered EMT. The myofibroblastic phenotype was repressed by ATL-1. The anti-fibrotic and anti-proliferative effects of ATL-1 were linked to the inactivation of Smad2/3 signaling, partially reversing FMD, as well as EMT and the repression of the myofibroblastic phenotype. Thus, the inhibition of myofibroblastic phenotype and fibrosis development in vivo and in vitro through proliferation-linked cascades of ATL-1 makes it a prospective therapeutic bio-agent to prevent renal fibrosis.
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http://dx.doi.org/10.1016/j.bcp.2020.114344DOI Listing
January 2021

Baohuoside I via mTOR Apoptotic Signaling to Inhibit Glioma Cell Growth.

Cancer Manag Res 2020 10;12:11435-11444. Epub 2020 Nov 10.

Neurology Department, Wenzhou Medical University First Affiliated Hospital, Wenzhou, Zhejiang, People's Republic of China.

Introduction: Baohuoside I, a novel oncotherapeutic agent, has been reported to have anti-cancer effects on a variety of cancers, but its role in glioma and its molecular mechanism are still unclear.

Methods: The proliferation of U251 cells was detected by real-time cellular analysis (RTCA), CCK-8, Ki67 immunofluorescence and colony formation assay. The effect of Baohuoside I on the invasion and migration of U251 cells was measured by transwell and scratch tests. The apoptosis of U251 cells was detected by flow cytometry. The expression level of related protein was detected by western blotting.

Results: Baohuoside I could inhibit the proliferation of human glioma cells and induce apoptosis. Further study showed that the migration and invasion ability of glioma was significantly decreased by Baohuoside I. Western blot revealed the expression of p-AMPKα1 protein was up-regulated, and the expression of p-mTOR and p-S6K was down-regulated after Baohuoside I treatment. Tumorigenesis in nude mice showed that Baohuoside I had an anti-glioma effect in vivo.

Conclusion: We propose a natural product, which can inhibit the proliferation, invasion and migration of glioma and may be a valuable anti-tumor candidate. The inhibitory effect of Baohuoside I on the glioma is achieved by inducing the apoptosis of the tumor cells, rather than autophagy. In addition, the pathway to induce cell apoptosis of Baohuoside I is to target the mTOR signal.
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http://dx.doi.org/10.2147/CMAR.S265803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667174PMC
November 2020

Quercetin suppresses pancreatic ductal adenocarcinoma progression via inhibition of SHH and TGF-β/Smad signaling pathways.

Cell Biol Toxicol 2021 06 17;37(3):479-496. Epub 2020 Oct 17.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive type of malignant tumor with a poor prognosis and high mortality. Aberrant activation of hedgehog signaling plays a crucial role in the maintenance and progression of PDA. Here, we report that the dietary bioflavonoid quercetin has therapeutic potential for PDA by targeting sonic hedgehog (SHH) signaling. The effects of quercetin on the proliferation, apoptosis, migration, and invasion of pancreatic cancer cells (PCCs) and tumor growth and metastasis in PDA xenograft mouse models were evaluated. Additionally, SHH signaling activity was determined. Quercetin significantly inhibited PCC proliferation by downregulating c-Myc expression. In addition, quercetin suppressed epithelial-mesenchymal transition (EMT) by reducing TGF-β1 level, which resulted in inhibition of PCC migration and invasion. Moreover, quercetin induced PCC apoptosis through mitochondrial and death receptor pathways. In nude mouse models, PDA growth and metastasis were reduced by quercetin treatment. Mechanically, quercetin exerts its therapeutic effects on PDA by decreasing SHH activity. Interestingly, quercetin-induced SHH inactivation is mainly dependent on Gli2, but not Gli1. Enhance SHH activity by recombinant Shh protein abolished the quercetin-mediated inhibition of PCC proliferation, migration, and invasion. Furthermore, Shh activated TGF-β1/Smad2/3 signaling and promoted EMT by inducing the expression of Zeb2 and Snail1 that eventually resulted in a partial reversal of quercetin-mediated inhibition of PCC migration and invasion. We conclude that quercetin inhibited the growth, migration, and invasion and induced apoptosis of PCCs by antagonizing SHH and TGF-β/Smad signaling pathways. Thus, quercetin may be a potential candidate for PDA treatment.
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http://dx.doi.org/10.1007/s10565-020-09562-0DOI Listing
June 2021

Corrigendum to "Baohuoside-1 targeting mTOR inducing apoptsis to inhibit hepatocellular carcinoma proliferation, invasion and migration" [Biomed. Pharmacother. 2020 (128) 110366].

Biomed Pharmacother 2020 Oct 19;130:110631. Epub 2020 Aug 19.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiffiffiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address:

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http://dx.doi.org/10.1016/j.biopha.2020.110631DOI Listing
October 2020

Corrigendum to "Baohuoside-1 targeting mTOR inducing apoptsis to inhibit hepatocellular carcinoma proliferation, invasion and migration" [Biomed. Pharmacother. 128 (2020) 110366].

Biomed Pharmacother 2020 Sep 17;129:110394. Epub 2020 Jun 17.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address:

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http://dx.doi.org/10.1016/j.biopha.2020.110394DOI Listing
September 2020

Baohuoside-1 targeting mTOR inducing apoptsis to inhibit hepatocellular carcinoma proliferation, invasion and migration.

Biomed Pharmacother 2020 Aug 8;128:110366. Epub 2020 Jun 8.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address:

Background: Baohuoside-1 is a flavonoid compound isolated from Epimedium koreanum Nakai. This study tried to systematically explore the potential anti-cancer functions of Baohuoside-1 in Hepatocellular Carcinoma and study related molecular mechanism. Moreover, as a potential candidate anti-cancer agent, Baohuoside-1 has relatively low toxic side effect.

Methods: The anti-cancer function including proliferation, invasion and migration of Baohuoside-1 in liver cancer was systematically assessed via colony formation, transwell assay and migration assay. Moreover, the anti-cancer functions of Baohuoside-1 was confirmed based on the nude mouse transplantation tumor experiment. The potential targeted signaling pathway was tested via flow cytometery and western blot analysis.

Results: In this study, we present the anti-HCC activity of Baohuoside-1 isolated from Epimedium through examing the effect of Baohuoside-1 on two different human liver cancer cell lines (HuH-7 and HepG2). Baohuoside-1 significantly inhibited the proliferation, invasion and migration of two liver cancer cell lines. Furthermore, the anticancer activity of Baohuoside-1 was confirmed via inhibiting liver tumor growth in nude mice in vivo. Additionally, the influence of Baohuoside-1 on liver cancer apoptosis was examined by analyzing the expression of pro/anti-apoptotic proteins (BAX, Bcl-2, caspase-3, and caspase-8). The potential targeting signaling of Baohuoside-1 was determined via testing key members' expression changes of mTOR and JAK2 signaling.

Conclusion: The inhibition of liver cancer by Baohuoside-1 is through targeting mTOR signaling not JAK2 signaling to induce apoptosis. Our study indicates that Baohuoside-1 is a potential candidate drug for therapy against liver cancer.
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http://dx.doi.org/10.1016/j.biopha.2020.110366DOI Listing
August 2020

Chemopreventive effect of Betulinic acid via mTOR -Caspases/Bcl2/Bax apoptotic signaling in pancreatic cancer.

BMC Complement Med Ther 2020 Jun 8;20(1):178. Epub 2020 Jun 8.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, Wenzhou Medical University First Affiliated Hospital, Wenzhou, Zhejiang, China.

Background: Pancreatic cancer is aggressive with no symptoms until the advanced stage reached. The increased resistance of pancreatic cancer to chemotherapy demonstrates a dilemma in the clinical field. Hence, it is a matter of great urgency to develop an effective drug to treat patients with pancreatic cancer. Betulinic acid is a major triterpene isolated from spina date seed. Several studies have suggested its low toxicity and side effects to patients with malaria and inflammation. However, relevant studies on betulinic acid in inhibiting cancer were insufficient and the molecular mechanism was unclear. This study aimed to systematically explore the potential anti-cancer functions of betulinic acid in pancreatic cancer, and investigate its underlying molecular mechanism.

Methods: The Counting Kit-8 assay, colony formation, transwell invasion assay, wound healing assay, flow cytometry and xenograft nude mice model were used to evaluate the effect of betulinic acid on the proliferation, invasion and migration ability of pancreatic cancer cells.

Results: Our results showed that betulinic acid obviously suppressed pancreatic cancer both in vitro and in vivo in a dose-dependent manner. We also determined that betulinic acid inhibited pancreatic cancer by specifically targeting mTOR signaling rather than Nrf2 or JAK2.

Conclusions: These findings clarify that betulinic acid is a potential and valuable anticancer agent for pancreatic cancer, and indicate the specific molecular target of betulinic acid.
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http://dx.doi.org/10.1186/s12906-020-02976-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282238PMC
June 2020

A network-regulative pattern in the pathogenesis of kidney injury following severe acute pancreatitis.

Biomed Pharmacother 2020 May 12;125:109978. Epub 2020 Feb 12.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China; Institute of Kidney Health, Center for Health Assessment, Wenzhou Medical University, Wenzhou, 325000, China. Electronic address:

Severe acute pancreatitis (SAP), a critical inflammatory pathological disease of the pancreas, is crucial for the manifestation of lethal multiple organ dysfunction syndrome and systemic inflammatory response syndrome. Acute kidney injury (AKI) is one of the most severe complications of severe acute pancreatitis. Yet, the specific pathogenesis of AKI following SAP is defectively understood, and involves in multiple pathological processes in a "network-regulative" pattern, including dysfunction of the intestinal barrier, prolonged activation of coagulation, elevated discharge of damage-associated molecular patterns, complication of abdominal compartment syndrome, excessive release of inflammatory mediators, overexpression of procalcitonin, and incitement of chronic metabolic diseases. Therefore, in this review, we summarize the current knowledge on the pathogenesis of kidney injury following SAP to provide a better understanding of the interactions involved and to encourage the identification of novel targeted therapies to treat SAP and associated AKI.
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http://dx.doi.org/10.1016/j.biopha.2020.109978DOI Listing
May 2020

Epithelial and interstitial Notch1 activity contributes to the myofibroblastic phenotype and fibrosis.

Cell Commun Signal 2019 11 12;17(1):145. Epub 2019 Nov 12.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.

Background: Notch1 signalling is a stem-cell-related pathway that is essential for embryonic development, tissue regeneration and organogenesis. However, the role of Notch1 in the formation of myofibroblasts and fibrosis in kidneys following injury remains unknown.

Methods: The activity of Notch1 signalling was evaluated in fibrotic kidneys in CKD patients and in ureteral obstructive models in vivo and in cultured fibroblasts and TECs in vitro. In addition, the crosstalk of Notch1 with TGF-β1/Smad2/3 signalling was also investigated.

Results: Notch1 activity was elevated in fibrotic kidneys of rat models and patients with chronic kidney disease (CKD). Further study revealed that epithelial and interstitial Notch1 activity correlated with an α-SMA-positive myofibroblastic phenotype. In vitro, injury stimulated epithelial Notch1 activation and epithelial-mesenchymal transition (EMT), resulting in matrix deposition in tubular epithelial cells (TECs). Additionally, interstitial Notch1 activation in association with fibroblast-myofibroblast differentiation (FMD) in fibroblasts mediated a myofibroblastic phenotype. These TGF-β1/Smad2/3-dependent phenotypic transitions were abolished by Notch1 knockdown or a specific antagonist, DAPT, and were exacerbated by Notch1 overexpression or an activator Jagged-1-Fc chimaera protein. Interestingly, as a major driving force behind the EMT and FMD, TGF-β1, also induced epithelial and interstitial Notch1 activity, indicating that TGF-β1 may engage in crosstalk with Notch1 signalling to trigger fibrogenesis.

Conclusion: These findings suggest that epithelial and interstitial Notch1 activation in kidneys following injury contributes to the myofibroblastic phenotype and fibrosis through the EMT in TECs and to the FMD in fibroblasts by targeting downstream TGF-β1/Smad2/3 signalling.
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http://dx.doi.org/10.1186/s12964-019-0455-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849313PMC
November 2019

Resveratrol suppresses the myofibroblastic phenotype and fibrosis formation in kidneys via proliferation-related signalling pathways.

Br J Pharmacol 2019 12 28;176(24):4745-4759. Epub 2019 Nov 28.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Background And Purpose: Renal fibrosis acts as the common pathway leading to the development of end-stage renal disease. Previous studies have shown that resveratrol has anti-fibrotic activity, but its potential molecular mechanisms of action are not well understood.

Experimental Approach: The anti-fibrotic effects of resveratrol were assayed in a rat model of unilateral ureteral obstruction (UUO) in vivo and in fibroblasts and tubular epithelial cells (TECs) stimulated by TGF-β1 in vitro. Gene and protein expression levels were analysed by PCR, Western blotting, and immunohistochemical staining.

Key Results: Resveratrol inhibits the myofibroblastic phenotype and fibrosis formation in UUO kidneys by targeting fibroblast-myofibroblast differentiation (FMD) and epithelial-mesenchymal transition (EMT). The anti-fibrotic effects of resveratrol correlated with decreased proliferation of TECs in the interstitium and tubules, resulting in suppressed activity of the proliferation-related signalling pathways, including that of the MAPK, PI3K/Akt, Wnt/β-catenin, and JAK2/STAT3 pathways. Resveratrol treatment suppressed TGF-β1-induced FMD and the expression of the myofibroblastic phenotype in fibroblasts in vitro by antagonizing the activation of proliferation-related signalling. Similarly, TGF-β1-mediated overactivation of the proliferation-related signalling in TECs induced EMT, and the myofibroblastic phenotype was suppressed by resveratrol. The anti-fibrotic and anti-proliferative effects of resveratrol were associated with the inactivation of Smad2/3 signalling and resulted in a partial reversal of FMD and EMT and the inhibition of the myofibroblastic phenotype.

Conclusions And Implications: Resveratrol suppresses the myofibroblastic phenotype and fibrosis formation in vivo and in vitro via proliferation-related pathways, making it a potential therapeutic agent for preventing renal fibrosis.
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http://dx.doi.org/10.1111/bph.14842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965682PMC
December 2019
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