Jun-li Liu - Academia.edu (original) (raw)

Papers by Jun-li Liu

FEBS letters, Jan 29, 2014

Murine regenerating (mReg) genes have been implicated in preserving islet cell biology. Expanding... more Murine regenerating (mReg) genes have been implicated in preserving islet cell biology. Expanding on our previous work showing that overexpression of mReg2 protects MIN6 insulinoma cells against streptozotocin-induced apoptosis, we now demonstrate that mReg2 induces glucose-regulated peptide 78 (GRP78) expression via the Akt-mTORC1 axis and protects MIN6 cells against ER stress induced by thapsigargin and glucolipotoxicity. Activation of mTORC1 activity results from both mReg2-induced increased mTOR phosphorylation as well as increased expression of Raptor and GβL. Inhibition of Akt and mTORC1 blunted the ability of mReg2 to induce GRP78 and attenuate unfolded protein response (UPR). Knockdown of GRP78 sensitized the cells overexpressing mReg2 to UPR without affecting its ability to activate Akt-mTORC1 signaling. Induced expression of mReg2 may protect insulin producing cells from ER stress in diabetes.

Regulatory Peptides, 2013

Poly(ADP-ribose) polymerase (Parp) 1 is a key regulator of cell death, its inhibition prevented s... more Poly(ADP-ribose) polymerase (Parp) 1 is a key regulator of cell death, its inhibition prevented streptozotocin-induced diabetes and attenuated caerulein-induced acute pancreatitis. Reg family proteins are significantly induced by Parp1 inhibitor, experimental diabetes and/or acute pancreatitis. We propose that Reg proteins are involved in the protection of pancreatic cells by Parp1 inhibition. To test this possibility, Parp1-/- and wild-type mice were injected with streptozotocin to induce diabetes. Separately, acute pancreatitis was induced with repeated injections of caerulein. Upon streptozotocin administration, Parp1-/- mice displayed much decreased hyperglycemia and preserved serum insulin level. The treatment induced similar levels of Reg1, -2, -3α and -3β genes in the pancreas of both wild-type and Parp1-/- mice, suggesting that the upregulation of Reg family genes during streptozotocin-induced diabetes was independent of Parp1 ablation. In caerulein-induced pancreatitis, unlike being reported, Parp1 knockout caused no relief on the severity of pancreatitis; the upregulation of pancreatic Reg1, -2, -3α and -3β genes upon caerulein was unaffected by Parp1 deletion. Our results reconfirmed the protective effect of Parp1 gene deletion on islet β-cells but questioned its effect on the acinar cells. In either case, the significant induction of Reg family genes seemed independent of Parp1-mediated cell death.

Molecular and Cellular Endocrinology, 2013

Reg family proteins are expressed in the pancreas and involved in pancreatitis and islet β-cell g... more Reg family proteins are expressed in the pancreas and involved in pancreatitis and islet β-cell growth. In order to explore transcriptional control, we transfected luciferase reporter genes driven by Reg promoters into acinar AR42J and islet MIN6 cells. Dexamethasone (DEX) significantly increased the promoter expression of Reg2 and Reg3β genes and the levels of endogenous Reg3β mRNA and protein in AR42J cells. DEX-induced promoter activation was inhibited by the inhibitor of poly(ADP-ribose) polymerase, nicotinamide. In MIN6 cells, DEX moderately stimulated the transcription of Reg3β but not Reg2 promoter. While IL-6 alone had no effect, coculture with DEX produced a remarkable synergism on Reg3β gene transcription, which was abolished by nicotinamide. Our results demonstrated a significant and direct stimulation of Reg2 and Reg3β genes by glucocorticoids, all three were activated in response to inflammation such as in pancreatitis. Prominent stimulation of specific Reg genes by glucocorticoids may constitute a functional synergism.

Evidence-Based Complementary and Alternative Medicine, 2013

Turmeric (Curcuma longa), a rhizomatous herbaceous perennial plant of the ginger family, has been... more Turmeric (Curcuma longa), a rhizomatous herbaceous perennial plant of the ginger family, has been used for the treatment of diabetes in Ayurvedic and traditional Chinese medicine. The active component of turmeric, curcumin, has caught attention as a potential treatment for diabetes and its complications primarily because it is a relatively safe and inexpensive drug that reduces glycemia and hyperlipidemia in rodent models of diabetes. Here, we review the recent literature on the applications of curcumin for glycemia and diabetes-related liver disorders, adipocyte dysfunction, neuropathy, nephropathy, vascular diseases, pancreatic disorders, and other complications, and we also discuss its antioxidant and anti-inflammatory properties. The applications of additional curcuminoid compounds for diabetes prevention and treatment are also included in this paper. Finally, we mention the approaches that are currently being sought to generate a “super curcumin” through improvement of the bioa...

Medical review, May 23, 2024

Communications Biology, 2021

Persistent acinar to ductal metaplasia (ADM) is a recently recognized precursor of pancreatic duc... more Persistent acinar to ductal metaplasia (ADM) is a recently recognized precursor of pancreatic ductal adenocarcinoma (PDAC). Here we show that the ADM area of human pancreas tissue adjacent to PDAC expresses significantly higher levels of regenerating protein 3A (REG3A). Exogenous REG3A and its mouse homolog REG3B induce ADM in the 3D culture of primary human and murine acinar cells, respectively. Both Reg3b transgenic mice and REG3B-treated mice with caerulein-induced pancreatitis develop and sustain ADM. Two out of five Reg3b transgenic mice with caerulein-induced pancreatitis show progression from ADM to pancreatic intraepithelial neoplasia (PanIN). Both in vitro and in vivo ADM models demonstrate activation of the RAS-RAF-MEK-ERK signaling pathway. Exostosin-like glycosyltransferase 3 (EXTL3) functions as the receptor for REG3B and mediates the activation of downstream signaling proteins. Our data indicates that REG3A/REG3B promotes persistent ADM through binding to EXTL3 and act...

Endocrinology, Jun 23, 2016

Maintaining pancreatic β-cell mass and function is essential for normal insulin production and gl... more Maintaining pancreatic β-cell mass and function is essential for normal insulin production and glucose homeostasis. Regenerating islet-derived 2 (Reg2, Reg II, human orthologue Reg1B) gene is normally expressed in pancreatic acinar cells and significantly induced in responses to diabetes, pancreatitis, high-fat diet and during pancreatic regeneration. In order to evaluate the role of endogenous Reg2 production in normal β-cell function, we characterized Reg2 gene deficient mice normally and when subjected to several pathological challenges. At a young age, Reg2 gene deficiency caused no obvious change in normal islet morphology or glucose tolerance. There was no change in the severity of streptozotocin-induced diabetes or caerulein-induced acute pancreatitis in the Reg2 deficient mice, indicating that the increased Reg2 expression under those conditions was not essential to protect the islet or acinar cells. However, 13-14 months old, aged Reg2 gene deficient mice developed glucose ...

Cancer research, Apr 18, 2016

We have read with great interest the recent report by Loncle and colleagues (1) investigating the... more We have read with great interest the recent report by Loncle and colleagues (1) investigating the role of REG3b in mediating protumoral effects of IL17. We agree in principal with their conclusion that Reg3b is involved in the initiation of pancreatic ductal adenocarcinoma (PDAC) and its progression. We also found Reg gene expression in duct-like structures in tumor-adjacent areas of pancreatic cancer in our study (article submitted to Modern Pathology, MP-2015-1066), which is an indicator of acinar-to-ductal metaplasia as described in this article. However, we would like to clarify two potential controversies. First, the results of Fig. 5B showing Reg3b expression in human peritumor and well-differentiated PDAC lesions are questionable because Reg3b (transcript ID NM_011036) is only expressed in rodents; its human ortholog is Reg3A (NM_002580.2; ref. 2). They share the name of pancreatitis-associated protein and are both expressed after pancreatitis and in normal intestine (3). The result obtained on human tissues by using mouse Reg3b antibody (Dynabio S.A.) is very different from what we have seen using human Reg3A antibody (sc-134854, against residues 107-175). In short, we

AJP: Gastrointestinal and Liver Physiology, 2010

Reg proteins are normally expressed in pancreatic acinar cells, and the level of several of these... more Reg proteins are normally expressed in pancreatic acinar cells, and the level of several of these proteins was significantly induced upon damage to the endocrine or exocrine pancreas. It has been established that Reg1 and pancreatic islet neogenesis-associated protein [INGAP, Reg3δ] promote the growth or regeneration of the endocrine islet cells. Recent reports suggest that Reg2 is an autoantigen normally expressed in islet β-cells. Reg2 overexpression in vitro offered protection to insulinoma cells. Overexpressed Reg3α increased cyclin D1 and CDK4 levels and the rate of proliferation in insulinoma cells. Acinar-specific overexpression of INGAP increased β-cell mass and protected the animals from streptozotocin-induced diabetes. Moreover, Reg2 gene expression was induced during pancreatitis. We hypothesized that Reg2 is a secreted protein that promotes the growth, survival, and/or regeneration of pancreatic endocrine and exocrine cells. To test its effectiveness, we used elastase-1 ...

American Journal of Physiology-Gastrointestinal and Liver Physiology, 2013

The antidiabetic mechanism of bariatric surgery includes specific changes in the secretion of inc... more The antidiabetic mechanism of bariatric surgery includes specific changes in the secretion of incretins. To identify additional players originating from the gut, we evaluated the effects of duodenal-jejunal bypass (DJB) in morbidly obese Zucker fatty rats. A fast relief of hyperglycemia and hyperinsulinemia was achieved even before a significant weight loss occurred. Fourteen days after DJB, we characterized the changes in intestinal histochemistry in the bypassed duodenum and shortcut jejunum that was reanastomosed directly to the starting point of the duodenum and compared with the corresponding regions of sham-operated rats. The bypassed duodenum exhibited mucosal atrophy and apoptosis and decreased proliferative renewal. In shortcut jejunum, DJB resulted in 40% significantly enlarged intestinal circumference and increased epithelial proliferation, especially in putative transit-amplifying (TA) cells and the crypt. Because Reg family proteins promote cell growth and survival, we ...

Oncotarget, Nov 24, 2016

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor. Acinar-to-ductal ... more Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor. Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) are both precursor lesions that lead to the development of PDAC. Reg family proteins (Reg1A, 1B, 3A/G, 4) are a group of calcium-dependent lectins that promote islet growth in response to inflammation and/or injuries. The aim of this study was to establish a role for Reg proteins in the development of PDAC and their clinical value as biomarkers. We found that Reg1A and Reg3A/G were highly expressed in the ADM tissues by immunohistochemistry. In the 3-dimensional culture of mouse acinar cells, Reg3A promoted ADM formation with concurrent activation of mitogen-acitvated protein kinase. Upregulation of Reg1A and Reg1B levels was observed as benign ductal epithelium progresses from PanIN to invasive PDAC. Patients with PDAC showed significantly higher serum levels of Reg1A and Reg1B than matching healthy subjects. These result...

Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih, Jan 27, 2017

Objective To construct a model of Seasonal Autoregressive Integrated Moving Average (SARIMA) for ... more Objective To construct a model of Seasonal Autoregressive Integrated Moving Average (SARIMA) for forecasting the epidemic of Japanese encephalitis (JE) in Xianyang, Shaanxi, China, and provide valuable reference information for JE control and prevention. Methods Theoretically epidemiologic study was employed in the research process. Monthly incidence data on JE for the period from Jan 2005 to Sep 2014 were obtained from a passive surveillance system at the Center for Diseases Prevention and Control in Xianyang, Shaanxi province. An optimal SARIMA model was developed for JE incidence from 2005 to 2013 with the Box and Jenkins approach. This SARIMA model could predict JE incidence for the year 2014 and 2015. Results SARIMA (1, 1, 1) (2, 1, 1)12 was considered to be the best model with the lowest Bayesian information criterion, Akaike information criterion, Mean Absolute Error values, the highest R2, and a lower Mean Absolute Percent Error. SARIMA (1, 1, 1) (2, 1, 1)12 was stationary a...

Scientific reports, Oct 21, 2016

Regenerating genes (Reg) have been found during the search for factors involved in pancreatic isl... more Regenerating genes (Reg) have been found during the search for factors involved in pancreatic islet regeneration. Our recent study discovered that pancreatic β-cell-specific overexpression of Reg3β protects against streptozotocin (Stz) -induced diabetes in mice. To investigate its potential roles in the treatment of diabetes, we produced a recombinant Reg3β protein and provided evidence that it is active in promoting islet β-cell survival against Stz- triggered cell death. Though ineffective in alleviating preexisting diabetes, pretreatment of recombinant Reg3β was capable of minimizing the Stz-induced hyperglycemia and weight loss, by preserving serum and pancreatic insulin levels, and islet β-cell mass. No obvious changes were observed in the rate of cell proliferation and hypertrophy in α- or acinar-cells after treatment with recombinant Reg3β. The underlying mechanism of Reg3β-mediated protection seems to involve Akt activation which upregulates Bcl-2 and Bcl-xL levels and conse...

Proceedings of the National Academy of Sciences, 2011

Endocrinology, 2014

IGF-I is normally produced from hepatocytes and other sources, stimulates protein synthesis, cell... more IGF-I is normally produced from hepatocytes and other sources, stimulates protein synthesis, cell survival, and proliferation through receptor-mediated activation of phosphatidylinositol 3-kinase and MAPK, and targets specific molecules within the pancreatic islet cells. The current study was designed to identify novel targets that may mediate its pro-islet actions. Whole-genome cDNA microarray analysis in IGF-I-overexpressing islets identified 82 genes specifically up-or downregulated. Prominent among them was CCN5/WISP2 whose expression was increased 3-and 2-fold at the mRNA and protein levels. Dual-labeled immunofluorescence revealed that CCN5 expression was low in the ␤-cells of wild-type islets but was significantly induced in response to IGF-I overexpression. In vitro treatment of mouse islets with IGF-I increased both CCN5 mRNA and protein levels significantly. To define the role of CCN5 in islet cell biology, we stably overexpressed its cDNA in insulinoma MIN6 cells and detected a 2-fold increase in the proliferation of MIN6-CCN5 compared with that in control cells, which correlated with significant elevations in the levels of cyclin D1 and the phosphorylation of Akt and Erk2. Moreover, MIN6-CCN5 cells were found to be resistant to streptozotocin-induced cell death. Using confocal microscopy and subcellular fractionation, we found that overexpressed CCN5 exhibited cytoplasmic accumulation upon stimulation by high glucose. Our results indicate that CCN5, which is minimally expressed in islet ␤-cells, is strongly and directly induced by IGF-I. CCN5 overexpression stimulates the proliferation of insulinoma cells, activates Akt kinase, and inhibits streptozotocin-induced apoptosis, suggesting that increased CCN5 expression contributes to IGF-I-stimulated islet cell growth and/or survival.

International Journal of Molecular Sciences, 2021

CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt sig... more CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt signaling and IGF-1. Our initial characterization supports the notion that CCN5 might promote the proliferation and survival of pancreatic β-cells and thus improve the metabolic profile of the animals. More recently, the roles of endogenous expression of CCN5 and its ectopic, transgenic overexpression on metabolic regulation have been revealed through two reports. Here, we attempt to compare the experimental findings from those studies, side-by-side, in order to further establish its roles in metabolic regulation. Prominent among the discoveries was that a systemic deficiency of CCN5 gene expression caused adipocyte hypertrophy, increased adipogenesis, and lipid accumulation, resulting in insulin resistance and glucose intolerance, which were further exacerbated upon high-fat diet feeding. On the other hand, the adipocyte-specific and systemic overexpression of CCN5 caused an increase in le...

Aging Cell, 2014

In addition to their extended lifespans, slow-aging growth hormone receptor/binding protein gene-... more In addition to their extended lifespans, slow-aging growth hormone receptor/binding protein gene-disrupted (knockout) (GHR-KO) mice are hypoinsulinemic and highly sensitive to the action of insulin. It has been proposed that this insulin sensitivity is important for their longevity and increased healthspan. We tested whether this insulin sensitivity of the GHR-KO mouse is necessary for its retarded aging by abrogating that sensitivity with a transgenic alteration that improves development and secretory function of pancreatic b-cells by expressing Igf-1 under the rat insulin promoter 1 (RIP::IGF-1). The RIP::IGF-1 transgene increased circulating insulin content in GHR-KO mice, and thusly fully normalized their insulin sensitivity, without affecting the proliferation of any non-b-cell cell types. Multiple (nonsurvivorship) longevity-associated physiological and endocrinological characteristics of these mice (namely beneficial blood glucose regulatory control, altered metabolism, and preservation of memory capabilities) were partially or completely normalized, thus supporting the causal role of insulin sensitivity for the decelerated senescence of GHR-KO mice. We conclude that a delayed onset and/or decreased pace of aging can be hormonally regulated.

Endocrinology, 2002

IGF-I has been suggested to be of importance for cardiovascular structure and function, but the r... more IGF-I has been suggested to be of importance for cardiovascular structure and function, but the relative role of locally produced and liver-derived endocrine IGF-I remains unclear. Using the Cre-LoxP recombination system, we have previously created transgenic mice with a liver-specific, inducible IGF-I knockout (LI-IGF-I؊/؊). To examine the role of liverderived IGF-I in cardiovascular physiology, liver-derived IGF-I was inactivated at 4 wk of age, resulting in a 79% reduction of serum IGF-I levels. At 4 months of age, systolic blood pressure (BP) was increased in LI-IGF-I؊/؊ mice. Echocardiography showed increased posterior wall thickness in combination with decreased stroke volume and cardiac output, whereas other systolic variables were unchanged, suggesting that these cardiac effects were secondary to increased peripheral resistance. Acute nitric oxide-synthase inhibition increased systolic BP more in LI-IGF-I؊/؊ mice than in control mice. LI-IGF-I؊/؊ mice showed impaired acetylcholineinduced vasorelaxation in mesenteric resistance vessels and increased levels of endothelin-1 mRNA in aorta. Thus, the increased peripheral resistance in LI-IGF-I؊/؊ mice might be attributable to endothelial dysfunction associated with increased expression of endothelin-1 and impaired vasorelaxation of resistance vessels. In conclusion, our findings suggest that liver-derived IGF-I is involved in the regulation of BP in mice. (Endocrinology 143: 4235-4242, 2002)