148 research outputs found
An improved continuity-preserving interface reconstruction method for multi-material flow
No full textThe dynamic programming interface reconstruction (DPIR) method introduced by Dumas et al.[1] is a volume-preserving and continuous interface reconstruction method. It is a two-step method, which comprises of an optimized step and a correction step. At first, in the optimized step, it minimizes a target function by the dynamic programming method to obtain a continuous interface. Then, it corrects the interface in each mixed cell to preserve the conservative of the volume fraction. However, only the difference of volume fraction is considered, and the interface normal is neglected in the target function. These make it easy to obtain different optimal results in the optimized step, and hence the resulting continuous interfaces always suffer from oscillations (i.e., the 'wave effects' [1]). In this paper, to suppress the continuous interfaces' oscillations in the optimized step and improve its accuracy, we constructed a non-dimensional target function based on the moment-of-fluid method's objective function, and also proposed a new correction method. Finally, several numerical tests are performed to show the new method's superiority over the original one of Dumas et al. [1]. (C) 2021 Elsevier Ltd. All rights reserved
Corrigendum: Sustainable housing development in China: does financial institutions overcome the risks and challenges to sustainable housing?
No full textShaodong Ma, author of the article “Sustainable housing development in China: does financial institutions overcome the risks and challenges to sustainable housing?”, published in Technological and Economic Development of Economy, 30(3), 627–645, https://doi.org/10.3846/tede.2024.20581 informs that in the article, pp. 627–630, some references were not strongly related to the content, and required refinement. The corresponding references needed to be removed from the list of references in pp. 640–642. This has now been corrected.
The author regrets the errors
The Role of Hepatic Estrogen Receptor Alpha in Control of Insulin Signaling Pathway and Glucose Homeostasis
No full textEstrogen has been reported to regulate various physiological processes such as cell growth,
reproduction, development, and differentiation. Estrogen has also been shown to be connected
with metabolic diseases by regulating glucose and lipid metabolism. The effects of estrogens are mediated mostly by estrogen receptors, estrogen receptor-�� (ER��) and estrogen receptor-�� (ER��). estrogens favor glucose homeostasis primarily through ER��, and ER�� is the major ER isoform expressed in the liver. However, how ER�� precisely regulates glucose metabolism in the liver remains unclear.
This study is aiming to explore the role of hepatic estrogen receptor alpha (ER��) in insulin
signaling pathway to regulate glucose homeostasis under both physiological and pathological conditions. To determine the specific role of ER�� in the liver, we use Cre-loxP recombination system to generate liver-specific ER�� knockout mice (ER��LivKO). ER�� flox mice (ER��F���F) were used
as control wild-type mice. These mice were fed with a high-fat diet (HFD) for 12 weeks at the
age of 5-6 weeks. Mice fed with a chow diet (CD) served as a control group. In the present studies, we found that in CD fed mice, hepatic ER�� deletion led to impaired glucose tolerance and insulin signaling as evidenced by glucose tolerance tests and western blot in both male and female mice. In HFD fed group, HFD treatment impaired glucose homeostasis and induced inflammatory response as evidenced by glucose or pyruvate tolerance tests and quantification of gene expression. In HFD fed male mice, we did not observe significant differences in body weight, glucose tolerance, or mRNA expression of IRS between WT and ER��LivKO mice. This may due to HFD treatment decreases ER�� expression in WT male mice, loss of ER�� protection in HFD fed male mice could be the reason. On the contrary, mice metabolic studies and histology studies showed hepatic ER�� deficiency exacerbated insulin resistance and promoted lipid deposition in the liver from HFD fed female mice. In summary, we conclude that hepatic ER�� plays an important role in mediating glucose and lipid homeostasis by participating in insulin signaling pathway under both healthy and pathological conditions
Design and synthesis of chiral ligands and their application in transition metal-catalyzed asymmetric hydrogenations
No full textTransition metal catalyzed hydrogenations are among the most powerful and direct approaches for the synthesis of organic molecules. During the past half century, chiral ligands have been extensively studied in transition metal catalyzed transformations. Development of new chiral ligands, efficient catalyst systems and their applications in the reduction of various prochiral unsaturated substrates are the focus of this dissertation. In chapter 1, novel chiral tridentate f-amphox ligands were designed and synthesized. Two chiral wings in the ligands form a chiral pocket which introduces the chirality in the asymmetric hydrogenation. Tridentate f-amphox ligand has formed a highly enantioselective Iridium catalyst for direct hydrogenation of β-aryl β-ketoesters (up to 99% ee) and 3-oxo-3-arylpropionic acid ethyl esters (up to 99% ee) with high turnover number (up to 1,000,000). In chapter 2, I focus on the highly enantioselective direct reductive amination of aromatic ketone. With phenylhydrazide as the nitrogen source, various chiral hydrazides were synthesized in excellent enantioselectivities and yields. In chapter 3, a highly efficient enantioselective hydrogenation of N-alkyl-2-arylpyridinium salts was discussed. This work provides the unique example of using a chiral phosphole-based ligand for highly efficient asymmetric catalysis. The mechanism of this transformation was studied and a mechanistic cycle was proposed.Ph.D.Includes bibliographical referencesby Shaodong Li
Adenosine Kinase: Nutritional Regulation and Role in Diet-Induced NAFLD
No full textAdenosine is at the crossroad of transmethylation reactions and adenosine signaling. Therefore, by regulating adenosine concentration, adenosine kinase (ADK) has been identified as an upstream regulator of a complex metabolic network. However, ADK-based therapeutics has been largely limited to neural diseases, and the relationship between ADK dysfunction and non-alcoholic fatty liver disease (NAFLD) has never been investigated to date. Since the liver is the major site for methylation reactions, and ADK widely expresses throughout the body with the highest abundance in the liver, we hypothesize that hepatic ADK dysfunction might be a novel contributor to diet-induced NAFLD. By employing liver-specific ADK knockout and overexpression mouse models, in the present study, we first confirmed the upregulation of hepatic ADK in response to High-fat diet (HFD) feeding. We then proved a protective role of hepatic ADK knockout in aspects of HFD-induced NAFLD, including insulin resistance, excessive fat deposition, and low-grade metabolic inflammation in the liver. Additionally, we observed that hepatic ADK overexpression predisposed mice to NAFLD without an HFD challenge. Lastly, we touched on the mechanisms of action and determined that following upregulated ADK expression upon HFD feeding, the global DNA hypermethylation and subsequent silencing of genes of target, peroxisome proliferator-activated receptor �� (PPAR��) in specific, could be the primary mechanism underlying ADK action. Besides, the reduced adenosine signaling mediated by adenosine 2A receptor (A���AR) took a limited effect in exacerbating the aforementioned pathological process. Taken together, our research indicated the causal effects of hepatic ADK overexpression on diet-induced NAFLD. Even though more studies are warranted to further extend the mechanisms, ADK-oriented strategies hold huge promise in terms of effectively treating NAFLD
Myeloid Specific Inhibition of Ghs-R Mitigates Experimental Type 2 Diabetes
No full textType 2 diabetes is characterized by insulin resistance and beta-cell dysfunction[1]. Macrophages are a major source of inflammatory cytokine IL-1��, which is a major regulator of inflammation in the pancreatic beta-cells [2, 3]. IL-1Ra antagonizes the activity of IL-1��[4]. Beta-cells are the primary source for islet IL-1Ra expression, and IL-1Ra expression in islets diminishes following T2D onset [5]. Ghrelin is nutrient sensor and metabolic regulator. Ghrelin���s known receptor is growth hormone secretagogue receptor (GHS-R), reported to govern glucose homeostasis and inflammation under both physiological and pathological conditions[6, 7]. However, little is known of the role of macrophage GHS-R in glycemic regulation of T2D conditions, and its effect on the IL-1Ra:IL-1�� ratio is totally unknown. In this study we utilized Western diet + multiple low dose streptozotocin to generate an experimental T2D model to evaluate the effects of myeloid-specific inhibition of GHS-R (LysM-Cre;Ghsr^f/f). We determined that the WD/STZ model emulated the natural pathogenesis of T2D, the severity of which was attenuated in LysM-Cre;Ghsr^f/f mice. We detected attenuated hyperglycemia, increased circulating insulin, reduced glucagon, improved hepatic glucose production, and improved glucose tolerance in vivo; as well as enhanced insulin secretion ex vivo. Furthermore, gene expression of whole islets exhibited increased insulin signaling genes and an increased ratio of IL-1Ra:IL-1��, suggesting increased IL-1Ra activity. In conclusion, myeloid-specific inhibition of GHS-R mitigated the severity of T2D via improvements of regulation of glucoregulatory hormones, hepatic glucose metabolism, and islet insulin signaling, at least in part due to increased IL-1Ra activity
The Role of Autophagy in Control of Glucose Homeostasis
No full textBlood glucose homeostasis is essential for human growth, physical activities, and health. The present study proposes a possible mechanism for autophagy-mediated hepatic glucose production (HGP) during starvation, which is likely to be in a FoxO1-dependent manner. HGP assay showed that autophagy deficiency induced by either chloroquine (CQ) or siRNA-ATG7 significantly suppressed the HGP in wild type (WT), but not in liver-specific FoxO1 knockout (L-FKO) mouse hepatocytes. Similarly, the glucagon tolerance test and pyruvate tolerance test showed that upon inhibition of autophagy, only WT mice but not L-FKO mice exhibited a significant reduction in glucose production compared to the WT or L-FKO mice without autophagy deficiency. Western blot results further revealed that under autophagy deficiency, the protein amount of FoxO1 was remarkably reduced, accompanied with a significant decrease of FoxO1 nuclear localization. Notably, the reduction of FoxO1 protein amounts induced by autophagy deficiency was independent of FoxO1-S253 and FoxO1-S273 phosphorylation, as the reduction of FoxO1 persisted in hepatocytes isolated from FoxO1-S253A/A and FoxO1-S273D/D knock-in (KI) mice. Even proteasome inhibitor MG132 did not prevent FoxO1 from decreasing under autophagy deficiency, suggesting that the FoxO1 degradation was unlikely the major cause. In addition, autophagy deficiency did not change FoxO1 mRNA level, meaning that the reduction of FoxO1 was likely happening in post-transcriptional activities. The HPLC results unveiled that autophagy deficiency significantly altered hepatic amino acid pools and amino acid transportation including ATF4-LAT1 axis. With an addition of exogenous amino acid mixture, we successfully restored the FoxO1 protein amount and HGP even under autophagy deficiency. Meanwhile, amino acid supplementation-induced restoration of FoxO1 and HGP was abolished by protein synthesis inhibitor cycloheximide (CHX), suggesting that the alteration of amino acid pools caused by autophagy deficiency impaired FoxO1 protein synthesis. The present study highlights an important role of autophagy involved in glucose homeostasis, which is to maintain the hepatic amino acid pools under starvation, subsequently supporting the activity of FoxO1 in control of the HGP
The Role of Hepatic Transforming Growth Factor Beta 1 in Glucose and Energy Metabolism
No full textLiver and adipose tissue are crucial for blood glucose and energy homeostasis, while unsuppressed hepatic glucose production (HGP) causes hyperglycemia and imbalanced energy expenditure could lead to excessive fat storage in type 2 diabetes mellitus (T2D). Genetic inactivation of hepatic insulin receptor substrate 1, 2 (IRS1/2) (DKO mice) caused hyperglycemia and systemic insulin resistance, which were resolved by additional hepatic deletion of the transcription factor Foxo1 (TKOfoxo1 mice). In this study, we identified a putative hepatokine-transforming growth factor-beta 1 (TGF-��1) that was dysregulated in DKO mice but normalized in TKOfoxo1 mice.
We investigated the role of hepatic TGF-��1 in regulating glucose and energy homeostasis. We generated DKO and TKObeta1 mice lack IRS1/2 and TGF-��1 and found that hepatic TGF-��1 ablation prevented hyperglycemia and hyperinsulinemia in DKO mice. Deletion of TGF-��1 or neutralization of TGF-��1 with antibody significantly decreased PKA signaling and HGP of DKO hepatocytes. Additionally, we found that hepatic insulin resistance in DKO mice caused imbalanced energy expenditure. Hepatic TGF-��1 ablation in DKO mice enhanced BAT-mediated thermogenesis and energy expenditure. Blockade of TGF-��1 signaling by inhibitor LY2157399 improves glucose and energy metabolism in DKO mice. To further explore the physiological and pathological role of hepatic TGF-��1 in systemic metabolism, we generated the liver-specific TGF-��1 knockout mice and found that these mice exhibited lower blood glucose, decreased hepatic glucose production (HGP) compared with wild type (WT) control mice under regular diet treatment. Under high-fat diet (HFD) treatment, hepatic TGF-��1 deficiency protected mice from HFD-induced obesity and insulin resistance, decreased HGP, and improved energy expenditure. These findings underscore an important role of hepatic TGF-��1 in contribution to systemic glucose and energy homeostasis. Thus, hepatic TGF-��1 may serve as a therapeutic target for control of glucose and energy homeostasis in insulin resistance and type 2 diabetes mellitus
Maternal Nutrition, Placenta Function and Offspring Health
No full textDiabetes mellitus has become a global health concern during past decades. Consequently, diabetic pregnancies were affected in an increasing amount of population. As the one of the major factors during diabetes, maternal hyperglycemia is considered to have great adverse influences on fetal development. As a transient organ connecting the mother and the fetus, the placenta plays many important roles in fetal development. Placental development is affected in diabetes related pregnancy, which further promotes diabetic pregnancy related complications. FOXO1, a transcriptional factor in the forkhead family, plays important roles in fetal cardiovascular and placental development, as well as glucose metabolism. The aim of the project is to understand the molecular mechanism underlying how hyperglycemia disrupts placenta function and promotes birth defects of the fetus, focusing on maternal overnutrition, diabetes and the transcription factor FOXO1. Therefore, three distinct but interconnected studies are involved in this PhD project. In study 1, in ovo hyperglycemia was generated in a chicken egg model to study the impact of ���hyperglycemia��� on the embryonic development. We reported that high dose of glucose was embryonic lethal and lower dose of glucose resulted in heart and limb defects. We further demonstrated that the limb defects induced by ���hyperglycemia��� were an outcome of disrupted proliferation and apoptosis of the limb mesenchymal cells, associated with down-regulation of Hedgehog signaling. In study 2, wild-type (WT) or FOXO1 heterozygous mice with diabetic pregnancy were generated by streptozotocin (STZ) injections. The placental function and the embryonic heart development were examined to understand the interaction between diabetic pregnancy and FOXO1 deficiency. The results demonstrated that diabetic pregnancy affected the placental growth and promoted angiogenesis of the placental labyrinth layer, which was further associated with the fetal overgrowth. But those effects were not observed when FOXO1 was downregulated. In study 3, we discovered the influence of maternal diet interventions on the offspring pancreatic ��-cell function while the offspring were exposed to postnatal high-fat (HF) diet. The results suggested that proliferation defects and degranulation of the ��-cells induced by maternal HF diet were rescued by a pre-gestational diet transition. This study could provide evidence for potential strategies to reduce the detrimental effects of maternal overnutrition. Taken together, this PhD project explored the impacts of maternal factors such as diabetes and overnutrition on placental and fetal development, and further investigated the mechanisms behind them. It provides important information that will lead to health care strategies to improve health outcomes of mothers and children
P38 ��lpha MAPK Regulates Foxo1 and Hepatic Glucose Production in Health and Disease
No full textGlucagon governs hepatic glucose production (HGP) by triggering glycogenolysis and gluconeogenesis. The p38�� MAPK (p38��) is activated by glucagon to promote hepatic glucose production (HGP), but underlying mechanisms have not been well elucidated. In this study, we showed that p38�� is activated by glucagon through the cAMP���EPAC pathway in primary hepatocytes in control of Foxo1-S273 phosphorylation. In both hepatocytes and mice, inhibition of p38�� blocked Foxo1-S273 phosphorylation, decreased Foxo1 protein level, and impaired glucagon- and fasting-induced HGP. However, the effect of p38�� inhibition was abolished by Foxo1-deficiency or Foxo1-S273A or D mutation. Moreover, the p38��-regulated Foxo1 pathway plays an indispensable role in stimulating HGP in inflammatory hepatocytes and insulin resistant mice. This study reveals a novel mechanism of p38�� by which it regulates Foxo1-S273 phosphorylation to mediate the action of glucagon on glucose homeostasis
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