scholarly journals Delineating the Role of TRP Channels in Metabolic Disease (P10-083-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Yan Qin Tan ◽  
Lai Kwok Leung
Keyword(s):  
Diabetes Mellitus ◽  
Western Blotting ◽  
Therapeutic Target ◽  
Adipocyte Differentiation ◽  
Metabolic Diseases ◽  
Trp Channels ◽  
Maturation Process ◽  
Novel Therapeutic

Abstract Objectives The objective of the present study is to elucidate the role of Transient Receptor Potential (TRP) channels in the process of adipogenesis and diabetes mellitus, in hopes of getting more understanding of the role of TRP channels in the process as well as in hopes of discovering a novel therapeutic target against metabolic diseases. Methods The role of TRP channels in adipogenesis and diabetes mellitus was investigated by using in vivo (C57/BL6J mice) and in vitro (3T3-L1 cells). The expressions of TRP isoforms were studied by using RT-PCR and western blotting assay. TRP channels agonist and antagonist were used to study the role of TRP channels while fat accumulation in cells was visualized by Oil Red O staining. Intracellular calcium inflow was estimated by confocal microscopy. Results Among the TRP channels screened, the authors identified the differential expressions of TRPC isoforms by using in vivo model. The results were further confirmed by using western blotting analysis. The changes in expression suggested the importance of the specific isoforms in the adipogenesis process. The agonist-antagonist study illustrated that the treatment of TRPC antagonists induced the maturation process while TRPC agonist attenuated adipocyte differentiation of 3T3-L1 cells. Conclusions The present study serves to illustrate the role of TRP channels in adipocyte biology. In conclusion, the current study demonstrated that the TRPC isoforms have differential expression during the maturation process of fat. Further, the modulation of TRPC could affect the adipocyte differentiation of 3T3-L1 cells. The understanding of TRPC channels in adipocyte biology serves as a novel therapeutic target against metabolic diseases such as obesity and diabetes mellitus. Funding Sources The research is funded by The Chinese University of Hong Kong Direct Grant. Supporting Tables, Images and/or Graphs

scholarly journals Phosphorylation of NF-κBp65 drives inflammation-mediated hepatocellular carcinogenesis and is a novel therapeutic target

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xuan Xu ◽  
Yiming Lei ◽  
Lingjun Chen ◽  
Haoxiong Zhou ◽  
Huiling Liu ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Normal Liver ◽  
Vital Role ◽  
Tnf Α ◽  
Hepatocellular Carcinogenesis ◽  
Mtor Signalling ◽  
Novel Therapeutic

Abstract Background Nuclear factor­κB (NF-κB) plays a vital role in hepatocellular carcinoma (HCC). β-arrestin1 (ARRB1) has been proved to enhance the activity of NF-κBp65, and our previous study indicated that ARRB1 promotes hepatocellular carcinogenesis and development of HCC. However, it remains unknown whether p65 is involved in hepatocellular carcinogenesis through the ARRB1-mediated pathway. Methods The levels of NF-κBp65 and NF-κBp65 phosphorylation (p-p65) were assessed in including normal liver, primary HCC and paired paracancerous tissues. Liver-specific p65 knockout mice were used to examine the role of p65 and p-p65 in hepatocarcinogenesis. The mechanism of NF-κBp65 and p-p65 in hepatocarcinogenesis via ARRB1 was also studied both in vitro and in vivo. Results Phosphorylation of NF-κBp65 was markedly upregulated in inflammation-related HCC patients and was significantly increased in mouse hepatic inflammation models, which were induced by tetrachloromethane (CCl4), diethylnitrosamine (DEN), TNF-α, as well as DEN-induced HCC. Hepatocyte-specific p65-deficient mice markedly decreased in the HCC incidence and size of tumours by the repressing of the proliferation of malignant cells in a DEN-induced HCC model. Furthermore, ARRB1 directly bounds p65 to promote the phosphorylation of NF-κBp65 at ser536, resulted in cell malignant proliferation through GSK3β/mTOR signalling. Conclusion The data demonstrated that phosphorylation of NF-κBp65 drives hepatocellular carcinogenesis in response to inflammation-mediated ARRB1, and that inhibition of the phosphorylation of NF-κBp65 restrains the hepatocellular carcinogenesis. The results indicate that phosphorylation of NF-κBp65 is a novel therapeutic target for HCC.

Diet and Nutritional Interventions with the Special Role of Myo-Inositol in Gestational Diabetes Mellitus Management. An Evidence-Based Critical Appraisal

2019 ◽  
Vol 25 (22) ◽  
pp. 2467-2473 ◽  
Author(s):  
Enrique Reyes-Muñoz ◽  
Federica Di Guardo ◽  
Michal Ciebiera ◽  
Ilker Kahramanoglu ◽  
Thozhukat Sathyapalan ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Metabolic Diseases ◽  
Nutritional Intervention ◽  
Attractive Alternative ◽  
Special Role ◽  
Dose Frequency ◽  
Nutritional Interventions

Background: Gestational Diabetes Mellitus (GDM), defined as glucose intolerance with onset or first recognition during pregnancy, represents one of the most common maternal-fetal complications during pregnancy and it is associated with poor perinatal outcomes. To date, GDM is a rising condition over the last decades coinciding with the ongoing epidemic of obesity and Type 2 Diabetes Mellitus (T2DM). Objective: The aim of this review is to discuss the role of diet and nutritional interventions in preventing GDM with the explanation of the special role of myo-inositol (MI) in this matter. Methods: We performed an overview of the most recent literature data on the subject with particular attention to the effectiveness of diet and nutritional interventions in the prevention of GDM with the special role of MI. Results: Nutritional intervention and physical activity before and during pregnancy are mandatory in women affected by GDM. Moreover, the availability of insulin-sensitizers such as different forms of inositol has dramatically changed the scenario, allowing the treatment of several metabolic diseases, such as those related to glucose dysbalance. Although the optimal dose, frequency, and form of MI administration need to be further investigated, diet supplementation with MI appears to be an attractive alternative for the GDM prevention as well as for the reduction of GDM-related complications. Conclusion: More studies should be conducted to prove the most effective nutritional intervention in GDM. Regarding the potential effectiveness of MI, further evidence in multicenter, randomized controlled trials is needed to draw firm conclusions.

scholarly journals CBP/β-Catenin/FOXM1 Is a Novel Therapeutic Target in Triple Negative Breast Cancer

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 525 ◽  
Author(s):  
Alexander Ring ◽  
Cu Nguyen ◽  
Goar Smbatyan ◽  
Debu Tripathy ◽  
Min Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Drug Resistance ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Triple Negative ◽  
Creb Binding Protein ◽  
Novel Therapeutic

Background: Triple negative breast cancers (TNBCs) are an aggressive BC subtype, characterized by high rates of drug resistance and a high proportion of cancer stem cells (CSC). CSCs are thought to be responsible for tumor initiation and drug resistance. cAMP-response element-binding (CREB) binding protein (CREBBP or CBP) has been implicated in CSC biology and may provide a novel therapeutic target in TNBC. Methods: RNA Seq pre- and post treatment with the CBP-binding small molecule ICG-001 was used to characterize CBP-driven gene expression in TNBC cells. In vitro and in vivo TNBC models were used to determine the therapeutic effect of CBP inhibition via ICG-001. Tissue microarrays (TMAs) were used to investigate the potential of CBP and associated proteins as biomarkers in TNBC. Results: The CBP/ß-catenin/FOXM1 transcriptional complex drives gene expression in TNBC and is associated with increased CSC numbers, drug resistance and poor survival outcome. Targeting of CBP/β-catenin/FOXM1 with ICG-001 eliminated CSCs and sensitized TNBC tumors to chemotherapy. Immunohistochemistry of TMAs demonstrated a significant correlation between FOXM1 expression and TNBC subtype. Conclusion: CBP/β-catenin/FOXM1 transcriptional activity plays an important role in TNBC drug resistance and CSC phenotype. CBP/β-catenin/FOXM1 provides a molecular target for precision therapy in triple negative breast cancer and could form a rationale for potential clinical trials.

scholarly journals BCAT1 Activates PI3K/AKT/mTOR Pathway and Contributes to the Angiogenesis and Tumorigenicity of Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiong Shu ◽  
Pan-Pan Zhan ◽  
Li-Xin Sun ◽  
Long Yu ◽  
Jun Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Western Blotting ◽  
Mtor Pathway ◽  
Clinical Samples ◽  
Xenograft Models ◽  
Cell Phenotypes

BackgroundFocusing on antiangiogenesis may provide promising choices for treatment of gastric cancer (GC). This study aimed to investigate the mechanistic role of BCAT1 in the pathogenesis of GC, particularly in angiogenesis.MethodsBioinformatics and clinical samples analysis were used to investigate the expression and potential mechanism of BCAT1 in GC. BGC823 cells with BCAT1 overexpression or silencing were induced by lentiviral transduction. Cell phenotypes and angiogenesis were evaluated. The relevant proteins were quantized by Western blotting, immunohistochemistry, or immunofluorescence. Xenograft models were constructed to confirm the role of BCAT1 in vivo.ResultsBCAT1 was overexpressed in GC patients and associated with lower survival. BCAT1 expression was correlated with proliferation-, invasion-, or angiogenesis-related markers expression and pathways. Silencing BCAT1 expression suppressed cell viability, colony formation, cycle progression, invasion, and angiogenesis of BGC823 cells, as well as the tumor growth of xenograft models, whereas overexpressing BCAT1 had the opposite results both in vitro and in vivo. Bioinformatics analysis and Western blotting demonstrated that BCAT1 activated the PI3K/AKT/mTOR pathway. The addition of LY294002 reversed the tumor growth induced by BCAT1 overexpression, further verifying this mechanism.ConclusionBCAT1 might act as an oncogene by facilitating proliferation, invasion, and angiogenesis through activation of the PI3K/AKT/mTOR pathway. This finding could aid the optimization of antiangiogenesis strategies.

Molecular Interactions of α-Synuclein, Mitochondria, and Cellular Degradation Pathways in Parkinson's Disease

2020 ◽  
pp. 212-234
Author(s):  
Mansi Verma ◽  
Sujata Basu ◽  
Manisha Singh ◽  
Rachana R. ◽  
Simrat Kaur ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Interactions ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Degradation Pathways ◽  
Functional Changes ◽  
The World ◽  
Novel Therapeutic

Parkinson's disease (PD) has been reported to be the most common neurodegenerative diseases all over the world. Several proteins are associated and responsible for causing PD. One such protein is α-synuclein. This chapter discusses the role of α-synuclein in PD. Various genetic and epigenetic factors, which cause structural and functional changes for α-synuclein, have been described. Several molecular mechanisms, which are involved in regulating mitochondrial and lysosomal related pathways and are linked to α-synuclein, have been discussed in detail. The knowledge gathered is further discussed in terms of using α-synuclein as a diagnostic marker for PD and as a novel therapeutic target for the same.

scholarly journals The Intricate Role of p53 in Adipocyte Differentiation and Function

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2621
Author(s):  
Yun Kyung Lee ◽  
Yu Seong Chung ◽  
Ji Hye Lee ◽  
Jin Mi Chun ◽  
Jun Hong Park
Keyword(s):  
Adipocyte Differentiation ◽  
Metabolic Diseases ◽  
Metabolic Stress ◽  
Health Concern ◽  
Metabolic Dysfunction ◽  
Direct Role ◽  
Proliferation And Apoptosis ◽  
Response To Stress ◽  
And Function

For more than three decades, numerous studies have demonstrated the function of p53 in cell cycle, cellular senescence, autophagy, apoptosis, and metabolism. Among diverse functions, the essential role of p53 is to maintain cellular homeostatic response to stress by regulating proliferation and apoptosis. Recently, adipocytes have been studied with increasing intensity owing to the increased prevalence of metabolic diseases posing a serious public health concern and because metabolic dysfunction can directly induce tumorigenesis. The prevalence of metabolic diseases has steadily increased worldwide, and a growing interest in these diseases has led to the focus on the role of p53 in metabolism and adipocyte differentiation with or without metabolic stress. However, our collective understanding of the direct role of p53 in adipocyte differentiation and function remains insufficient. Therefore, this review focuses on the newly discovered roles of p53 in adipocyte differentiation and function.

scholarly journals The Nrf2/Keap1/ARE Pathway and Oxidative Stress as a Therapeutic Target in Type II Diabetes Mellitus

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Joshua A. David ◽  
William J. Rifkin ◽  
Piul S. Rabbani ◽  
Daniel J. Ceradini
Keyword(s):  
Diabetes Mellitus ◽  
Oxidative Damage ◽  
Therapeutic Target ◽  
Type Ii Diabetes ◽  
Animal Studies ◽  
Cell Types ◽  
Type Ii Diabetes Mellitus ◽  
Type Ii ◽  
And Oxidative Stress

Despite improvements in awareness and treatment of type II diabetes mellitus (TIIDM), this disease remains a major source of morbidity and mortality worldwide, and prevalence continues to rise. Oxidative damage caused by free radicals has long been known to contribute to the pathogenesis and progression of TIIDM and its complications. Only recently, however, has the role of the Nrf2/Keap1/ARE master antioxidant pathway in diabetic dysfunction begun to be elucidated. There is accumulating evidence that this pathway is implicated in diabetic damage to the pancreas, heart, and skin, among other cell types and tissues. Animal studies and clinical trials have shown promising results suggesting that activation of this pathway can delay or reverse some of these impairments in TIIDM. In this review, we outline the role of oxidative damage and the Nrf2/Keap1/ARE pathway in TIIDM, focusing on current and future efforts to utilize this relationship as a therapeutic target for prevention, prognosis, and treatment of TIID.

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