Energenesis Biomedical Co.

Taipei, Taiwan

Energenesis Biomedical Co.

Taipei, Taiwan
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Young G.-H.,Energenesis Biomedical Co. | Young G.-H.,National Taiwan University Hospital | Lin J.-T.,Energenesis Biomedical Co. | Cheng Y.-F.,Energenesis Biomedical Co. | And 5 more authors.
Journal of Proteomics | Year: 2015

AMP-activated protein kinase (AMPK) is a metabolic master switch maintaining the energy homeostasis in cells and thought to modulate cellular response to stresses. Adenine as well as a pharmacological AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), induced the phosphorylation of AMPK and acetyl-CoA carboxylase in NIH/3T3 cells. Administration of adenine or AICAR increased the expression and translocation of glucose transporter 4, enhanced the cellular glucose uptake, and elevated the intracellular ATP level. To better understand the proteomic changes in response to exogenous adenine treatment, we performed two-dimensional difference gel electrophoresis (2DE-DIGE) and grouped protein spots with similar intensities prior to MS analysis. These process allowed us to exclude these constant expressed proteins, reduce the coverage from abundant signals and increase the identification of middle/lower expressed proteins. Bioinformatics analysis on the proteomic alterations suggested that both of adenine and AICAR could induce up-regulation of a panel of proteins associated with glucose metabolism. We also found that adenine upregulated expression of the glycolytic enzyme, hexokinase 2, indicating a link between adenine and AMPK-mediated glycolysis. Taken together, by demonstrating the adenine-mediated proteome changes in NIH/3T3 cells, our study provides useful information for the characteristics of adenine-induced AMPK activation and development of efficient AMPK activator. Biological significance: AMPK is a fuel sensing enzyme that responds to a central role of energy homeostasis and contributes to the acceleration of insulin signaling. Recently, we have shown that exogenous adenine exerted anti-inflammatory effects through activation of AMPK, suggesting the treatment is a potent therapeutic strategy against hyperglycemia. Adenine had similar effects with 5-amino-4-imidazole-carboxamide riboside (AICAR, an AMPK activator) in modulating glucose uptake via AMPK-mediated signaling. In this study, we performed a 2DE-DIGE/MS-based approach to investigate the mechanism of exogenous adenine in NIH/3T3 cells. Our results provide evidence of a novel role for adenine in AMPK-mediated signaling and glucose metabolism and suggest potential therapeutic perspectives in insulin resistance and metabolic dysfunctions. © 2015 Elsevier B.V.


PubMed | Energenesis Biomedical Co., National Laboratory Animal Center, Fu Jen Catholic University and National Taiwan University Hospital
Type: | Journal: Journal of proteomics | Year: 2015

AMP-activated protein kinase (AMPK) is a metabolic master switch maintaining the energy homeostasis in cells and thought to modulate cellular response to stresses. Adenine as well as a pharmacological AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), induced the phosphorylation of AMPK and acetyl-CoA carboxylase in NIH/3T3 cells. Administration of adenine or AICAR increased the expression and translocation of glucose transporter 4, enhanced the cellular glucose uptake, and elevated the intracellular ATP level. To better understand the proteomic changes in response to exogenous adenine treatment, we performed two-dimensional difference gel electrophoresis (2DE-DIGE) and grouped protein spots with similar intensities prior to MS analysis. These process allowed us to exclude these constant expressed proteins, reduce the coverage from abundant signals and increase the identification of middle/lower expressed proteins. Bioinformatics analysis on the proteomic alterations suggested that both of adenine and AICAR could induce up-regulation of a panel of proteins associated with glucose metabolism. We also found that adenine upregulated expression of the glycolytic enzyme, hexokinase 2, indicating a link between adenine and AMPK-mediated glycolysis. Taken together, by demonstrating the adenine-mediated proteome changes in NIH/3T3 cells, our study provides useful information for the characteristics of adenine-induced AMPK activation and development of efficient AMPK activator.AMPK is a fuel sensing enzyme that responds to a central role of energy homeostasis and contributes to the acceleration of insulin signaling. Recently, we have shown that exogenous adenine exerted anti-inflammatory effects through activation of AMPK, suggesting the treatment is a potent therapeutic strategy against hyperglycemia. Adenine had similar effects with 5-amino-4-imidazole-carboxamide riboside (AICAR, an AMPK activator) in modulating glucose uptake via AMPK-mediated signaling. In this study, we performed a 2DE-DIGE/MS-based approach to investigate the mechanism of exogenous adenine in NIH/3T3 cells. Our results provide evidence of a novel role for adenine in AMPK-mediated signaling and glucose metabolism and suggest potential therapeutic perspectives in insulin resistance and metabolic dysfunctions.


Chen C.-C.,Fu Jen Catholic University | Lin J.-T.,Energenesis Biomedical Co. | Cheng Y.-F.,Energenesis Biomedical Co. | Kuo C.-Y.,Energenesis Biomedical Co. | And 6 more authors.
BioMed Research International | Year: 2014

Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis via modulating metabolism of glucose, lipid, and protein. In addition to energy modulation, AMPK has been demonstrated to associate with several important cellular events including inflammation. The results showed that ENERGI-F704 identified from bamboo shoot extract was nontoxic in concentrations up to 80 M and dose-dependently induced phosphorylation of AMPK (Thr-172) in microglia BV2 cells. Our findings also showed that the treatment of BV2 with ENERGI-F704 ameliorated the LPS-induced elevation of IL-6 and TNF-α production. In addition, ENERGI-F704 reduced increased production of nitric oxide (NO) and prostaglandin E2 (PGE2) via downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), respectively. Moreover, ENERGI-F704 decreased activated nuclear translocation and protein level of NF-B. Inhibition of AMPK with compound C restored decreased NF-B translocation by ENERGI-F704. In conclusion, ENERGI-F704 exerts inhibitory activity on LPS-induced inflammation through manipulating AMPK signaling and exhibits a potential therapeutic agent for neuroinflammatory disease. © 2014 Chin-Chen Chen et al.


Hsu C.-Y.,Tungs Taichung Metro Harbor Hospital | Lin C.-H.,Chung Shan Medical University | Lin J.-T.,Fu Jen Catholic University | Cheng Y.-F.,Energenesis Biomedical Co. | And 3 more authors.
Molecular Medicine Reports | Year: 2015

Purine compounds are known to activate 5'-adenosine monophosphate-activated protein kinase (AMPK), which has important roles in treatments for renal cell carcinoma. The present study was aimed to investigate the effects of the purine analogue ENERGI-F706 on the human renal carcinoma cell line 786-O and the underlying mechanisms. The results revealed that ENERGI-F706 (0.2-0.6 mg/ml) significantly decreased the cell viability to up to 36.4±2.4% of that of the control. Compared to 786-O cells, ENERGI-F706 exerted less suppressive effects on the viability of the human non-tumorigenic renal cell line HK-2. Flow cytometric analysis showed that ENERGI-F706 contributed to cell cycle arrest at S-phase and triggered apoptosis of 786-O cells. Immunoblot analysis revealed that anti-apoptotic B-cell lymphoma 2 (Bcl-2) levels were reduced and pro-apoptotic Bcl-2-associated X protein levels were diminished. In addition, activation of caspase-9, caspase-3 and poly(adenosine diphosphate ribose) polymerase (PARP) was promoted in 786-O cells in response to ENERGI-F706. Effects of ENERGI-F706 on AMPK cascades were investigated and the results showed that ENERGI-F706 enhanced phosphorylation of AMPKα (T172) and p53(S15), a downstream target of AMPK. In addition, the AMPK activation, p53 (S15) phosphorylation, reduction of Bcl-2, cleavage of caspase-3 and PARP as well as suppressed cell viability induced by ENERGI-F706 were reversed in the presence of AMPK inhibitor compound C (dorsomorphin). In conclusion, the findings of the present study revealed that ENERGI-F706 significantly suppressed the viability of 786-O cells via induction of cell cycle arrest and apoptosis, attributing to AMPK and p53 activation and subsequent cell cycle regulatory and apoptotic signaling. It was therefore indicated that ENERGI-F706 may be suitable for the treatment of renal cell carcinoma.


Huang B.-P.,Tungs Taichung MetroHarbor Hospital | Lin C.-H.,Chung Shan Medical University | Chen H.-M.,Fu Jen Catholic University | Chen H.-M.,Energenesis Biomedical Co. | And 3 more authors.
DNA and Cell Biology | Year: 2015

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a central role in energy homeostasis and regulation of inflammatory responses. The present study is aimed to investigate the anti-inflammatory effects of ENERGI-F704, a nucleobase analogue isolated from bamboo leaves, on expression of proinflammatory mediators in murine macrophage RAW264.7 in response to lipopolysaccharide (LPS). ENERGI-F704 enhanced phosphorylation of AMPK(T172) but insignificantly affected the viability of RAW264.7 cells. Further investigation showed that ENERGI-F704 decreased mRNA expression of interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS) induced by LPS, as well as suppressed the production of prostaglandin E2 (PGE2) and nitric oxide (NO). Additionally, the inhibitory effects of ENERGI-F704 on the LPS-induced proinflammatory mediators were diminished by pretreatment of AMPK inhibitor Compound C. ENERGI-F704 also inhibited LPS-triggered activation of nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase (PI3K), and p38 mitogen-activated protein kinase (p38), whereas extracellular signal-regulated kinase (Erk)1/2 and c-Jun N-terminal kinase (JNK) were insignificantly influenced. Our findings indicate that ENERGI-F704 may exert anti-inflammatory activity on RAW264.7 cells in response to LPS through the activation of AMPK and suppression of PI3K/P38/NF-κB signaling and the consequent decreased expression of proinflammatory mediators, suggesting that ENERGI-F704 is beneficial to the amelioration of inflammatory disorders. © 2015, Mary Ann Liebert, Inc.


Lin J.-T.,Energenesis Biomedical Co. | Chen H.-M.,Fu Jen Catholic University | Chiu C.-H.,National Taiwan University of Science and Technology | Liang Y.-J.,Fu Jen Catholic University
Expert Opinion on Investigational Drugs | Year: 2014

Introduction: Diagnosed cases of diabetes have gradually increased year by year, and research on diabetes mellitus (DM) has attracted greater attention from the medical profession. Diabetic ulcers present persistent pain and the risk of bacterial infection. However, no promising treatment methods have been found. As a regulator of cellular energy balance, 5' adenosine monophosphate-activated protein kinase (AMPK) has been suggested as a drug target for DM, including such drugs as metformin.Areas covered: This review summarizes the current research and clinical trials of AMPK activators on diabetic wound healing and diabetic ulcers. Furthermore, it discusses the feasibility of AMPK activators in the treatment of diabetic wounds.Expert opinion: Animal studies have demonstrated that AMPK activators are a potential treatment for diabetic ulcers. AMPK activators alleviate tissue inflammation and promote re-epithelialization in diabetic wounds. However, due to the complicated pathological mechanism of diabetic foot ulcers, AMPK activators should be combined with other approaches. The new strategies for combination therapy with AMPK activator may provide a therapeutic advantage for patients with diabetic ulcers. © 2014 Informa UK, Ltd.


PubMed | Chung Shan Medical University, National Taiwan University, Fu Jen Catholic University and Energenesis Biomedical Co.
Type: Journal Article | Journal: PloS one | Year: 2015

The AMP-activated protein kinase (AMPK) signaling system plays a key role in cellular stress by repressing the inflammatory responses induced by the nuclear factor-kappa B (NF-B) system. Previous studies suggest that the anti-inflammatory role of AMPK involves activation by adenine, but the mechanism that allows adenine to produce these effects has not yet been elucidated. In human umbilical vein endothelial cells (HUVECs), adenine was observed to induce the phosphorylation of AMPK in both a time- and dose-dependent manner as well as its downstream target acetyl Co-A carboxylase (ACC). Adenine also attenuated NF-B targeting of gene expression in a dose-dependent manner and decreased monocyte adhesion to HUVECs following tumor necrosis factor (TNF-) treatment. The short hairpin RNA (shRNA) against AMPK 1 in HUVECs attenuated the adenine-induced inhibition of NF-B activation in response to TNF-, thereby suggesting that the anti-inflammatory role of adenine is mediated by AMPK. Following the knockdown of adenosyl phosphoribosyl transferase (APRT) in HUVECs, adenine supplementation failed to induce the phosphorylation of AMPK and ACC. Similarly, the expression of a shRNA against APRT nullified the anti-inflammatory effects of adenine in HUVECs. These results suggested that the role of adenine as an AMPK activator is related to catabolism by APRT, which increases the cellular AMP levels to activate AMPK.


PubMed | Chung Shan Medical University, Chang Gung University, Fu Jen Catholic University and Energenesis Biomedical Co.
Type: | Journal: BioMed research international | Year: 2014

Adenosine 5-monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis via modulating metabolism of glucose, lipid, and protein. In addition to energy modulation, AMPK has been demonstrated to associate with several important cellular events including inflammation. The results showed that ENERGI-F704 identified from bamboo shoot extract was nontoxic in concentrations up to 80M and dose-dependently induced phosphorylation of AMPK (Thr-172) in microglia BV2 cells. Our findings also showed that the treatment of BV2 with ENERGI-F704 ameliorated the LPS-induced elevation of IL-6 and TNF- production. In addition, ENERGI-F704 reduced increased production of nitric oxide (NO) and prostaglandin E2 (PGE2) via downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), respectively. Moreover, ENERGI-F704 decreased activated nuclear translocation and protein level of NF-B. Inhibition of AMPK with compound C restored decreased NF-B translocation by ENERGI-F704. In conclusion, ENERGI-F704 exerts inhibitory activity on LPS-induced inflammation through manipulating AMPK signaling and exhibits a potential therapeutic agent for neuroinflammatory disease.


PubMed | Chung Shan Medical University, Energenesis Biomedical Co., University of Taipei and Tungs Taichung Metro Harbor Hospital
Type: Journal Article | Journal: Molecular medicine reports | Year: 2015

Purine compounds are known to activate 5-adenosine monophosphate-activated protein kinase (AMPK), which has important roles in treatments for renal cell carcinoma. The present study was aimed to investigate the effects of the purine analogue ENERGIF706 on the human renal carcinoma cell line 786O and the underlying mechanisms. The results revealed that ENERGIF706 (0.20.6 mg/ml) significantly decreased the cell viability to up to 36.42.4% of that of the control. Compared to 786O cells, ENERGIF706 exerted less suppressive effects on the viability of the human nontumorigenic renal cell line HK2. Flow cytometric analysis showed that ENERGIF706 contributed to cell cycle arrest at Sphase and triggered apoptosis of 786O cells. Immunoblot analysis revealed that antiapoptotic Bcell lymphoma 2 (Bcl2) levels were reduced and proapoptotic Bcl2associated X protein levels were diminished. In addition, activation of caspase9, caspase3 and poly(adenosine diphosphate ribose) polymerase (PARP) was promoted in 786O cells in response to ENERGIF706. Effects of ENERGIF706 on AMPK cascades were investigated and the results showed that ENERGIF706 enhanced phosphorylation of AMPK (T172) and p53 (S15), a downstream target of AMPK. In addition, the AMPK activation, p53 (S15) phosphorylation, reduction of Bcl2, cleavage of caspase3 and PARP as well as suppressed cell viability induced by ENERGIF706 were reversed in the presence of AMPK inhibitor compound C (dorsomorphin). In conclusion, the findings of the present study revealed that ENERGIF706 significantly suppressed the viability of 786O cells via induction of cell cycle arrest and apoptosis, attributing to AMPK and p53 activation and subsequent cell cycle regulatory and apoptotic signaling. It was therefore indicated that ENERGIF706 may be suitable for the treatment of renal cell carcinoma.

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