Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • 2024-06
  • 2024-07
  • 2024-08
  • 2024-09
  • 2024-10

    • deoxythymidine synthesis Though we have proved that VA could

    2024-04-02

    Though, we have proved that VA could suppress hepatic gluconeogenesis, the mechanisms of VA on gluconeogenesis in vivo and in vitro remain unclear. AMP-activated protein kinase (AMPK), which is called an energy receptor enzyme, is widely expressed in liver and other tissues [23]. AMPK has become another important target for the treatment of type 2 diabetes because of its effects on regulating glucose metabolism and reducing peripheral insulin resistance. Many anti-diabetic drugs reduce blood glucose through the suppression of gluconeogenesis program, taking metformin for an example [24]. Metformin inhibits the hepatic gluconeogenesis through AMPK signaling pathway, inducing hypoglycemic effects. Also some researches have shown that the activation of AMPK can reduce glucose production and fasting blood glucose by inhibiting the expression of key enzymes of gluconeogenesis, PEPCK and G6Pase [2,25]. Therefore, activating AMPK to reduce the expression of PEPCK and G6Pase has become one of the important targets for inhibiting gluconeogenesis in type 2 diabetes. We speculated that AMPK activation contributed to the inhibitory effect on gluconeogenesis induced by VA administration. As the present results showed, AMPK activity decreased in the liver of STZ-induced mice and in HepG2 deoxythymidine synthesis induced by PA. In contrast, VA administration markedly reversed the reduction of p-AMPK protein induced by STZ and PA. These results indicated that VA indeed activates AMPK pathway. The mechanism was further confirmed in HepG2 cells. We used the AMPK inhibitor (Compound C) to block the AMPK activation induced by VA treatment. Compound C, an AMPK inhibitor, can inhibit AMPK activity and be used as an important tool in the investigation of AMPK function [26]. We also examined the effect of VA on glucose production in HepG2 cells induced by PA. As the results showed, the excessive glucose output in PA-induced HepG2 cells was inhibited by VA, while Compound C attenuated the inhibitory effect of VA. We further measured the expression of key enzymes of gluconeogenesis. VA significantly up-regulated the phosphorylation of AMPK and phosphorylation of ACC and reduced the expression of the PEPCK and G6Pase proteins. Interestingly, these effects could be reversed by Compound C. Therefore, these results indicate AMPK plays a key effect on the inhibition of gluconeogenesis induced by VA.
    Conflict of interest statement
    Acknowledgement This study was supported by the Science and Technology Project of Xiamen, China (No. 3502Z20159018).
    Introduction Diabetes mellitus is now considered an epidemic disease [1], [2]. Careful glycemic control is challenging and it is well known that hyperglycemia leads to several complications including nephropathy despite existing therapeutic measures [3], [4]. Approximately 25% of patients with type 1 and type 2 diabetes develop renal injury [5], [6]. Diabetic renal injury is mainly characterized by albuminuria, hypertension and loss of renal function [7]. Diabetic nephropathy is the primary cause of end-stage renal disease worldwide [8]. Microvascular dysfunction in the glomerulus appears as an early pathogenic event in progression of diabetic renal complication [9], [10]. Current treatment of diabetic renal injury involves blood pressure and glucose control [11]. Renin–angiotensin system blockers have been modestly successful in delaying the progression of renal injury. This necessitates the need of new therapeutic interventions that reverse early pathophysiological changes of diabetic renal complications and hence prevent the progression to end-stage renal failure. The etiology of diabetic renal injury is multi-factorial; however, oxidative stress and inflammation play a crucial role in the progression of diabetic renal injury [12], [13], [14]. Hyperglycemia increases oxidative stress in diabetic animal models and it is well known that NAD(P)H oxidase is the major source of superoxide production in the vasculature [15], [16]. Besides its ability to elevate inflammatory cytokines production, superoxide also scavenges NO decreasing NO availability and leads to the production of peroxynitrite, which has deleterious effects on the vasculature [17], [18], [19]. On the other hand, evidence suggests that renal infiltration of monocytes/macrophages also contributes to the pathogenesis of diabetic renal injury [20], [21]. The subsequent immune response to infiltrated monocytes/macrophages leads to renal fibrosis and extra cellular matrix deposition due to the release of lysosomal enzymes, superoxide and inflammatory cytokines perturbing the renal inflammatory cascade during diabetes [13], [22], [23]. Thus, pharmacological manipulation of inflammation is a rational approach to prevent early pathological changes of diabetic renal injury and subsequent loss of renal function.