BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1α proteasomal degradation

Thirusangu, Prabhu; Vigneshwaran, V.; Prashanth, T.; Avin, B.R. Vijay; Malojirao, Vikas H.; Heer, Rakesh; Khanum, Shaukath Ara; Mahmood, Riaz; Prabhakar, B.T.

doi:10.1007/s10456-016-9528-3

Cited by 45 publications

(20 citation statements)

References 57 publications

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“…In the present study, we explored the role of OPA1 in renal I/R injury. OPA1, the mitochondrial outer membrane GTPase, plays a key role in initiating mitophagy in pancreatic cancer, hepatic IR injury, Alzheimer’s disease, and gastric cancer [68]. In agreement with a previous study, OPA1 activated mitophagy and subsequently degraded the damaged mitochondria, interrupting the mitochondrial damage signalling.…”

Section: Discussionsupporting

confidence: 72%

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

Feng¹,

Li²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The aim of our study is to investigate the molecular mechanism by which mammalian STE20-like kinase 1 (Mst1) participates in renal I/R injury through modifying mitophagy and the AMPK-YAP signalling pathway. Methods: WT mice and Mst1-knockout mice were subjected to renal ischaemia-reperfusion (I/R) in vivo. In vitro, the hypoxia-reoxygenation model was used with renal tubular epithelial cells to mimic renal I/R injury. Mitochondrial function was monitored via western blotting and immunofluorescence. Pathway blocker and siRNA knockout technology were used to establish the role of the AMPK-YAP signalling pathway in Mst1-mediated mitochondrial apoptosis in the setting of renal I/R injury. Results: Our data demonstrated that Mst1 expression was upregulated in response to renal I/R injury in vivo, and a higher Mst1 content was positively associated with renal dysfunction and more tubular epithelial cell apoptosis. However, genetic ablation of Mst1 improved renal function, alleviated reperfusion-mediated tubular epithelial cell apoptosis, and attenuated the vulnerability of kidney to I/R injury. In vitro, Mst1 upregulation induced mitochondrial damage including mitochondrial potential reduction, ROS overloading, cyt-c liberation and caspase-9 apoptotic pathway activation. At the molecular levels, I/R-mediated mitochondrial damage via repressing mitophagy and Mst1 suppressed mitophagy via inactivating AMPK signalling pathway and dowregulating OPA1 expression. Re-activation of AMPK-YAP-OPA1 signalling pathway provided a survival advantage for the tubular epithelial cell in the context of renal I/R injury by repressing mitochondrial fission. Conclusion: Overall, our results demonstrate that the pathogenesis of renal I/R injury is closely associated with an increase in Mst1 expression and the inactive AMPK-YAP-OPA1 signalling pathway. Based on this, strategies to repress Mst1 expression and activate mitophagy could serve as therapeutic targets to treat kidney ischaemia-reperfusion injury.

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Section: Discussionsupporting

confidence: 72%

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

Feng¹,

Li²,

Zhang³

et al. 2018

Cell Physiol Biochem

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“…A subsequent study shows that MKP1 deficiency induces JNK activation and thus causes tubular cell damage in response to renal oxidative stress [20]. Furthermore, decreased MKP1 expression is associated with poor prognosis in clear cell renal cell carcinoma [54]. The above information suggests that MKP1 could be considered a defender to sustain kidney homeostasis ranging from renal development and stress response, to tumour formation.…”

Section: Discussionmentioning

confidence: 99%

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

Zhang¹,

Feng²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hyperglycaemia stress-induced renal injury is closely associated with mitochondrial dysfunction through poorly understood mechanisms. The aim of our study is to explore the upstream trigger and the downstream effector driving diabetic nephropathy via modulating mitochondrial homeostasis. Methods: A diabetic nephropathy model was generated in wild-type (WT) mice and MAP Kinase phosphatase 1 transgenic (MKP1-TG) mice using STZ injection. Cell experiments were conducted via high-glucose treatment in the human renal mesangial cell line (HRMC). MKP1 overexpression assay was carried out via adenovirus transfection. Renal function was evaluated via ELISA, western blotting, histopathological staining, and immunofluorescence. Mitochondrial function was determined via mitochondrial potential analysis, ROS detection, ATP measurement, mitochondrial permeability transition pore (mPTP) opening evaluation, and immunofluorescence for mitochondrial pro-apoptotic factors. Loss- and gain-of-function assays for mitochondrial fragmentation were performed using a pharmacological agonist and blocker. Western blotting and the pathway blocker were used to establish the signalling pathway in response to MKP1 overexpression in the presence of hyperglycaemia stress. Results: MKP1 was downregulated in the presence of chronic high-glucose stress in vivo and in vitro. However, MKP1 overexpression improved the metabolic parameters, enhanced glucose control, sustained renal function, attenuated kidney oxidative stress, inhibited the renal inflammation response, alleviated HRMC apoptosis, and repressed tubulointerstitial fibrosis. Molecular investigation found that MKP1 overexpression enhanced the resistance of HRMC to the hyperglycaemic injury by abolishing mitochondrial fragmentation. Hyperglycaemia-triggered mitochondrial fragmentation promoted mitochondrial dysfunction, as evidenced by decreased mitochondrial potential, elevated mitochondrial ROS production, increased pro-apoptotic factor leakage, augmented mPTP opening and activated caspase-9 apoptotic pathway. Interestingly, MKP1 overexpression strongly abrogated mitochondrial fragmentation and sustained mitochondrial homeostasis via inhibiting the JNK-CaMKII-Fis1 pathway. After re-activation of the JNK-CaMKII-Fis1 pathway, the beneficial effects of MKP1 overexpression on mitochondrial protection disappeared. Conclusion: Taken together, our data identified the protective role played by MKP1 in regulating diabetic renal injury via repressing mitochondrial fragmentation and inactivating the JNK-CaMKII-Fis1 pathway, which may pave the road to new therapeutic modalities for the treatment of diabetic nephropathy.

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“…In summary, the lateral scratch wound assay [55] and the Boyden chamber assay are both robust and reliable platforms to study EC migration. They are suitable for scaled-up purposes in order to perform manual or automated large-scale compound screens.…”

Section: Endothelial Cell and Monocyte Migration Assaysmentioning

confidence: 99%

Consensus guidelines for the use and interpretation of angiogenesis assays

et al. 2018

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The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.

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BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1α proteasomal degradation

Cited by 45 publications

References 57 publications

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

Consensus guidelines for the use and interpretation of angiogenesis assays

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