Effect of Voacamine upon inhibition of hypoxia induced fatty acid synthesis in a rat model of methyln-nitrosourea induced mammary gland carcinoma

Singh, Lakhveer; Singh, Manjari; Rastogi, Shubham; Choudhary, Anurag; Kumar, Deepak; Raj, Ritu; Ansari, Mohd Nazam; Saeedan, Abdulaziz S.; Kaithwas, Gaurav

doi:10.1186/s12860-021-00371-9

Cited by 14 publications

(5 citation statements)

References 55 publications

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“…Consistently, a marked elevation in mitochondrial ROS after FA injection was observed in our study, and this elevation was attenuated by FG-4592 pretreatment. In addition, up-regulation of HIF-1α level was found to be closely associated with dysfunction of mitochondria, which can induce mammary gland carcinoma progression (Singh et al, 2021b). Polyl hydroxylase (PHD-2) activation was considered as a novel strategy to control HIF-1α to modulate mitochondrial stress in mammary gland pathophysiology of ER + subtype (Singh et al, 2021a).…”

Section: Discussionmentioning

confidence: 99%

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

et al. 2022

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Incomplete recovery from acute kidney injury induced by folic acid is a major risk factor for progression to chronic kidney disease. Mitochondrial dysfunction has been considered a crucial contributor to maladaptive repair in acute kidney injury. Treatment with FG-4592, an inhibitor of hypoxia inducible factor prolyl-hydroxylase, is emerging as a new approach to attenuate renal damage; however, the underlying mechanism has not been fully elucidated. The current research demonstrated the protective effect of FG-4592 against renal dysfunction and histopathological damage on the 7th day after FA administration. FG-4592 accelerated tubular repair by promoting tubular cell regeneration, as indicated by increased proliferation of cell nuclear antigen-positive tubular cells, and facilitated structural integrity, as reflected by up-regulation of the epithelial inter-cellular tight junction molecule occludin-1 and the adherens junction molecule E-cadherin. Furthermore, FG-4592 ameliorated tubular functional recovery by restoring the function-related proteins aquaporin1, aquaporin2, and sodium chloride cotransporter. Specifically, FG-4592 pretreatment inhibited hypoxia inducible factor-1α activation on the 7th day after folic acid injection, which ameliorated ultrastructural abnormalities, promoted ATP production, and attenuated excessive reactive oxygen species production both in renal tissue and mitochondria. This was mainly mediated by balancing of mitochondrial dynamics, as indicated by down-regulation of mitochondrial fission 1 and dynamin-related protein 1 as well as up-regulation of mitofusin 1 and optic atrophy 1. Moreover, FG-4592 pretreatment attenuated renal tubular epithelial cell death, kidney inflammation, and subsequent interstitial fibrosis. In vitro, TNF-α-induced HK-2 cells injury could be ameliorated by FG-4592 pretreatment. In summary, our findings support the protective effect of FG-4592 against folic acid-induced mitochondrial dysfunction; therefore, FG-4592 treatment can be used as a useful strategy to facilitate tubular repair and mitigate acute kidney injury progression.

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Section: Discussionmentioning

confidence: 99%

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

et al. 2022

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“…Many studies have reported that FASN activity is required for lipid biosynthesis and cellular proliferation in various cancer pathologies ( Currie et al, 2013 ; Zaidi et al, 2013 ). Moreover, downregulation of FASN was found to promote breast cancer prognosis ( Roy et al, 2020 ; Singh et al, 2021b ; 2021a ) ( Singh et al, 2016 ; Roy et al, 2017 ; Singh M. et al, 2018 ; Devi et al, 2019a ). It has been suggested that FASN activity is upregulated in response to an increase in the expression of SREBP-1c by HIF-1α ( Furuta et al, 2008 ; Singh L. et al, 2018 ).…”

Section: How Do Tumor Cells Adapt Under Hypoxia?mentioning

confidence: 99%

NF-κB mediated regulation of tumor cell proliferation in hypoxic microenvironment

et al. 2023

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Hypoxia is caused by a cancer-promoting milieu characterized by persistent inflammation. NF-κB and HIF-1α are critical participants in this transition. Tumor development and maintenance are aided by NF-κB, while cellular proliferation and adaptability to angiogenic signals are aided by HIF-1α. Prolyl hydroxylase-2 (PHD-2) has been hypothesized to be the key oxygen-dependent regulator of HIF-1α and NF-transcriptional B’s activity. Without low oxygen levels, HIF-1α is degraded by the proteasome in a process dependent on oxygen and 2-oxoglutarate. As opposed to the normal NF-κB activation route, where NF-κB is deactivated by PHD-2-mediated hydroxylation of IKK, this method actually activates NF-κB. HIF-1α is protected from degradation by proteasomes in hypoxic cells, where it then activates transcription factors involved in cellular metastasis and angiogenesis. The Pasteur phenomenon causes lactate to build up inside the hypoxic cells. As part of a process known as lactate shuttle, MCT-1 and MCT-4 cells help deliver lactate from the blood to neighboring, non-hypoxic tumour cells. Non-hypoxic tumour cells use lactate, which is converted to pyruvate, as fuel for oxidative phosphorylation. OXOPHOS cancer cells are characterized by a metabolic switch from glucose-facilitated oxidative phosphorylation to lactate-facilitated oxidative phosphorylation. Although PHD-2 was found in OXOPHOS cells. There is no clear explanation for the presence of NF-kappa B activity. The accumulation of the competitive inhibitor of 2-oxo-glutarate, pyruvate, in non-hypoxic tumour cells is well established. So, we conclude that PHD-2 is inactive in non-hypoxic tumour cells due to pyruvate-mediated competitive suppression of 2-oxo-glutarate. This results in canonical activation of NF-κB. In non-hypoxic tumour cells, 2-oxoglutarate serves as a limiting factor, rendering PHD-2 inactive. However, FIH prevents HIF-1α from engaging in its transcriptional actions. Using the existing scientific literature, we conclude in this study that NF-κB is the major regulator of tumour cell growth and proliferation via pyruvate-mediated competitive inhibition of PHD-2.

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“…A large perturbation in serum metabolites was observed in toxicant treated animals. Overall, conclusion of the study was that hypoxic cancer cells reprogrammed their glycolytic pathway to enhance lactic acid production ( 106 , 107 ). Interestingly, higher levels of lipids (polyunsaturated fatty acids) were also observed in the same animals with increased lactate level.…”

Section: Lipid Reprogramming Of Cancer Cellsmentioning

confidence: 99%

Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival

et al. 2023

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It is well known that solid hypoxic tumour cells oxidise glucose through glycolysis, and the end product of this pathway is fermented into lactate which accumulates in the tumour microenvironment (TME). Initially, it was proclaimed that cancer cells cannot use lactate; therefore, they dump it into the TME and subsequently augment the acidity of the tumour milieu. Furthermore, the TME acts as a lactate sink with stope variable amount of lactate in different pathophysiological condition. Regardless of the amount of lactate pumped out within TME, it disappears immediately which still remains an unresolved puzzle. Recent findings have paved pathway in exploring the main role of lactate acidosis in TME. Cancer cells utilise lactate in the de novo fatty acid synthesis pathway to initiate angiogenesis and invasiveness, and lactate also plays a crucial role in the suppression of immunity. Furthermore, lactate re-programme the lipid biosynthetic pathway to develop a metabolic symbiosis in normoxic, moderately hypoxic and severely hypoxic cancer cells. For instance: severely hypoxic cancer cells enable to synthesizing poly unsaturated fatty acids (PUFA) in oxygen scarcity secretes excess of lactate in TME. Lactate from TME is taken up by the normoxic cancer cells whereas it is converted back to PUFAs after a sequence of reactions and then liberated in the TME to be utilized in the severely hypoxic cancer cells. Although much is known about the role of lactate in these biological processes, the exact molecular pathways that are involved remain unclear. This review attempts to understand the molecular pathways exploited by lactate to initiate angiogenesis, invasiveness, suppression of immunity and cause re-programming of lipid synthesis. This review will help the researchers to develop proper understanding of lactate associated bimodal regulations of TME.

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Effect of Voacamine upon inhibition of hypoxia induced fatty acid synthesis in a rat model of methyln-nitrosourea induced mammary gland carcinoma

Cited by 14 publications

References 55 publications

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

NF-κB mediated regulation of tumor cell proliferation in hypoxic microenvironment

Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival

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