Tag Archives: HIF-1α
Multiple effects of angiostatins in injured cornea
V. L. Bilous*, A. O. Tykhomyrov
Department of Enzyme Chemistry and Biochemistry, Palladin Institute of Biochemistry,
National Academy of Sciences of Ukraine, Kyiv;
*e-mail: basil.bilous@gmail.com
Received: 07 October 2023; Revised: 01 November 2023;
Accepted: 01 February 2024; Available on-line: 26 February 2024
Prolonged inflammation and excessive neovascularization of the cornea due to severe injury can impair optical clarity and lead to vision impairment. Plasminogen kringle (K) fragments, known as angiostatins (AS), play a well-established role as inhibitors of neovascularization by suppressing pro-angiogenic signaling. However, AS effects in the cornea, beyond inhibiting the angiogenesis, are still unexplored. In this study, we estimate the protective effect of two AS variants (K1-3 and K5) against alkali burn injury induced in rabbit and rat corneas. AS K1-3 in the single doses of 0.075 or 0.75 μg (0.1 or 1.0 μM, respectively) or 0.3 μg of AS K5 (1.0 μM) were applied locally as eye drops daily for 14 days after the injury. A significant regression of corneal vessels in-growth in injured eyes treated with AS was revealed. Western blot analysis of corneal tissue lysates revealed that injury-induced overexpression of protein markers of hypoxia (HIF-1α), angiogenesis (VEGF), tissue remodeling and fibrosis (MMP-9), autophagy (beclin-1) and endoplasmic reticulum stress (GRP-78) was significantly reduced under AS treatment. Besides, the level of tight junctions protein ZO-1 was shown to be up-regulated after the treatment of the damaged cornea with AS K1-3. Summarizing, our study uncovered novel biological functions of the kringle-containing plasminogen fragments indicating its beneficial effects during corneal healing in the experimental model of alkali burn. The data obtained can be helpful for the development of novel efficient formulations to manage complications of ocular surface injuries.
Phenobarbital ameliorates hyperglycemia-induced angiogenesis in diabetic nephropathy-possible intervention at the HIF-1α/VEGF axis
M. M. Mohammed1*, S. R. A. Rehim1, A. M. M. Okasha1, H. El-Mezayen2,
D. G. A. N. Mohammed2, W. Gomaa3, F. Mourad4, E. G. Ayad2
1Department of Biochemistry, Faculty of Medicine, Minia University, El-Minia, Egypt;
2Department of Chemistry, Faculty of Science, Helwan University, Helwan, Egypt;
3Department of Pathology, Faculty of Medicine, Minia University, El-Minia, Egypt;
4MSP, Faculty of Pharmacy, Deraya University, El-Minia, Egypt;
*e-mail: mostafa.mohamed@mu.edu.eg
Received: 17 September 2023; Revised: 17 November 2023;
Accepted: 01 December 2023; Available on-line: 18 December 2023
Hyperglycemia contributes to a cascade of inflammatory responses in kidneys that result in the development of renal hypoxia and angiogenesis with subsequent chronic renal failure. As the hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) axis is a key pathway for neovascularization, the inhibition of this axis is a target for renal angiogenesis therapy. We speculate that Phenobarbital (PB) which has a potential to reduce vascularization in clinical settings might have an influence on the development of angiogenesis in diabetic kidney. The aim of the study was to explore the effects of PB on the HIF-1α and VEGF expression and angiogenesis in renal tissue of rats with hyperglycemia and diabetic nephropathy. Sixty-four male Wistar rats were devided into 4 groups: control group received a single intraperitoneal saline injection; PB group received 0.05% PB orally in drinking water; diabetic group received a single intra-peritoneal STZ (65 mg/kg) injection; PB-STZ group received 0.05% PB orally two weeks before STZ administration. At the end of the experiment period (8 weeks), the kidneys were removed and used for biochemical analyses. Serum glucose, urea and creatinine levels, IL-6 levels in kidney homogenate and changes in HIF-1α and VEGF gene expression were estimated. Hematoxylin-eosin staining was performed for histopathological examination. The results obtained showed that both HIF-1α and VEGF gene expression and IL6 level in diabetic rat group were significantly elevated compared to that in control group, whereas in PB and PB-STZ groups, these indices were significantly down-regulated compared to the diabetic group. Abundant glomerular congestion and mesangial proliferation were detected in diabetic rat renal tissues. However, in PB-treated diabetic group, newly formed vessels were significantly decreased. These findings confirmed that phenobarbital, affecting the HIF-1α/VEGF signaling pathway, ameliorates angiogenesis after hyperglycemic kidney injury.
Oxydative stress in type 2 diabetic patients: involvement of HIF-1 alpha AND mTOR genes expression
Y. A. Saenko1, O. O. Gonchar2*, I. M. Mankovska2,
T. I. Drevytska2, L. V. Bratus2, B. M. Mankovsky1,3
1SI “The Scientific and Practical Medical Center of Pediatric Cardiology and Cardiac Surgery
of the Ministry of Health of Ukraine”, Clinic for Adults, Kyiv;
2Department of Hypoxia, Bogomoletz Institute of Physiology,
National Academy of Sciences of Ukraine, Kyiv;
3Shupyk National Healthcare University of Ukraine, Kyiv;
*e-mail:olga.gonchar@i.ua
Received: 22 March 2023; Revised: 25 May 2023;
Accepted: 05 June 2023; Available on-line: 20 June 2023
Biochemical and genetic mechanisms of oxidative stress (OS) developing in the blood of patients with type 2 Diabetes mellitus (T2DM) were studied. Twenty patients with T2DM and 10 healthy persons participated in this study. Lipid peroxidation, the content of protein carbonyls and H2O2 production were measured in blood plasma and erythrocytes as OS biomarkers. Activity of SOD, catalase, and GPx as well as reduced glutathionе (GSH) level in plasma and erythrocytes were estimated. The gene expression of key regulators of oxygen and metabolic homeostasis (HIF-1α and mTOR) in leukocytes were studied. It was found a significant rise in TBARS and protein carbonyls content in plasma as well as H2O2 production in erythrocytes from patients with T2DM compared to control. The diabetic patients also demonstrated an increase in the SOD and catalase activity in plasma and significantly lower GSH content and GPx activity in erythrocytes compared to the healthy participants. The established marked inhibition of mTOR gene expression and the tendency to an increase in HIF-1α gene expression in leukocytes of patients with T2DM may serve as a protective mechanism which counteracts OS developing and oxidative cell damage.