Hypoxia Inducible Factor (HIF) 1-Α dan Vascular Endothelial Growth Factor (VEGF) pada Stroke Iskemik Fase Akut

Stroke iskemik merupakan salah satu penyebab stroke tersering, disebabkan oleh oklusi pembuluh darah serebral dan penyebab kematian ketiga. Saat awitan stroke iskemik terjadi, area otak yang diperdarahi oleh pembuluh darah akan kekurangan oksigen dan nutrisi sehingga sel otak terutama neuron berada dalam risiko, neuron ini masih dapat berfungsi yang dikenal sebagai penumbra. Hipoksik, salah satu karakteristik penumbra merupakan stimulus utama regulasi protein HIF-1α. Hipoksik sendiri merupakan stimulus utama prekondisi iskemik. Prekondisi iskemik akan menghasilkan fenotipe tahan hipoksia yakni protein hypoxia inducible factor (HIF)-1α. HIF-1α merupakan satu-satunya zat yang dikeluarkan oleh jaringan yang mengalami hipoksia. HIF-1α bertindak sebagai protein sinyal yang dapat meregulasi gen protein lain. Efektor HIF-1α antara lain eritropoitin dan vascular endothelial growth factor (VEGF). Pertumbuhan, diferensiasi dan ketahanan sel endotel diregulasi oleh VEGF yang distimulasi dari HIF-1α. Selama iskemik serebral, jaringan yang rusak mencoba untuk meningkatkan pengiriman oksigen melalui induksi angiogenesis melalui produksi VEGF. Hal ini ditandai dengan adanya peningkatan jumlah pembuluh-pembuluh darah mikro di area infark. VEGF dan reseptornya diregulasi oleh HIF-1α dalam hari pertama iskemik.Hypoxia Inducible Factor (HIF) 1-Α and Vascular Endothelial Growth Factor (VEGF) in Acute Ischemic StrokeAbstractIschemic stroke is one of the most common causes of stroke, caused by cerebral vascular occlusion and the third cause of death. When the onset of an ischemic stroke occurs, the area of the brain bleeding by blood vessels will lack oxygen and nutrients so that brain cells, especially neurons, are at risk, these neurons can still function known as penumbra. Hypoxic, one of the characteristics of penumbra is the main stimulus for regulation of HIF-1α protein. Hypoxia itself is the main stimulus of ischemic precondition. The ischemic precondition will produce a hypoxic-resistant phenotype namely protein hypoxia inducible factor (HIF) -1α. HIF-1αis the only substance released by tissue that experiences hypoxia. HIF-1α acts as a signaling protein that can regulate other protein genes. Effectors of HIF-1αinclude erythropoitin and vascular endothelial growth factor (VEGF). Growth, differentiation and endurance of endothelial cells are regulated by VEGF stimulated from HIF-1α. During cerebral ischemia, damaged tissue tries to increase oxygen delivery through induction of angiogenesis through VEGF production. This is characterized by an increase in the number of micro blood vessels in the infarct area. VEGF and its receptors are regulated by HIF-1α in the first day of ischemia.

Superagonistic CD28 Protects against Renal Ischemic Injury by Expansion of Regulatory T-Cell

Background: Regulatory T (Treg) cells are a highly suppressive subset of CD4+ lymphocytes and have recently been proved to be crucial to suppress the inflammatory responses of ischemic kidney injury. CD28 superagonists (CD28sa) are monoclonal antibodies that preferentially expand Treg cells without a T-cell receptor and a costimulatory signal. This study aims to test the protection and discover the mechanisms of CD28sa treatment against renal ischemia-reperfusion (IR) injury (IRI). Methods: Male C57BL/6N mice were treated with CD28sa via peritoneal injection (0.1 mg) 6 days before the induction of IRI, or with 18-min ischemic precondition (IPC). IRI was induced by bilateral clamping of renal pedicles for 35 min followed by reperfusion. The role of Treg expansion in renal protection conferred by CD28sa treatment was examined using anti-CD25 antibody. Results: CD28sa treatment alone significantly increased the percentage of Treg cells in the spleen (18.10 ± 2.00 vs. 6.64 ± 0.86%, p < 0.01), peripheral blood (16.43 ± 5.94 vs. 2.57 ± 1.09%, p < 0.01), and kidney (2.69 ± 0.90 vs. 0.53 ± 0.14%, p < 0.01) of C57BL/6N mice 6 days after the administration. Mice pretreated with CD28sa or IPC had less renal injury at 24 h after IRI with attenuation of renal tubular damage and lower serum creatinine compared with the mice that underwent renal IRI alone. The number of infiltrating macrophages in the kidney and IFN-γ secreting CD4+ T cells in peripheral blood were diminished in the CD28sa-IR group and the IPC-IR group. The renal protection bestowed by CD28sa or IPC was abolished by anti-CD25 antibody administration. Conclusions: Treg expansion induced by CD28sa ameliorated renal IRI.

The use of gliclazide in the mirror of the individualized sulfonylurea therapy

In addition to the common blood glucose lowering effect, sulfonylurea compounds are different in many aspects from each other. Based on earlier findings the second generation gliclazide has special advantages within this group. Although the number of experimental and clinical observations on gliclazide is continuously increasing, these novel findings are not in the focus anymore due to the appearance of new antidiabetics. The article overviews recent experimental (receptorial effect, the absence of Epac2 activation, antioxidant properties, possible incentive of factors participating in beta-cell differentiation) and pharmacogenomic data, and compares them with clinical observations obtained from gliclazide treatment (hypoglycaemias, parameters of cardiovascular outcome). The data underline the advantages of gliclazide, the highly pancreas-selective nature, preservation of the ischemic precondition, favourable hemodynamic properties and potential reduction of the beta-cell loss as compared to other compounds of the group. However, gliclazide is not free from disadvantages characteristic to sulfonylureas in general (blood glucose independent insulin stimulation, beta-cell depletion). Comparing gliclazide with other derivatives of the group, the above data indicate individual benefits for the application when sulfonylurea compound is the drug of choice. Orv. Hetil., 2014, 155(14), 541–548.