Hypoxic or ischemic stress causes serious brain injury via various pathologic mechanisms including suppressed protein synthesis, neuronal apoptosis, and the release of neurotoxic substances. Many neuroprotective treatments of hypoxic or ischemic brain injury rely on these pathologic mechanisms. The mammalian target of rapamycin (mTOR), an atypical Ser/Thr protein kinase, could be a novel therapeutic target. mTOR plays a critical role in regulating many activities such as protein synthesis, cell growth, and cell death. Furthermore, mTOR could promote angiogenesis, neuronal regeneration, and synaptic plasticity, reduce neuronal apoptosis, and remove neurotoxic substances, which are all closely associated with the repair and survival mechanisms of hypoxic or ischemic brain injury. Although there is currently controversy with regard to regulating the activation of mTOR, the effective neuroprotective functions resulting from mTOR activation have been confirmed by various studies. Considering the potential capability for mTOR in regulating the repair and survival mechanisms of hypoxic or ischemic brain injury, mTOR may be a novel target for neuroprotective treatment.

Hypoxic-ischemic (HI) brain injury is one of the most severe diseases in the neonatal central nervous system (CNS). The pathological mechanisms of HI brain injury, including cellular apoptosis, excitotoxicity, oxidative stress, etc., are complicated and not well known. Cellular processes such as angiogenesis, neuronal survival and neurogenesis have been proven to be closely associated with brain repair following HI injury. Telomerase reverse transcriptase (TERT), a component of telomerase, plays a primary role in maintaining telomere length. In addition, recent studies have demonstrated that TERT can protect neurons from apoptosis and excitotoxicity, and promote angiogenesis, neurogenesis and neuronal survival. However, there are few reports on the roles of TERT in neonatal HI brain injury and the mechanisms involved are unclear. It is reported that TERT is activated and plays a protective role in adult brains with ischemia and recently we have shown that TERT was induced and may act protectively in a neonatal rat model of HI brain injury. Therefore, it is quite possible that TERT plays an important role in neuroprotection in developing brains following HI injury by inhibiting apoptosis and excitotoxicity, and promoting angiogenesis, neuronal survival and neurogenesis. These very novel mechanisms could lead to more effective neuroprotective strategies against hypoxic-ischemic brain injury in neonates.

TERT attenuates astrocyte proliferation and promotes neuronal survival in the developing rat brain after hypoxia-ischemia, partly through its enhancement of p15 and neurotrophin-3 expression in astrocytes.

Hypoxia/ischemia brain damage (HIBD) is one of the most common central nervous system insults in newborns. Brain repair following HIBD is closely associated with cellular processes such as cell survival, angiogenesis, and neurogenesis. In recent years, many studies have suggested that ginsenoside Rg1, one of the major active ingredients of ginseng, may increase neural viability, promote angiogenesis, and induce neurogenesis. However, there are few reports on roles of Rg1 in HIBD repair, and the mechanisms involved are unclear. Recently, a Chinese drug consisting of Rg1 has been shown to be a potential regulator of hypoxia-inducible factor-1α expression in HIBD. Since it has been shown that HIF-1α is a key transcription factor involved in the neuroprotective response to HIBD, it is possible that Rg1 could facilitate the process of brain repair, possibly modulating cell survival, angiogenesis, and neurogenesis after HIBD by targeting HIF-1α.

Rg1 plays a neuroprotective role in brain repair following neonatal HI, and HIF-1α is a potential target for therapeutic intervention in neonates with HI brain injury.

Hypoxia-inducible factor 1alpha affects the proliferation, apoptosis, and migration of UCC SiHa cells in part by regulating the expression of its target genes such as VEGF, HGTD-P, and CXCR4. Targeting HIF-1alpha may be a promising strategy for molecular therapy for UCC.

Hypoxia-inducible factor (HIF)-1α has been reported to be associated with malignancy in a number of types of cancer. However, the role of HIF-1 α in the regulation of prostate cancer (PCa) growth has yet to be elucidated. The present study aimed to investigate the effect of HIF-1α on the biological characteristics of the PCa PC3 cell line. Full-length (fL) HIF-1α and dominant-negative (dn) HIF-1α were transfected into PC3 cells. The expression of HIF-1α and its downstream genes, including vascular endothelial growth factor (VEGF), erythropoietin (EPO) and CXC chemokine receptor 4 (CXCR4), were detected using western blot analysis. Cell proliferation, apoptosis and migration were assessed using MTT, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Boyden chamber assays. The expression of VEGF, EPO and CXCR4 was found to be upregulated in the fL HIF-1α-transfected PC3 cells and downregulated in the dn HIF-1α-transfected PC3 cells. The overexpression of HIF-1α was observed to enhance cell proliferation and migration and decrease docetaxol-induced cell apoptosis. However, dn HIF-1α was found to attenuate cell proliferation and migration, and promote docetaxol-induced cell apoptosis. These findings indicate that HIF-1α regulates the proliferation, apoptosis and migration of PC3 cells, at least in part, by regulating the expression of its target genes, including VEGF, EPO and CXCR4. Thus, the use of HIF-1α inhibitors may be a promising therapy for the treatment of PCa.

Integrin β8 is a key regulator of vascular homeostasis in brain development and in vitro studies show that β8 protects against oxygen-glucose deprivation-induced neuronal apoptosis. However, the role β8 plays in vivo in neonatal rats with hypoxic-ischemic (HI) brain injury is not known. Here, we report the function of β8 and signaling pathways involved in neuroprotection after neonatal brain HI. Neonatal HI model was performed in postnatal day 10 rats by ligating the right common carotid artery, followed by hypoxia exposure. Expressions of β8 were determined by immunohistochemistry, immunofluorescence, reverse transcription polymerase chain reaction, and western blot. We used lentiviral vector-mediated β8 RNAi to inhibit integrin β8, GM6001 to inhibit matrix metalloprotease, and the TGF-β1 neutralizing antibody 1d11 to inhibit TGF-β1. The expression of vascular endothelial growth factor, ERK1/2 and p-ERK1/2, Bcl-2, Bax, and cleaved caspase 3 (CC3) were detected by western blot. Cellular apoptosis was detected with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling. β8 was mainly localized to astrocytes and upregulated immediately upon HI. When β8/TGF-β1 was inhibited, phosphorylated ERK1/2 was downregulated, followed by the downregulation of vascular endothelial growth factor (VEGF) and Bcl-2/Bax, and upregulation of CC3 and cellular apoptosis. The activation of TGF-β1 and ERK1/2 are involved in β8-induced VEGF expression and neuronal survival. The anti-apoptotic effect of β8 may be attributed to regulation of Bcl-2/Bax balance and caspase 3. β8 might be a potential target for therapeutic intervention in neonates with HI brain injury.