Vasoprotective effect of PDGF-CC mediated by HMOX1 rescues retinal degeneration

Blood vessel degeneration is critically involved in nearly all types of degenerative diseases. Therefore strategies to enhance blood vessel protection and survival are highly needed. In this study, using different animal models and cultured cells, we show that PDGF-CC is a potent vascular protective and survival factor. PDGF-CC deficiency by genetic deletion exacerbated blood vessel regression/degeneration in various animal models. Importantly, treatment with PDGF-CC protein not only increased the survival of retinal blood vessels in a model of oxygen-induced blood vessel regression but also markedly rescued retinal and blood vessel degeneration in a disease model of retinitis pigmentosa. Mechanistically, we revealed that heme oxygenase-1 (HMOX1) activity is critically required for the vascular protective/survival effect of PDGF-CC, because blockade of HMOX1 completely abolished the protective effect of PDGF-CC in vitro and in vivo. We further found that both PDGF receptors, PDGFR-β and PDGFR-α, are required for the vasoprotective effect of PDGF-CC. Thus our data show that PDGF-CC plays a pivotal role in maintaining blood vessel survival and may be of therapeutic value in treating various types of degenerative diseases.Blood vessel degeneration and regression are vital pathologies in numerous human diseases and are associated with nearly all types of degenerative diseases, such as retinitis pigmentosa (RP), diabetic retinopathy, age-related macular degeneration, Alzheimer’s disease, Parkinson''s disease, and amyotrophic lateral sclerosis (1–3). RP is a retinal degenerative disorder in which blood vessel degeneration contributes significantly to retinal atrophy, ultimately leading to loss of vision. In addition, recent studies have shown that prolonged treatment with antiangiogenic drugs may cause tissue degeneration (4–6). Given the increasing incidence of many degenerative diseases in an aging population and the rapidly growing clinical use of antiangiogenic drugs, there is an urgent need for strategies promoting blood vessel survival and protection. Because the pathological process of vascular degeneration involves complex mechanisms (7), treating such diseases remains challenging. Identifying effective vascular protective factors and the underlying mechanisms therefore is highly warranted.The PDGF family plays important roles in the vascular system (8–11). PDGF-CC was the third of the four PDGF family members discovered (12, 13), long after the finding of PDGF-AA and PDGF-BB. PDGF-CC is highly expressed in the vascular system (8, 14) and is produced as a secreted homodimer that binds to and activates the PDGF receptors PDGFR-α and PDGFR-β (12, 15). PDGF-CC is a critical survival/protective factor for neuronal cells (8, 9, 16) and macrophages (17) and has been shown to be a potent angiogenic factor (10, 15, 18–20). However, whether PDGF-CC plays a role in the survival/regression of blood vessels remains unknown thus far.In this study we used different animal models and cultured cells and investigated the potential effect of PDGF-CC on blood vessel survival. We found that PDGF-CC is a potent vasoprotective factor that rescues blood vessels from degeneration/regression under developmental and pathological conditions. Mechanistically, we show that heme oxygenase-1 (HMOX1), a potent antioxidative and anti-inflammatory factor, is required for the vasoprotective effect of PDGF-CC. Our data indicate that PDGF-CC may be of therapeutic use in treating different types of degenerative diseases in which blood vessel survival is impaired.     

Neuroprotective effects of miR-532-5p against ischemic stroke

Metabolic Brain Disease - Stroke can cause death and disability and has a high incidence with many complications. So far, effective treatment options for stroke are still limited. MicroRNA-532-5p...     

Inhibition of cysteine cathepsin B and L activation in astrocytes contributes to neuroprotection against cerebral ischemia via blocking the tBid‐mitochondrial apoptotic signaling pathway

The roles of cathepsins in the ischemic astrocytic injury remain unclear. Here, we test the hypothesis that activation of cathepsin B and L contributes to the ischemic astrocyte injury via the tBid‐mitochondrial apoptotic signaling pathways. In the rat models of pMCAO, CA‐074Me or Clik148, a selective inhibitor of cathepsin B or cathepsin L, reduced the infarct volume, improved the neurological deficits and increased the MAP₂ and GFAP levels. In OGD‐induced astrocyte injury, CA‐074Me or Clik148 decreased the LDH leakage and increased the GFAP levels. In the ischemic cortex or OGD‐induced astrocytes injury, Clik148 or CA‐074Me reversed pMCAO or OGD‐induced increase in active cathepsin L or cathepsin B at 3 h or 6 h, increase in tBid, reduction in mitochondrial cytochrome‐c (Cyt‐c) and increase in cytoplastic Cyt‐c and active caspase‐3 at 12–24 h of the late stage of pMCAO or OGD. CA‐074Me or Clik148 also reduced cytosolic and mitochondrial tBid, increased mitochondrial Cyt‐c and decreased cytoplastic Cyt‐c and active caspase‐3 at 6 h of the early stage of Bid activation. CA‐074Me or Clik148 blocked the pMCAO‐induced release of cathepsin B or L from the lysosomes into the cytoplasm and activation of caspase‐3 in ischemic astrocytes at 12 h after ischemia. Concurrent inhibition of cathepsin B and cathepsin L provided better protection on the OGD‐induced astrocytic apoptosis than obtained with separate use of each inhibitor. These results suggest that inhibition of the cysteine cathepsin B and cathepsin L activation in ischemic astrocytes contributes to neuroprotection via blocking the tBid‐mitochondrial apoptotic signaling pathway. GLIA 2014;62:855–880     

Predictors of CNS injury as measured by proton magnetic resonance spectroscopy in the setting of chronic HIV infection and CART

The reasons for persistent brain dysfunction in chronically HIV-infected persons on stable combined antiretroviral therapies (CART) remain unclear. Host and viral factors along with their interactions were examined in 260 HIV-infected subjects who underwent magnetic resonance spectroscopy (MRS). Metabolite concentrations (NAA/Cr, Cho/Cr, MI/Cr, and Glx/Cr) were measured in the basal ganglia, the frontal white matter, and gray matter, and the best predictive models were selected using a bootstrap-enhanced Akaike information criterion (AIC). Depending on the metabolite and brain region, age, race, HIV RNA concentration, ADC stage, duration of HIV infection, nadir CD4, and/or their interactions were predictive of metabolite concentrations, particularly the basal ganglia NAA/Cr and the mid-frontal NAA/Cr and Glx/Cr, whereas current CD4 and the CPE index rarely or did not predict these changes. These results show for the first time that host and viral factors related to both current and past HIV status contribute to persisting cerebral metabolite abnormalities and provide a framework for further understanding neurological injury in the setting of chronic and stable disease.     

A novel neuroprotective strategy for ischemic stroke: transient mild acidosis treatment by CO2 inhalation at reperfusion

Acidosis is one of the key components in cerebral ischemic postconditioning that has emerged recently as an endogenous strategy for neuroprotection. We set out to test whether acidosis treatment at reperfusion can protect against cerebral ischemia/reperfusion injury. Adult male C57BL/6 J mice were subjected to 60-minute middle cerebral arterial occlusion followed by 24-hour reperfusion. Acidosis treatment by inhaling 10%, 20%, or 30% CO₂ for 5 or 10 minutes at 5, 50, or 100 minutes after reperfusion was applied. Our results showed that inhaling 20% CO₂ for 5 minutes at 5 minutes after reperfusion-induced optimal neuroprotection, as revealed by reduced infarct volume. Attenuating brain acidosis with NaHCO₃ significantly compromised the acidosis or ischemic postconditioning-induced neuroprotection. Consistently, both acidosis-treated primary cultured cortical neurons and acute corticostriatal slices were more resistant to oxygen–glucose deprivation/reperfusion insult. In addition, acidosis inhibited ischemia/reperfusion-induced apoptosis, caspase-3 expression, cytochrome c release to cytoplasm, and mitochondrial permeability transition pore (mPTP) opening. The neuroprotection of acidosis was inhibited by the mPTP opener atractyloside both in vivo and in vitro. Taken together, these findings indicate that transient mild acidosis treatment at reperfusion protects against cerebral ischemia/reperfusion injury. This neuroprotection is likely achieved, at least partly, by inhibiting mPTP opening and mitochondria-dependent apoptosis.     

精神疾病患者未成年一级亲属病耻感与情绪行为问题的关系

目的探讨精神疾病患者未成年一级亲属病耻感与情绪行为问题的关系,以及自我效能和心理弹性在病耻感与情绪行为问题关系中的中介效应。方法选取山东省某精神卫生中心前来门诊就诊及住院的精神疾病患者未成年子女104人作为研究对象,采用Link贬低-歧视感知量表、一般自我效能量表(GSES)、心理弹性量表(RS)、长处和困难问卷(SDQ)进行调查。结果精神疾病患者未成年一级亲属的情绪行为问题分别在性别、居住地、就读学校和是否独生子女上存在显著差异性(P0.05,P0.01);精神疾病患者未成年一级亲属SDQ总分与病耻感呈显著正相关(P0.01),与自我效能和心理弹性均呈显著负相关(均P0.01);病耻感分别与心理弹性和自我效能均呈显著负相关(均P0.01);心理弹性与自我效能呈显著正相关(P0.01);自我效能和心理弹性在病耻感与情绪行为问题之间起到完全中介作用(P0.05,P0.01)。结论感知到病耻感的精神疾病患者未成年一级亲属存在情绪行为问题,而自我效能和心理弹性在病耻感与精神疾病患者未成年一级亲属情绪行为问题关系中起完全中介作用。