Oxidative stress in neurodegeneration: cause or consequence?

Modulation of Fibroblasts in Conjunctival Wound Healing.

We recently reported that angiotensin II (Ang II) induced IL-6 mRNA expression in cardiac fibroblasts, which played an important role in Ang II–induced cardiac hypertrophy in paracrine fashion. The present study investigated the regulatory mechanism of Ang II–induced IL-6 gene expression, focusing especially on reactive oxygen species (ROS)-mediated signaling in cardiac fibroblasts. Ang II increased intracellular ROS in cardiac fibroblasts, and the increase was completely inhibited by the AT-1 blocker candesartan and the NADH/NADPH oxidase inhibitor diphenyleneiodonium (DPI). We first confirmed that antioxidant N-acetylcysteine, superoxide scavenger Tiron, and DPI suppressed Ang II–induced IL-6 expression. Because we observed that exogenous H2O2 also increased IL-6 mRNA, the signaling pathways downstream of Ang II and exogenous H2O2 were compared. Ang II, as well as exogenous H2O2, activated ERK, p38 MAPK, and JNK, which were significantly inhibited by N-acetylcysteine and DPI. In contrast with exogenous ...

ERK and p38 MAPK, but not NF-κB, Are Critically Involved in Reactive Oxygen Species–Mediated Induction of IL-6 by Angiotensin II in Cardiac Fibroblasts

Endoplasmic reticulum (ER) stress-induced apoptosis plays an important role in a range of neurological disorders, such as neurodegenerative diseases, spinal cord injury, and diabetic neuropathy. Valproate (VPA), a typical antiepileptic drug, is commonly used in the treatment of bipolar disorder and epilepsy. Recently, VPA has been reported to exert neurotrophic effects and promote neurite outgrowth, but its molecular mechanism is still unclear. In the present study, we investigated whether VPA inhibited ER stress and promoted neuroprotection and neuronal restoration in SH-SY5Y cells and in primary rat cortical neurons, respectively, upon exposure to thapsigargin (TG). In SH-SY5Y cells, cell viability was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and the expression of ER stress-related apoptotic proteins such as glucose‑regulated protein (GRP78), C/EBP homologous protein (CHOP), and cleaved caspase-12/-3 were analyzed with Western blot analyses and immunofluorescence assays. To explore the pathway involved in VPA-induced cell proliferation, we also examined p-AKT, GSK3β, p-JNK and MMP-9. Moreover, to detect the effect of VPA in primary cortical neurons, immunofluorescence staining of β-III tubulin and Anti-NeuN was analyzed in primary cultured neurons exposed to TG. Our results demonstrated that VPA administration improved cell viability in cells exposed to TG. In addition, VPA increased the levels of GRP78 and p-AKT and decreased the levels of ATF6, XBP-1, GSK3β, p-JNK and MMP-9. Furthermore, the levels of the ER stress-induced apoptosis response proteins CHOP, cleaved caspase-12 and cleaved caspase-3 were inhibited by VPA treatment. Meanwhile, VPA administration also increased the ratio of Bcl-2/Bax. Moreover, VPA can maintain neurite outgrowth of primary cortical neurons. Collectively, the neurotrophic effect of VPA is related to the inhibition of ER stress-induced apoptosis in SH-SY5Y cells and the maintenance of neuronal growth. Collectively, our results suggested a new approach for the therapeutic function of VPA in neurological disorders and neuroprotection.

https://www.mdpi.com/1422-0067/18/2/315/pdf

Valproate Attenuates Endoplasmic Reticulum Stress-Induced Apoptosis in SH-SY5Y Cells via the AKT/GSK3β Signaling Pathway.

As our knowledge expands, it is now clear that the renin–angiotensin (Ang) system (RAS) mediates functions other than regulating blood pressure (BP). The RAS plays a central role in the pathophysiology of different neurovascular unit disorders including stroke and retinopathy. Moreover, the beneficial actions of RAS modulation in brain and retina have been documented in experimental research, but not yet exploited clinically. The RAS is a complex system with distinct yet interconnected components. Understanding the different RAS components and their functions under brain and retinal pathological conditions is crucial to reap their benefits. The aim of the present review is to provide an experimental and clinical update on the role of RAS in the pathophysiology and treatment of stroke and retinopathy. Combining the evidence from both these disorders allows a unique opportunity to move both fields forward.

* ACE, : angiotensin-converting enzyme; ACEI, : angiotensin-converting enzyme inhibitors; AD, : Alzheimer’s disease; AGE, : advanced glycation end products; Ang, : angiotensin; ARB, : angiotensin type 1 receptor blocker; AT1R/AT2R, : angiotensin II type 1/2 receptor; BBB, : blood–brain barrier; BDNF, : brain derived neurotrophic factor; BP, : blood pressure; C21, : compound 21; CA, : cerebral aneurysms; CBF, : cerebral blood flow; CNS, : central nervous system; DIRECT, : DIabetic REtinopathy Candesartan Trial; DR, : diabetic retinopathy; eNOS, : endothelial nitric oxide synthase; HA, : heat acclimation; i.p., : intraperitoneal; ICH, : intracerebral haemorrhage; ICV, : intracerebroventricular; INTERACT, : Intensive blood pressure reduction in acute cerebral haemorrhage trial; INWEST, : Intravenous Nimodipine West European Stroke Trial; IRAP, : insulin regulated aminopeptidase; KO, : knockout; LDH, : lactate dehydrogenase; MCA, : middle cerebral artery; MCAO, : middle cerebral artery occlusion; NEJM, : New England Journal of Medicine; OGD, : oxygen glucose deprivation; pMCAO, : permanent middle cerebral artery occlusion; PPAR-γ, : peroxisome proliferator-activated receptor γ; PROGRESS, : The perindopril protection against recurrent stroke study; RAGE, : receptor for AGE; RAS, : renin–angiotensin system; ROP, : retinopathy of prematurity; ROS, : reactive oxygen species; SAH, : subarachnoid haemorrhage; SCAST, : Scandinavian Candesartan Acute Stroke Trial; SCOPE, : Study on COgnition and Prognosis in the Elderly; SHR, : spontaneously hypertensive rat; STZ, : streptozotocin; TBI, : traumatic brain injury; tPA, : tissue plasminogen activator; VEGF, : vascular endothelial growth factor; WT, : wild-type

Renin-angiotensin system as a potential therapeutic target in stroke and retinopathy: experimental and clinical evidence.

Recent evidence suggests that chloride channels are critical for cell proliferation, migration, and differentiation. We examined the effects of transforming growth factor (TGF)-β1 on chloride channel expression and associations with human conjunctival fibroblast (HConF) biology. To investigate the potential role of chloride channel (CLC)-2 in migration, transition to myofibroblasts and extracellular matrix (ECM) synthesis of HconF, a small interfering RNA (siRNA) approach was applied. TGF-β1-induced migration and transition of fibroblasts to myofibroblasts characterized by α-smooth muscle actin (α-SMA) expression, supported by increased endogenous expression of CLC-2 protein and mRNA transcripts. ECM (collagen I and fibronectin) synthesis in HConF was enhanced by TGF-β1. CLC-2 siRNA treatment reduced TGF-β1-induced cell migration, transition of fibroblasts to myofibroblasts, and ECM synthesis of HConF. CLC-2 siRNA treatment in the presence of TGF-β1 inhibited phosphorylation of PI3K and Akt in HConF. These findings demonstrate that CLC-2 chloride channels are important for TGF-β1-induced migration, differentiation, and ECM synthesis via PI3K/Akt signaling in HConF.

The CLC-2 Chloride Channel Modulates ECM Synthesis, Differentiation, and Migration of Human Conjunctival Fibroblasts via the PI3K/Akt Signaling Pathway

When treating glaucoma, excessive scar tissue reactions reduce the postoperative survival rate of the filtering bleb. Accumulating evidence has demonstrated that the proliferation, migration and extracellular matrix (ECM) synthesis of fibroblasts are important molecular mechanisms underlying scar formation. Recent evidence has demonstrated that chloride channels play an important role in controlling cell proliferation, apoptosis, migration and the cell cycle process in several cell types, but the effects of chloride channels on conjunctival fibroblasts have not be studied. The aim of the present study was to investigate the effects of the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) on cell proliferation, apoptosis, migration, cell cycle progression and ECM synthesis in human conjunctival fibroblasts (HConFs), and to further investigate the mechanism of resistance to scar formation following glaucoma filtration surgery. HConFs were exposed to NPPB or lubiprostone. Cell proliferation and viability was evaluated using the Cell Counting Kit-8. Cell migration was measured using Transwell migration and scratch-wound assays. Flow cytometry was used to study apoptosis and cell cycle progression. Quantitative polymerase chain reaction and western blot analyses were performed to determine mRNA and protein expression levels, respectively. Following NPPB treatment, HConFs exhibited reduced proliferation and migration, along with increased apoptosis. NPPB also inhibited cell cycle progression by arresting cells in the G0/G1 phase and reducing collagen I and fibronectin expression, as well as the phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT). However, lubiprostone treatment exerted the opposite effects on HConFs. Therefore, NPPB treatment inhibited proliferation, migration, cell cycle progression and synthesis of the ECM, while promoting apoptosis in HConFs, by inhibiting the PI3K/AKT signaling pathway.

/pdf/nppb-modulates-apoptosis-proliferation-migration-and-1xl7ba60a4.pdf

NPPB modulates apoptosis, proliferation, migration and extracellular matrix synthesis of conjunctival fibroblasts by inhibiting PI3K/AKT signaling.

Exposure to reactive oxygen species (ROS) leads to the development and progression of retinal degenerative diseases. However, the exact mechanisms are not fully understood. In this article, the role of angiotensin II type 1 receptor (AT1R) signaling in H2O2-induced retinal damage was examined. Mouse photoreceptor-derived 661 W cells were treated with the AT1R blockers valsartan, losartan and candesartan before exposure to H2O2. Cell viability, intracellular ROS level, mitochondrial membrane potential (MMP), cytochrome-c level, DNA fragmentation, caspase activity and gene expression were detected. Pre-treatment of 661 W cells with AT1R blockers significantly decreased H2O2-mediated toxicity and reduced the ROS level. In addition, apoptosis-related biochemical indicators showed that pre-incubation of AT1R blockers would elevate the MMP, decrease the release of cytochrome-c and formation of DNA fragmentation, and inhibit activities of caspase-3 and caspase-9 in exogenous H2O2-treated 661 W cells. Mor...

Angiotensin II type 1 receptor blockade suppresses H2O2-induced retinal degeneration in photoreceptor cells

We describe a case of bilateral hypoperfusion retinopathy (HR) in a 17-year-old man with intraocular pressure (IOP) of >40 mm Hg. After 6 months of antiglaucoma drug therapy, the patient's bilateral IOP remained over 35 mm Hg, and features of HR were found bilaterally in the absence of carotid artery obstruction. On restoration of IOP to normal by means of trabeculectomy, the bilateral signs of HR regressed. We speculate that the elevated IOP contributed to HR in this patient.

Hypoperfusion retinopathy and elevated intraocular pressure in a 17-year-old

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The CLC-2 Chloride Channel Modulates ECM Synthesis, Differentiation, and Migration of Human Conjunctival Fibroblasts via the PI3K/Akt Signaling Pathway

NPPB modulates apoptosis, proliferation, migration and extracellular matrix synthesis of conjunctival fibroblasts by inhibiting PI3K/AKT signaling.

Angiotensin II type 1 receptor blockade suppresses H2O2-induced retinal degeneration in photoreceptor cells

Hypoperfusion retinopathy and elevated intraocular pressure in a 17-year-old