Taming Reactive Oxygen Species:Mitochondria-Targeting Aggregation-Induced Emission Luminogen for Neuron Protection via Photosensitization-Triggered Autophagy

Oxidative damage to cells leads to accumulated harmful wastes,which in turn aggravate the imbalance of reactive oxygen species(ROS)and related diseases.Therefore,provoking the cellular defense system against severe oxidation and maintaining ROS homeostasis are desired.Herein,we designed and synthesized a powerful mitochondria-targeting aggregation-induced emission photosensitizer(named DTCSPY)by maximal restriction of heat dissipation.It is demonstrated that taming ROS generation within mitochondria through photosensitization-triggered autophagy via DTCSPY achieved a better neuroprotective effect against oxidative damages than Nacety-L-cysteine and vitamin C.This work not only provides a new way to design high-performance photosensitizers by regulating the photophysical property,but also verifies the concept that taming ROS can be used for cell protection against destructive oxidation,thereby displaying broad prospects for alleviating oxidation-related diseases and promoting cell-based therapy.

MicroRNAs:protective regulators for neuron growth and development

MicroRNAs(miRNAs)play an important regulatory role in neuronal growth and development.Different mi RNAs target different genes to protect neurons in different ways,such as by avoiding apoptosis,preventing degeneration mediated by conditional mediators,preventing neuronal loss,weakening certain neurotoxic mechanisms,avoiding damage to neurons,and reducing inflammatory damage to them.The high expression of mi RNAs in the brain has significantly facilitated their development as protective targets for therapy,including neuroprotection and neuronal recovery.mi RNA is indispensable to the growth and development of neurons,and in turn,is beneficial for the development of the brain and checking the progression of various diseases of the nervous system.It can thus be used as an important therapeutic target for models of various diseases.This review provides an introduction to the protective effects of mi RNA on neurons in case of different diseases or damage models,and then provides reference values and reflections on the relevant treatments for the benefit of future research in the area.

Exosomes derived from human induced pluripotent stem cell-derived neural progenitor cells protect neuronal function under ischemic conditions

Compared with other stem cells,human induced pluripotent stem cells-derived neural progenitor cells(iPSC-NPCs)are more similar to cortical neurons in morphology and immunohistochemistry.Thus,they have greater potential for promoting the survival and growth of neurons and alleviating the proliferation of astrocytes.Transplantation of stem cell exosomes and stem cells themselves have both been shown to effectively repair nerve injury.However,there is no study on the protective effects of exosomes derived from iPSC-NPCs on oxygen and glucose deprived neurons.In this study,we established an oxygen-glucose deprivation model in embryonic cortical neurons of the rat by culturing the neurons in an atmosphere of 95%N2 and 5%CO2 for 1 hour and then treated them with iPSC-NPC-derived exosomes for 30 minutes.Our results showed that iPSC-NPC-derived exosomes increased the survival of oxygen-and glucose-deprived neurons and the level of brain-derived neurotrophic factor in the culture medium.Additionally,it attenuated oxygen and glucose deprivation-induced changes in the expression of the PTEN/AKT signaling pathway as well as synaptic plasticity-related proteins in the neurons.Further,it increased the length of the longest neurite in the oxygen-and glucose-deprived neurons.These findings validate the hypothesis that exosomes from iPSCNPCs exhibit a neuroprotective effect on oxygen-and glucose-deprived neurons by regulating the PTEN/AKT signaling pathway and neurite outgrowth.This study was approved by the Animal Ethics Committee of Sir Run Run Shaw Hospital,School of Medicine,Zhejiang University,China(approval No.SRRSH20191010)on October 10,2019.

Pre-B-cell colony-enhancing factor as a target for protecting against apoptotic neuronal death and mitochondrial damage in ischemia

Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,the treatment strategies are still limited.Tissue plasminogen activator is the only FDA-approved drug currently available for acute stroke treatment,

Neuroprotective effects of ganoderma lucidum polysaccharides against oxidative stress-induced neuronal apoptosis

Ganoderma lucidum polysaccharides have protective effects against apoptosis in neurons exposed to ischemia/reperfusion injury, but the mechanisms are unclear. The goal of this study was to investigate the underlying mechanisms of the effects of ganoderma lucidum polysaccharides against oxidative stress-induced neuronal apoptosis. Hydrogen peroxide（H_2O_2） was used to induce apoptosis in cultured cerebellar granule cells. In these cells, ganoderma lucidum polysaccharides remarkably suppressed H_2O_2-induced apoptosis, decreased expression of caspase-3, Bax and Bim and increased that of Bcl-2. These findings suggested that ganoderma lucidum polysaccharides regulate expression of apoptosis-associated proteins, inhibit oxidative stress-induced neuronal apoptosis and, therefore, have significant neuroprotective effects.

Protective effect of melatonin on neurons after oxidative-stress injury

BACKGROUND: It has been suggested that melatonin (MT) can protect secondary neuronal injury. However, the protective effect of MT on neuronal injury in ischemia/reperfusion models in vitro still has not been proved. OBJECTIVE: To investigate the protective effect of MT on central ischemic injury of nerve cells and analyze its possible mechanism. DESIGN: Contrast observational study. SETTING: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology. MATERIALS: Rats aged 7-8 days and weighing 10-12 g were provided by Medical Experimental Animal Center, Tongji Medical College, Huazhong University of Science and Technology. MT was provided by Sigma Company, USA. METHODS: The experiment was carried out in the Laboratory of Biochemistry and Molecular Biology, Tongji Hospital, Huazhong University of Science and Technology from October 2002 to March 2004. The effects of MT on the neurodegeneration induced by oxygen-glucose-deprivation (OGD) were tested in cultured rat cerebellar granule cells. Neuron damage was quantitatively assessed by Typan Blue exclusion and MTT assay at different time points after oxygen-glucose-deprivation (90 minutes). DNA gel electrophoresis and acridine orange stain were performed to determine the nature of cell damage. And fluorescence spectrophotometer was used for quantification of intracellular malondialdehyde (MDA) at various time intervals. MAIN OUTCOME MEASURES: Correlation between degrees of neuronal injury and reperfusion times, apoptosis, and production of MDA in cells. RESULTS: ① The neuron injury was aggravated with reperfusion time. ② The protective effect of MT was time- and dose-dependent when its concentration was not higher than 10 μmol/L. ③ When neurons were exposed to OGD for 90 minutes, part of the cells exhibited typical features of apoptosis: internucleosomal DNA condensation and DNA ladder on agarose gel electrophoresis. MT added to cells recovering from OGD exerted neuroprotective action against OGD-induced apoptosis. ④ In OGD exposed cultures, the production of MDA burst 12 hours after OGD, while MT significantly decreased the generation of MDA (P < 0.05) in a time-dependent manner. CONCLUSION: MT may have therapeutic potential in the prevention and treatment of ischemic/hypoxic neuronal damage, and this neuroprotective action may contribute to the antioxidant nature of MT.

Expression of c-Fos protein and nitricoxide synthase in neurons of cerebral cortex from fetal rats in hypoxia and protective role of Angelica sinensis

BACKGROUND： Both c-Fos protein and nitricoxide synthase （NOS） have been used as general indexes in relative research about neurons, but it is lack of reports that c-Fos protein and NOS are applied synchronously to study the neurons of hypoxic fetal rats in uterus. OBJECTIVE： To study the effect of hypoxia in uterus on the expression of c-Fos protein and NOS in neurons of cerebral cortex from fetal rats and whether Angelica sinensis has the protective effect on these neurons in hypoxia. DESIGN： Randomized control experiment.SETTING ： Department of Histology and Embryology, Luzhou Medical College.MATERIALS ： Twelve adult female Wistar rats in oestrum and 1 male Wistar rat with bodymass from 220 to 250 g were chosen. Parenteral solution of Angelica sinensis mainly contained angelica sinensis, 10 mL/ampoule, was provided by Department of Agent of the Second Hospital Affiliated to Hubei Medical University （batch number： 01062310）. METHODS ： This experiment was completed in the Department of Histology and Embryology of Luzhou Medical College from September 2003 to June 2004. ①Twelve adult female Wistar rats in oestrum and 1 male Wistar rat were housed in one rearing cage. Vaginal embolus was performed on conceive female rat at 8： 00 am next day. On the 15^th conceiving day, all conceiving rats were divided randomly into three groups： control group, hypoxia group and Angelica group with 4 in each group. Rats in hypoxia group and Angelica group were modeled with hypotonic hypoxia in uterus. Angelica group： Rats were injected with 8 mL/kg Angelica sinensis injection through caudal veins before hypoxia. Hypoxia group： Rats were injected with the same volume of saline. Control group： Rats were not modeled and fed with normal way. ② Twenty embryos of rats were chosen randomly from each group and then routinely embedded in paraffin. Paraffin sections were cut from the brain of embryos to anterior fontanelle. Double-label staining was used to detect the expression of nNOS and c-Fos in neurons of cerebral cortex from embryos of rats. OLYMPUS Bx-50 microscope was used to observe sections and DP12 digit camera was also used under 400 times to detect types of cells. Under microscope, the number of c-Fos, NOS, c-Fos/NOS positive neurons in cerebral cortex from embryos of rats were counted in 2 fields with magnification of 400 in one section per animal. ③ The data in experiments were analyzed by one-way analysis of variance （ANOVA） followed by q test. MAIN OUTCOME MEASURES： ① Results of immunohistochemical double-label staining of c-Fos/NOS from cerebral cortex; ② Comparison of amount immunohistochemical double-label staining of c-Fos/NOS positive cells from cerebral cortex. RESULTS：① The positive NOS cells and c-Fos/NOS cells in the three groups were mainly distributed in cerebral cortex, but positive c-Fos neurons were not observed. ② Positive NOS cells and c-Fos/NOS cells in hypoxia group were more than those in control group （76.55±12.02, 50.45±10.39; 33.35±7.42, 26.35±6.67, P 〈 0.05）, but those in Angelica group were less than those in hypoxia group （51.70±9.82, 35.65±8.37, P 〈 0.05）. CONCLUSION： Hypoxia can stimulate the increase of expression of c-Fos protein and NOS in neurons of cerebral cortex. However, Angelica sinensis can decrease this expression so as to play a protective role in cerebral neurons of hypoxic fetal rats.

Protective effect of sodium valproate on motor neurons in the spinal cord following sciatic nerve injury in rats

BACKGROUND: Sodium valproate (VPA) is used to be an effective anti-epileptic drug. VPA possesses the characteristics of penetrating rapidly through the blood-brain barrier (BBB) and increasing levels of Bcl-2 and growth cone-associated protein (GAP) 43 in spinal cord. OBJECTIVE: To observe the effect of VPA on Bcl-2 expression and motor neuronal apoptosis in spinal cord of rats following sciatic nerve transection. DESIGN: Randomized controlled experiment. SETTING: Department of Hand Surgery and Microsurgery, Wuhan Puai Hospital. MATERIALS: A total of 30 male healthy SD rats of clean grade and with the body mass of 180-220 g were provided by Experimental Animal Center of Medical College of Wuhan University. Sodium Valproate Tablets were purchases from Hengrui Pharmaceutical Factory, Jiangsu. METHODS: The experiment was performed in the Central Laboratory of Wuhan Puai Hospital and Medical College of Wuhan University from February to May 2006. Totally 30 rats were randomly divided into two groups: treatment group (n =15) and model group (n =15). Longitudinal incision along backside of right hind limbs of rats was made to expose sciatic nerves, which were sharply transected 1 cm distal to the inferior margin of piriform muscle after nerve liberation under operation microscope to establish sciatic nerve injury rat models. Sodium Valproate Tablets were pulverized and diluted into 50 g/L suspension with saline. On the day of operation, the rats in the treatment group received 6 mL/kg VPA suspension by gastric perfusion, once a day, whereas model group received 10 mL/kg saline by gastric perfusion, once a day. L4-6 spinal cords were obtained at days 1, 4, 7, 14 and 28 after operation, respectively. Terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) technique and immunohistochemical method (SP method) were used to detect absorbance (A) of neurons with positive Bcl-2 expression. Apoptotic rate of cells (number of apoptotic cells/total number of cells×100%) was calculated. MAIN OUTCOME MEASURES: A value of neurons with positive Bcl-2 expression and apoptotic rate in spinal cord of rats in the two groups. RESULTS: A total of 30 SD rats were involved in the result analysis. ①expression of positive Bcl-2 neurons: A value of positive Bcl-2 neurons were 0.71±0.02, 0.86±0.04, 1.02±0.06 at days 4, 7 and 14, respectively after operation in the treatment group, which were obviously higher than those in the model group (0.62±0.03, 0.71±0.05, 0.89±0.04, t = 3.10-4.50, P < 0.05). ②apoptotic result of motor neurons: Apoptotic rate of motor neurons in spinal cord was (6.91±0.89)% and (15.12±2.34)% at days 7 and 14 in the treatment group, which was significantly lower than those in the model group [(9.45±1.61)%, (19.35±0.92)%, t = 2.39, 3.03. P < 0.05]. CONCLUSION: VPA can increase expression of Bcl-2 in spinal cord and reduce neuronal apoptosis in rats following sciatic nerve injury, and has protective effect on motor neuron in spinal cord of rats.

Effects of wind-dispelling drugs and deficiency-nourishing drugs of Houshiheisan compound prescription on astrocyte activation and inflammatory factor expression in the corpus striatum of cerebral ischemia rats

This study explored protective effects of Houshiheisan and its compound prescription of wind-dispelling drugs and deficiency-nourishing drugs on cerebral ischemia in terms of astrocyte activation and inflammatory factor expression.Results suggested that Houshiheisan lessened neuronal degeneration in the corpus striatum on the ischemic side of rats following cerebral ischemia/reperfusion injury,contributed to astrocyte activation and glial fibrillary acidic protein expression in the corpus striatum and decreased the levels of interleukin-2,interleukin-6, interleukin-1βand tumor necrosis factor-α.Factor analysis results demonstrated that deficiency-nourishing drugs were more beneficial in protecting neurons and upregulating glial fibrillary acidic protein expression than wind-dispelling drugs.However,wind-dispelling drugs were more effective in increasing the number of glial fibrillary acidic protein-positive cells and reducing inflammatory factor expression than deficiency-nourishing drugs.These indicate that different ingredients of Houshiheisan suppress cerebral ischemic injury by promoting astrocyte activation and diminishing inflammatory factor expression.

A shape shifting organelle: unusual mitochondrial phenotype determined with three-dimensional electron microscopy reconstruction

Mitochondria,the powerhouses of the cell,are dynamic organelles that constantly move and change their size and morphology to meet energetic demands of the cell（Wai and Langer,2016）.Recent studies demonstrated that energy production is dependent on the ability of mitochondria to undergo cycles of fission and fusion collectively termed“mitochondrial dynamics”（Youle and van der Bliek,2012）.

Neuron Protective Constituents from Rheum Nanum and Rheum Sublanceolatum

The neuron protective activity of the chemical constituents from Rheum nanum and Rheum sublanceolatum in vitro was investigated using cultured embryonic mouse cortical cells exposed to oxygen-glucose deprivation. The protective effect was quantitatively evaluated by measuring the lactate dehydrogenase release rate. Most of the compounds reduce the lactate dehydrogenase release rate, including emodin, chrysophanol-8-O-β-D-glucopyranoside, 6-hydroxymusizin-8-O-β-D-glucopyranoside, gnetin C, torachrysone-8-O-β-D-glucopyranoside, and maesopsin, and all possess potent neuron protective activity. Chrysophanol and aloe-emodin exhibit neuron protection only at low concentrations. Emodin-8-O-β-D-glucopyranoside protects the neuron cells at high concentration. Aloe-emodin-8-O-β-D- glucopyranoside is inactive.

Activation of GABAB receptors protects cerebellar granule neurons from apoptosis via IGF-I receptor transactivation

γ-amidobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system and mediates fast synaptic inhibition through GABAA and GABAC

A NOVEL DIRECT ACTIVATOR OF TFEB PROMOTES AUTOPHAGY AND LYSOSOME BIOGENESIS AND PROTECTS NEURONS IN THE BRAIN

Autophagy dysfunction is a common feature in neurodegenerative disorders caused by the accumulation of toxic,aggregate-prone proteins.Increasing evidence have demonstrated that genetic or pharmacological activation of transcription factor EB(TFEB),a master regulator of autophagy and lysosomal biogenesis,ameliorates neurotoxicity and rescues neurodegenerative phenotypes in several animal models of neurodegenerative diseases.