Maintaining moderate levels of hypochlorous acid promotes neural stem cell proliferation and differentiation in the recovery phase of stroke

It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke.Indeed,previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue.Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke,but its specific role and mechanism are currently unclear.To simulate stroke in vivo,a middle cerebral artery occlusion rat model was established,with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke.We found that in the early stage(within 24 hours)of ischemic stroke,neutrophils produced a large amount of hypochlorous acid,while in the recovery phase(10 days after stroke),microglia were activated and produced a small amount of hypochlorous acid.Further,in acute stroke in rats,hypochlorous acid production was prevented using a hypochlorous acid scavenger,taurine,or myeloperoxidase inhibitor,4-aminobenzoic acid hydrazide.Our results showed that high levels of hypochlorous acid(200μM)induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation.However,in the recovery phase of the middle cerebral artery occlusion model,a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes.This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury.Lower levels of hypochlorous acid(5 and 100μM)promoted nuclear translocation ofβ-catenin.By transfection of single-site mutation plasmids,we found that hypochlorous acid induced chlorination of theβ-catenin tyrosine 30 residue,which promoted nuclear translocation.Altogether,our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.

Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion

Ischemic accumulation of succinate causes cerebral damage by excess production of reactive oxygen species. However, it is unknown whether ischemic accumulation of succinate affects neural stem cell proliferation. In this study, we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery. We found that succinate levels increased in serum and brain tissue(cortex and hippocampus) after ischemia/reperfusion injury. Oxygen-glucose deprivation and reoxygenation stimulated primary neural stem cells to produce abundant succinate. Succinate can be converted into diethyl succinate in cells. Exogenous diethyl succinate inhibited the proliferation of mouse-derived C17.2 neural stem cells and increased the infarct volume in the rat model of cerebral ischemia/reperfusion injury. Exogenous diethyl succinate also increased the succinylation of the Rho family GTPase Cdc42 but repressed Cdc42 GTPase activity in C17.2 cells. Increasing Cdc42 succinylation by knockdown of the desuccinylase Sirt5 also inhibited Cdc42 GTPase activity in C17.2 cells. Our findings suggest that ischemic accumulation of succinate decreases Cdc42 GTPase activity by induction of Cdc42 succinylation, which inhibits the proliferation of neural stem cells and aggravates cerebral ischemia/reperfusion injury.

Effectiveness and safety of herbal medicines in the treatment of irritable bowel syndrome:A systematic review

AIM:To explore the efficacy and safety of herbal medicines (HM) in the treatment of irritable bowel syndrome (IBS). METHODS: A computer-based as well as manual literature search was performed. We reviewed randomized controlled trials on the treatment of IBS with and without HM. RESULTS: A total of 22 studies with 25 HMs met the inclusion criteria. Four of these studies were of good quality, while the remaining 18 studies involving 17 Chinese herbal medicine (CHM) formulas were of poor quality. Eight of these reports using 9 HMs showed global improvement of IBS symptoms, 4 studies with 3 HMs were efficacious in diarrhea-predominant IBS, and 2 studies with 2 HMs showed improvement in constipation- predominant IBS. Out of a total of 1279 patients, 15 adverse events in 47 subjects were reported with HM. No serious adverse events or abnormal laboratory tests were observed. The incidence of the adverse events was low (2.97%; 95% CI: 2.04%-3.90%). CONCLUSION: Herbal medicines have therapeutic benefit in IBS, and adverse events are seldom reported in literature. Nevertheless, herbal medicines should be used with caution. It is necessary to conduct rigorous, well-designed clinical trials to evaluate their effectiveness and safety in the treatment of IBS.

Active Compounds and Molecular Targets of Chinese Herbal Medicine for Neurogenesis in Stroke Treatment: Implication for Cross Talk between Traditional Chinese Medicine and Biomedical Sciences

Neural stem/progenitor cells (NSCs) could be attractive therapeutic targets for promoting adult neurogenesis, brain plasticity, and repair in stroke and neurodegenerative diseases, raising great potentials for regeneration therapy. In adult ischemic brains, NSCs have limited capacities of growth, differentiation, and generating new neurons for repairing the damaged central nervous system. However, the spontaneous brain repair seems to be insufficient to recover neurological deficits in most stroke cases. To overcome those problems, pharmacological manipulations targeting on endogenous NSCs or transplanted stem cells could be a promoting strategy for regeneration therapy. Chinese herbal medicine has great potentials for developing novel therapeutic strategies for adult neurogenesis and brain repair in poststroke treatment. Chinese herbal medicine has a long history for poststroke treatment. Recent studies create great opportunity for drug discovery for promoting neurogenesis and improving the recovery of neurological fimctions in poststroke treatment. Many active compounds or extracts from medicinal herbs have shown promising effects on regulating proliferation, self-renewal and differentiation of NSCs, and promoting neural network formation as well as neurological functional recovery with in vitro and in vivo experimental evidence. Therefore, targeting neural stem/progenitor cells can be an important opportunity for the studies of Traditional Chinese Medicine in regeneration medicine. Due to the complex interactions of herbal ingredients in network regulation, huge challenge remains to be resolved for further study.