Dihydromyricetin confers cerebroprotection against subarachnoid hemorrhage via the Nrf2-dependent Prx2 signaling cascade.

BACKGROUND: Several clinical and experimental studies have shown that therapeutic strategies targeting oxidative damage are beneficial for subarachnoid hemorrhage (SAH). A brain-permeable flavonoid, dihydromyricetin (DHM), can modulate redox/oxidative stress and has cerebroprotective effects in several neurological disorders. The effects of DHM on post-SAH early brain injury (EBI) and the underlying mechanism have yet to be clarified. PURPOSE: This work investigated a potential role for DHM in SAH, together with the underlying mechanisms. METHODS: Cerebroprotection by DHM was studied using a SAH rat model and primary cortical neurons. Atorvastatin (Ato) was a positive control drug in this investigation. The effects of DHM on behavior after SAH were evaluated by performing the neurological rotarod and Morris water maze tests, as well as by examining its effects on brain morphology and on the molecular and functional phenotypes of primary cortical neurons using dichlorodihydrofluorescein diacetate (DCFH-DA), immunofluorescent staining, biochemical analysis, and Western blot. RESULTS: DHM was found to significantly reduce the amount of reactive oxygen species (ROS), suppress mitochondrial disruption, and increase intrinsic antioxidant enzymatic activity following SAH. DHM also significantly reduced neuronal apoptosis in SAH rats and improved short- and long-term neurological functions. DHM induced significant increases in peroxiredoxin 2 (Prx2) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression, while decreasing phosphorylation of p38 and apoptotic signal-regulated kinase 1 (ASK1). In contrast, reduction of Prx2 expression using small interfering ribonucleic acid or by inhibiting Nrf2 with ML385 attenuated the neuroprotective effect of DHM against SAH. Moreover, DHM dose-dependently inhibited oxidative damage, decreased neuronal apoptosis, and increased the viability of primary cultured neurons in vitro. These positive effects were associated with Nrf2 activation and stimulation of Prx2 signaling, whereas ML385 attenuated the beneficial effects. CONCLUSION: These results reveal that DHM protects against SAH primarily by modulating the Prx2 signaling cascade through the Nrf2-dependent pathway. Hence, DHM could be a valuable therapeutic candidate for SAH treatment.

Comparison of revascularization and conservative treatment for hemorrhagic moyamoya disease in East Asian Countries: a single-center case series and a systematic review with meta-analysis.

Objective: The optimal treatment approach for hemorrhagic moyamoya disease (HMMD) remains a topic of debate, particularly regarding the comparative efficacy of revascularization versus conservative treatment. Our study, which included a single-center case series and a systematic review with meta-analysis, aimed to determine whether surgical revascularization is associated with a significant reduction in postoperative rebleeding, ischemic events, and mortality compared to conservative treatment among East Asian HMMD patients. Methods: We conducted a systematic literature review by searching PubMed, Google Scholar, Wanfang Med Online (WMO), and the China National Knowledge Infrastructure (CNKI). The outcomes of surgical revascularization and conservative treatment, including rebleeding, ischemic events and mortality, were compared. The authors' institutional series of 24 patients were also included and reviewed in the analysis. Results: A total of 19 East Asian studies involving 1,571 patients as well as our institution's retrospective study of 24 patients were included in the study. In the adult patients-only studies, those who underwent revascularization had significantly lower rates of rebleeding, ischemic events, and mortality compared to those who received conservative treatment (13.1% (46/352) vs. 32.4% (82/253), P < 0.00001; 4.0% (5/124) vs. 14.9% (18/121), P = 0.007; and 3.3% (5/153) vs. 12.6% (12/95), P = 0.01, respectively). In the adult/pediatric patients' studies, similar statistical results of rebleeding, ischemic events, and mortality have been obtained (70/588 (11.9%) vs. 103/402 (25.6%), P = 0.003 or <0.0001 in a random or fixed-effects model, respectively; 14/296 (4.7%) vs. 26/183 (14.2%), P = 0.001; and 4.6% (15/328) vs. 18.7% (23/123), P = 0.0001, respectively). Conclusion: The current single-center case series and systematic review with meta-analysis of studies demonstrated that surgical revascularization, including direct, indirect, and a combination of both, significantly reduces rebleeding, ischemic events, and mortality in HMMD patients in the East Asia region. More well-designed studies are warranted to further confirm these findings.

MAC mediates mammary duct epithelial cell injury in plasma cell mastitis and granulomatous mastitis.

Plasma cell mastitis (PCM) and granulomatous mastitis (GM) are common inflammatory nonbacterial mastitis (NBM). However, the pathogenesis of NBM is still unclear. METHODS: In this study, we statistically analyzed the pathological features of PCM and GM using pathological HE staining and tissue transmission electron microscopy. The levels of MAC (C5b-9n), P-selectin, E-selectin, and ICAM-1 were detected through IHC, WB, ELISA, and qPCR. The expression level and location of MAC were observed by tissue immunological electron microscopy. In addition, exosomes were isolated from tissues, identified using transmission electron microscopy, and the densities were detected by Nano-FCM. Finally, the expression intensity of MAC in exosomes was detected by flow cytometry and immunoelectron microscopy. RESULTS: The damage and apoptosis of mammary duct epithelial cells are the common pathological features of PCM and GM. MAC is primarily located in the cell membrane of mammary ductal epithelial cells and is significantly expressed in PCM and GM. The density of exosomes in PCM and GM tissues was elevated, and MAC was highly expressed in exosomes. In addition, the expression of P-selectin, E-selectin, and ICAM-1 in PCM and GM was significantly higher than in the normal group. CONCLUSION: We found severe damage of the mammary duct epithelial cells in PCM and GM tissues, which was verified by relevant pathological methods. Earlier studies demonstrated that MAC is highly expressed in PCM and GM tissues and exosomes seem to play a very important role in the understanding of MAC. Furthermore, MAC is involved in inflammatory infiltration and lesion of mammary duct epithelial cells upregulated by P-selectin, E-selectin, and ICAM-1. These findings provide new insights into PCM and GM molecular mechanisms.

Isoliquiritigenin mitigates oxidative damage after subarachnoid hemorrhage in vivo and in vitro by regulating Nrf2-dependent Signaling Pathway via Targeting of SIRT1.

BACKGROUND: Oxidative stress is a crucial factor leading to subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). Isoliquiritigenin has been verified as a powerful anti-oxidant in a variety of diseases models and can activate sirtuin 1 and nuclear factor-erythroid 2-related factor 2 (Nrf2) pathways. However, the effects of isoliquiritigenin against EBI after SAH and the underlying mechanisms remain elusive. PURPOSE: The primary goal of this study is to verify the therapeutic effects of isoliquiritigenin on EBI after SAH and the possible molecular mechanisms. STUDY DESIGN: A prechiasmatic cistern SAH model in rats and a hemoglobin incubation SAH model in primary neurons were established. Isoliquiritigenin was administered after SAH induction. EX527 was employed to inhibit sirtuin 1 activation and ML385 was used to suppress Nrf2 signaling. METHODS: In our study, neurological scores, brain edema, biochemical estimation, western blotting, and histopathological study were performed to explore the therapeutic action of isoliquiritigenin against SAH. RESULTS: Our data revealed that isoliquiritigenin significantly mitigated oxidative damage after SAH as evidenced by decreased reactive oxygen species overproduction and enhanced intrinsic anti-oxidative system. Concomitant with the reduced oxidative insults, isoliquiritigenin improved neurological function and reduced neuronal death in the early period after SAH. Additionally, isoliquiritigenin administration significantly enhanced Nrf2 and sirtuin 1 expressions. Inhibition of Nrf2 by ML385 reversed the anti-oxidative and neuroprotective effects of isoliquiritigenin against SAH. Moreover, inhibiting sirtuin 1 by EX527 pretreatment suppressed isoliquiritigenin-induced Nrf2-dependent pathway and abated the cerebroprotective effects of isoliquiritigenin. In primary cortical neurons, isoliquiritigenin treatment also ameliorated oxidative insults and repressed neuronal degeneration. The beneficial aspects of isoliquiritigenin were attributed to the promotion of sirtuin 1 and Nrf2 signaling pathways and were counteracted by EX527. CONCLUSION: Our findings suggest that isoliquiritigenin exerts cerebroprotective effects against SAH-induced oxidative insults by modulating the Nrf2-mediated anti-oxidant signaling in part through sirtuin 1 activation. Isoliquiritigenin might be a new potential drug candidate for SAH.

Activation of C3 and C5 May Be Involved in the Inflammatory Progression of PCM and GM.

Plasma cell mastitis (PCM) and granulomatous mastitis (GM) are the most common inflammatory diseases constituting nonbacterial mastitis (NBM). However, the pathogenesis of NBM remains unclear. In this study, risk factors for NBM were assessed, as well as the pathological features of PCM and GM. The levels of C3/C3a-C3aR and C5/C5a-C5aR1 of tissues were detected by IHC and WB. Exosomes were isolated from serum and identified by transmission electron microscopy. Then, C3 and C5 levels were detected in peripheral blood, and exosomes were assessed by flow cytometry and immunoelectron microscopy. Obesity and prolonged lactation were risk factors for NBM. The infiltration of plasma cells and lymphocytes around the dilated catheter in PCM and the formation of granulomatous structures in GM were the respective pathological features. C3/C3a-C3aR and C5/C5a-C5aR1 levels were elevated in PCM and GM tissue samples. There were no differences in peripheral blood levels of C3 and C5, while C3a and C5a were highly expressed in exosomes. These results suggest that the complement family is activated in PCM and GM, exosomes enrich C3a and C5a, and mediate the spread of inflammation. These findings provide new insights into the molecular mechanisms of PCM and GM and identify therapeutic targets.

SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage.

Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro, SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling.

Luteolin Confers Cerebroprotection after Subarachnoid Hemorrhage by Suppression of NLPR3 Inflammasome Activation through Nrf2-Dependent Pathway.

Luteolin (LUT) possesses multiple biologic functions and has beneficial effects for cardiovascular and cerebral vascular diseases. Here, we investigated the protective effects of LUT against subarachnoid hemorrhage (SAH) and the involvement of underlying molecular mechanisms. In a rat model of SAH, LUT significantly inhibited SAH-induced neuroinflammation as evidenced by reduced microglia activation, decreased neutrophil infiltration, and suppressed proinflammatory cytokine release. In addition, LUT markedly ameliorated SAH-induced oxidative damage and restored the endogenous antioxidant systems. Concomitant with the suppressed oxidative stress and neuroinflammation, LUT significantly improved neurologic function and reduced neuronal cell death after SAH. Mechanistically, LUT treatment significantly enhanced the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), while it downregulated nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation. Inhibition of Nrf2 by ML385 dramatically abrogated LUT-induced Nrf2 activation and NLRP3 suppression and reversed the beneficial effects of LUT against SAH. In neurons and microglia coculture system, LUT also mitigated oxidative stress, inflammatory response, and neuronal degeneration. These beneficial effects were associated with activation of the Nrf2 and inhibitory effects on NLRP3 inflammasome and were reversed by ML385 treatment. Taken together, this present study reveals that LUT confers protection against SAH by inhibiting NLRP3 inflammasome signaling pathway, which may be modulated by Nrf2 activation.

Cerebroprotection by dioscin after experimental subarachnoid haemorrhage via inhibiting NLRP3 inflammasome through SIRT1-dependent pathway.

BACKGROUND AND PURPOSE: Dioscin has multiple biological activities and is beneficial for cardiovascular and cerebral vascular diseases. Here, we investigated the protective effects of dioscin against subarachnoid haemorrhage and the molecular mechanisms involved. EXPERIMENTAL APPROACH: Dioscin was administered after subarachnoid haemorrhage induced in rats. MCC950, a potent selective nod-like receptor pyrin domain-containing 3 (NLRP3) inhibitor, was used to suppress NLRP3 and EX527 (selisistat) was used to inhibit sirtuin 1 (SIRT1). KEY RESULTS: In vivo, dioscin inhibited acute inflammatory response, oxidative damage, neurological impairment and neural cell degeneration after subarachnoid haemorrhage along with dramatically suppressing NLRP3 inflammasome activation. While pretreatment with MCC950 reduced the inflammatory response and improved neurological outcomes it did not lessen ROS production. However, giving dioscin after MCC950 reduced acute brain damage and ROS production. Dioscin increased SIRT1 expression after subarachnoid haemorrhage, whereas EX527 abolished the up-regulation of SIRT1 induced by dioscin and offset the inhibitory effects of dioscin on NLRP3 inflammasome activation. EX527 pretreatment also reversed the neuroprotective effects of dioscin against subarachnoid haemorrhage. Similarly, in vitro, dioscin dose-dependently suppressed inflammatory response, oxidative damage and neuronal degeneration and improved cell viability in neurons and microglia co-culture system. These effects were associated with inhibition of the NLRP3 inflammasome and stimulation of SIRT1 signalling, which could be inhibited by EX527 pretreatment. CONCLUSION AND IMPLICATIONS: Dioscin provides protection against subarachnoid haemorrhage via the suppression of NLRP3 inflammasome activation through SIRT1-dependent pathway. Dioscin may be a new candidate to ameliorate early brain injury after subarachnoid haemorrhage.

Resolvin D1 Attenuates Innate Immune Reactions in Experimental Subarachnoid Hemorrhage Rat Model.

Excessive inflammation is a major cause contributing to early brain injury (EBI) and is associated with negative or catastrophic outcomes of subarachnoid hemorrhage (SAH). Resolvin D1 (RvD1) exerts strong anti-inflammatory and pro-resolving effects on either acute or chronic inflammation of various origin. Henceforth, we hypothesized that RvD1 potentially attenuates excessive inflammation in EBI following SAH. Therefore, we generated a filament perforation SAH model and administered 3 different doses (0.3, 0.6, and 1.2 nmol) of RvD1 after experimental SAH. Neurological scores, brain edema, and blood-brain barrier integrity were evaluated; besides, neutrophil infiltration, neuronal deaths, and microglial pro-inflammatory polarization were observed using histopathology or immunofluorescence staining, western blots, and qPCR. After confirming the effectiveness of RvD1 in SAH, we administered the FPR2-specific antagonist Trp-Arg-Trp-Trp-Trp-Trp-NH2 (WRW4) 30 min before SAH establishment to observe whether this compound could abolish the anti-inflammatory effect of RvD1. Altogether, our results showed that RvD1 exerted a strong anti-inflammatory effect and markedly reduced neutrophil infiltration and microglial pro-inflammatory activation, leading to remarkable improvements in neurological function and brain tissue restoration. After addition of WRW4, the anti-inflammatory effects of RvD1 were abolished. These results indicated that RvD1 could exert a good anti-inflammatory effect and alleviate EBI, which suggested that RvD1 might be a novel therapeutic alternative for SAH-induced injury.

Astaxanthin ameliorates oxidative stress and neuronal apoptosis via SIRT1/NRF2/Prx2/ASK1/p38 after traumatic brain injury in mice.

BACKGROUND AND PURPOSE: Oxidative stress and neuronal apoptosis play key roles in traumatic brain injury. We investigated the protective effects of astaxanthin against traumatic brain injury and its underlying mechanisms of action. EXPERIMENTAL APPROACH: A weight-drop model of traumatic brain injury in vivo and hydrogen peroxide exposure in vitro model were established. Brain oedema, behaviour tests, western blot, biochemical analysis, lesion volume, histopathological study and cell viability were performed. KEY RESULTS: Astaxanthin significantly reduced oxidative insults on Days 1, 3 and 7 after traumatic brain injury. Neuronal apoptosis was also ameliorated on Day 3. Additionally, astaxanthin improved neurological functions up to 3 weeks after traumatic brain injury. Astaxanthin treatment dramatically enhanced the expression of peroxiredoxin 2 (Prx2), nuclear factor-erythroid 2-related factor 2 (NRF2/Nrf2) and sirtuin 1 (SIRT1), while it down-regulated the phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) and p38. Inhibition of Prx2 by siRNA injection reversed the beneficial effects of astaxanthin against traumatic brain injury. Additionally, Nrf2 knockout prevented the neuroprotective effects of astaxanthin in traumatic brain injury. In contrast, overexpression of Prx2 in Nrf2 knockout mice attenuated the secondary brain injury after traumatic brain injury. Moreover, inhibiting SIRT1 by EX527 dramatically inhibited the neuroprotective effects of astaxanthin and suppressed SIRT1/Nrf2/Prx2/ASK1/p38 pathway both in vivo and in vitro. CONCLUSION AND IMPLICATIONS: Astaxanthin improved the neurological functions and protected the brain from injury after traumatic brain injury, primarily by reducing oxidative stress and neuronal death via SIRT1/Nrf2/Prx2/ASK1/p38 signalling pathway and might be a new candidate to ameliorate traumatic brain injury.

Fucoxanthin Mitigates Subarachnoid Hemorrhage-Induced Oxidative Damage via Sirtuin 1-Dependent Pathway.

Oxidative stress is a key component of the pathological cascade in subarachnoid hemorrhage (SAH). Fucoxanthin (Fx) possesses a strong antioxidant property and has shown neuroprotective effects in acute brain injuries such as ischemic stroke and traumatic brain injury. Here, we investigated the beneficial effects of Fx against SAH-induced oxidative insults and the possible molecular mechanisms. Our data showed that Fx could significantly inhibit SAH-induced reactive oxygen species production and lipid peroxidation, and restore the impairment of endogenous antioxidant enzymes activities. In addition, Fx supplementation improved mitochondrial morphology, ameliorated neural apoptosis, and reduced brain edema after SAH. Moreover, Fx administration exerted an improvement in short-term and long-term neurobehavior functions after SAH. Mechanistically, Fx inhibited oxidative damage and brain injury after SAH by deacetylation of forkhead transcription factors of the O class and p53 via sirtuin 1 (Sirt1) activation. EX527, a selective Sirt1 inhibitor, significantly abated Fx-induced Sirt1 activation and abrogated the antioxidant and neuroprotective effects of Fx after SAH. In primary neurons, Fx similarly suppressed oxidative insults and improved cell viability. These effects were associated with Sirt1 activation and were reversed by EX527 treatment. Taken together, our study explored that Fx provided protection against SAH-induced oxidative insults by inducing Sirt1 signaling, indicating that Fx might serve as a potential therapeutic drug for SAH.

Berberine Ameliorates Subarachnoid Hemorrhage Injury via Induction of Sirtuin 1 and Inhibiting HMGB1/Nf-κB Pathway.

Excessive cerebral inflammation plays a key role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Berberine, an isoquinoline alkaloid isolated from Chinese herb Coptis chinensis, possesses anti-inflammatory, and neuroprotective effects. Here we evaluated the beneficial effects of berberine against SAH-induced inflammatory response and the subsequent brain injury. Our data showed that berberine treatment significantly inhibited microglia activation and proinflammatory cytokines release. Concomitant with suppressed cerebral inflammation, berberine mitigated the subsequent brain injury as demonstrated by improved neurological behavior, reduced brain edema, and decreased neural apoptosis. Moreover, berberine significantly inhibited high mobile group box 1 (HMGB1)/nuclear factor-κB (Nf-κB)-dependent pathway and enhanced sirtuin 1 (SIRT1) expression after SAH. Treatment with ex527, a selective SIRT1 inhibitor, reversed berberine-induced SIRT1 activation and inhibitory effects on HMGB1/Nf-κB activation. In addition, ex527 pretreatment abated the anti-inflammatory and neuroprotective effects of berberine on SAH. Taken together, these findings suggest that berberine provides beneficial effects against SAH-triggered cerebral inflammation by inhibiting HMGB1/Nf-κB pathway, which may be modulated by SIRT1 activation.

Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury.

BACKGROUND: Aucubin (Au), an iridoid glycoside from natural plants, has antioxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in an H2O2-induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model. METHODS: In vitro experiments, the various concentrations of Au (50 µg/ml, 100 µg/ml, or 200 µg/ml) were added in culture medium at 0 h and 6 h after neurons stimulated by H2O2 (100 µM). After exposed for 12 h, neurons were collected for western blot (WB), immunofluorescence, and M29,79-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. In vivo experiments, Au (20 mg/kg or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling. Brain water content, neurological deficits, and cognitive functions were measured at specific time, respectively. Cortical tissue around focal trauma was collected for WB, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry, and enzyme linked immunosorbent assay (ELISA) at 72 h after TBI. RNA interference experiments were performed to determine the effects of nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with Au (40 mg/kg) treatment. Mice were intracerebroventricularly administrated with lentivirus at 72 h before TBI establishment. The cortex was obtained at 72 h after TBI and used for WB and q-PCR. RESULTS: Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS), and reduced cell apoptosis both in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages, and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1 (HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au. CONCLUSIONS: Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system.

DHEA Attenuates Microglial Activation via Induction of JMJD3 in Experimental Subarachnoid Haemorrhage.

BACKGROUND: Microglia are resident immune cells in the central nervous system and central to the innate immune system. Excessive activation of microglia after subarachnoid haemorrhage (SAH) contributes greatly to early brain injury, which is responsible for poor outcomes. Dehydroepiandrosterone (DHEA), a steroid hormone enriched in the brain, has recently been found to regulate microglial activation. The purpose of this study was to address the role of DHEA in SAH. METHODS: We used in vivo models of endovascular perforation and in vitro models of haemoglobin exposure to illustrate the effects of DHEA on microglia in SAH. RESULTS: In experimental SAH mice, exogenous DHEA administration increased DHEA levels in the brain and modulated microglial activation. Ameliorated neuronal damage and improved neurological outcomes were also observed in the SAH mice pretreated with DHEA, suggesting neuronal protective effects of DHEA. In cultured microglia, DHEA elevated the mRNA and protein levels of Jumonji d3 (JMJD3, histone 3 demethylase) after haemoglobin exposure, downregulated the H3K27me3 level, and inhibited the transcription of proinflammatory genes. The devastating proinflammatory microglia-mediated effects on primary neurons were also attenuated by DHEA; however, specific inhibition of JMJD3 abolished the protective effects of DHEA. We next verified that DHEA-induced JMJD3 expression, at least in part, through the tropomyosin-related kinase A (TrkA)/Akt signalling pathway. CONCLUSIONS: DHEA has a neuroprotective effect after SAH. Moreover, DHEA increases microglial JMJD3 expression to regulate proinflammatory/anti-inflammatory microglial activation after haemoglobin exposure, thereby suppressing inflammation.

Receptor-Mediated Delivery of Astaxanthin-Loaded Nanoparticles to Neurons: An Enhanced Potential for Subarachnoid Hemorrhage Treatment.

Astaxanthin (ATX) is a carotenoid that exerts strong anti-oxidant and anti-inflammatory property deriving from its highly unsaturated molecular structures. However, the low stability and solubility of ATX results in poor bioavailability, which markedly hampers its application as therapeutic agent in clinic advancement. This study investigated a promising way of transferrin conjugated to poly (ethylene glycol) (PEG)-encapsulated ATX nanoparticles (ATX-NPs) on targeted delivery and evaluated the possible mechanism underlying neuroprotection capability. As a result, the ATX integrated into nanocarrier presented both well water-dispersible and biocompatible, primely conquering its limitations. More than that, the transferrin-containing ATX-NPs exhibited enhanced cellular uptake efficiency than that of ATX-NPs without transferrin conjugated in primary cortical neurons. Additionally, compared to free ATX, transferrin-containing ATX-NPs with lower ATX concentration showed powerful neuroprotective effects on OxyHb-induced neuronal damage. Taken together, the improved bioavailability and enhanced neuroprotective effects enabled ATX-NPs as favorable candidates for targeted delivery and absorption of ATX. We believe that these in vitro findings will provide insights for advancement of subarachnoid hemorrhage therapy.

Allicin attenuates early brain injury after experimental subarachnoid hemorrhage in rats.

Early Brain Injury, rather than Cerebral Vasospasm, has been demonstrated to be more important for patients with Subarachnoid hemorrhage. It is considered that allicin can make sense in a wide range of pharmacological areas and can be taken as a therapeutic method in many pathologic situations. We have explored the potential effect of allicin and possible mechanisms in Early Brain Injury after Experimental Subarachnoid Hemorrhage in Rats. With therapy (70 mg/kg Allicin, rather than 30 mg/kg) 30 min post SAH, groups showed better neurological scores in 24 h. Significant differences could be found in body weight ratio between the SAH + vehicle groups and SAH + Allicin groups. Treatment with 70 mg/kg, not 30 mg/kg, Allicin significantly reduced brain edema and EB extravasation in 24 h after SAH. Assessments in 24 h after SAH showed that treatment with 70 mg/kg Allicin in 30 min after SAH significantly restrained the expression of cleaved caspase-3, mitigated the severity of neuronal degeneration, decreased the proportion of apoptotic neurons and the elevated MDA levels, and increased the suppressed GSH and SOD levels. We demonstrated for the first time that Allicin extenuated brain edema and blood-brain barrier dysfunction, improved neurological outcomes by the suppression of apoptosis and oxidative stress damage after SAH in experimental models, which may shade new light on the treatments of SAH.

Peroxiredoxin 1/2 protects brain against H2O2-induced apoptosis after subarachnoid hemorrhage.

Recent studies suggest that peroxiredoxin1/2 (Prx1/2) may be involved in the pathophysiology of postischemic inflammatory responses in the brain. In this study, we assessed the distribution and function of Prx1/2 in mice after experimental subarachnoid hemorrhage (SAH). We investigated the distribution of Prx1/2 in the brains of mice both in vivo and in vitro using immunofluorescence staining. The expression of Prx1/2 after SAH was determined by Western blot. Adenanthin was used to inhibit Prx1/2 function, and Prx1/2 overexpression was achieved by injecting adeno-associated virus. Oxidative stress and neuronal apoptosis were assessed both in vivo and in vitro. The neurologic function, inflammatory response, and related cellular signals were analyzed. The results showed that Prx1 was mainly expressed in astrocytes, and Prx2 was abundant in neurons. The expression of Prx1/2 was elevated after SAH, and their expression levels peaked before proinflammatory cytokines. Inhibiting Prx1/2 promoted neuronal apoptosis by increasing the hydrogen peroxide (H2O2) levels via the apoptosis signal-regulating kinase 1/p38 pathway. By contrast, overexpression of Prx1/2 attenuated oxidative stress and neuronal apoptosis after SAH. Thus, early expression of Prx1/2 may protect the brain from oxidative damage after SAH and may provide a novel target for treating SAH.-Lu, Y., Zhang, X.-S., Zhou, X.-M., Gao, Y.-Y., Chen, C.-L., Liu, J.-P., Ye, Z.-N., Zhang, Z.-H., Wu, L.-Y., Li, W., Hang, C.-H. Peroxiredoxin 1/2 protects brain against H2O2-induced apoptosis after subarachnoid hemorrhage.

[Low-intensity extracorporeal shockwave therapy for Peyronie's disease: A preliminary study of 32 cases].

OBJECTIVE: To investigate the clinical effect of low-intensity extracorporeal shockwave therapy (LI-ESWT) on Peyronie's disease. METHODS: From October 2016 to December 2017, we treated 32 cases of Peyronie's disease by LI-ESWT, with the therapeutic index of 0.09 mJ/mm2 and a pulse frequency of 120 beats/min. Each plaque was approached from two angles, each angle with a shockwave output of 900 times, and the larger ones from three points, each with an output of 600 times in addition to 300 times from the distal and proximal ends of the plaque, respectively. All the patients received 12 courses of treatment (2 courses a week) with a break of 3 weeks between the 1st and 2nd 6 courses. Then we observed the plague size and penile curvature of the patients, obtained their scores on the Visual Analogue Scale (VAS) and International Index of Erectile Function 5 (IIEF-5), and recorded their adverse reactions. RESULTS: The plagues were softened or diminished in different degrees in 9 of the 32 cases and erectile pain was alleviated in 15 cases after treatment. Penile curvature at erection, however, showed no significant improvement. The IIEF-5 scores were increased in 18 of the patients complicated with varied degrees of erectile dysfunction after LI-ESWT. No obvious complications were observed in any of the patients. CONCLUSIONS: Low-intensity extracorporeal shockwave therapy has a certain effect on Peyronie's disease by relieving plague-induced pain and improving the patient's penile erection and quality of life.