Glymphatic and lymphatic communication with systemic responses during physiological and pathological conditions in the central nervous system.

Crosstalk between central nervous system (CNS) and systemic responses is important in many pathological conditions, including stroke, neurodegeneration, schizophrenia, epilepsy, etc. Accumulating evidence suggest that signals for central-systemic crosstalk may utilize glymphatic and lymphatic pathways. The glymphatic system is functionally connected to the meningeal lymphatic system, and together these pathways may be involved in the distribution of soluble proteins and clearance of metabolites and waste products from the CNS. Lymphatic vessels in the dura and meninges transport cerebrospinal fluid, in part collected from the glymphatic system, to the cervical lymph nodes, where solutes coming from the brain (i.e., VEGFC, oligomeric α-syn, ß-amyloid) might activate a systemic inflammatory response. There is also an element of time since the immune system is strongly regulated by circadian rhythms, and both glymphatic and lymphatic dynamics have been shown to change during the day and night. Understanding the mechanisms regulating the brain-cervical lymph node (CLN) signaling and how it might be affected by diurnal or circadian rhythms is fundamental to find specific targets and timing for therapeutic interventions.

Severe cutaneous adverse reactions associated with immune checkpoint inhibitors therapy and anti-VEGF combination therapy: a real-world study of the FDA adverse event reporting system.

BACKGROUND: Immune checkpoint inhibitors (ICIs) therapy combined with anti-vascular endothelial growth factor (anti-VEGF) regimens showed new hope for cancer patients and considered as future pillar of cancer therapy. However, severe cutaneous adverse reactions (SCARs) in patients with ICIs and anti-VEGF combined therapy raise a serious concern and remain thoroughly assessed in clinics. RESEARCH DESIGN AND METHODS: Data retrieved from the first quarter of 2004 to the third quarter of 2022 in FAERS database underwent disproportionality analysis and Bayesian analysis were utilized to detect and assess the SCAR signals of ICIs and ICIs and anti-VEGF combined therapy for comparison. RESULTS: In total, 854 (1.10%) and 80 (1.06%) reports on SCARs associated with ICIs and a combination of ICIs and anti-VEGF therapy, respectively, were analyzed. Most of SCARs reports were associated with the use of pembrolizumab (36.01%), nivolumab (23.97%) and a combination of ipilimumab and nivolumab (19.71%). A use of atezolizumab and bevacizumab combined therapy (60.00%) caused the most SCARs records out of ICIs and anti-VEGF combined therapies. CONCLUSIONS: Treatment with joint therapy of ICIs and anti-VEGF agents may cause severe cutaneous adverse events. It is vital to identify ICI-related SCARs early, and to manage them appropriately.

Detection of drug safety signal of drug-induced neutropenia and agranulocytosis in all-aged patients using electronic medical records.

PURPOSE: We explored the adverse drug reaction signals of drug-induced neutropenia (DIN) and drug-induced agranulocytosis (DIA) in hospitalized patients and evaluated the novelty of these correlations. METHOD: A two-step method was established to identify the relationship between drugs and DIN or DIA using 5-year electronic medical records (EMRs) obtained from 242 000 patients at Qilu Hospital of Shandong University. First, the drugs suspected to induce DIN or DIA were selected. The associations between suspected drugs and DIN or DIA were evaluated by a retrospective cohort study using unconditional logistic regression analysis and multiple linear regression model. RESULTS: Twelve suspected drugs (vancomycin, meropenem, voriconazole, acyclovir, ganciclovir, fluconazole, oseltamivir, linezolid, compound borax solution, palonosetron, polyene phosphatidylcholine, and sulfamethoxazole) were associated with DIN, and six suspected drugs (vancomycin, voriconazole, acyclovir, ganciclovir, fluconazole, and oseltamivir) were associated with DIA. The multivariate linear regression model revealed that nine drugs (vancomycin, meropenem, voriconazole, ganciclovir, fluconazole, oseltamivir, compound borax solution, palonosetron, and polyene phosphatidylcholine) and four drugs (vancomycin, voriconazole, ganciclovir, and fluconazole) were found to be associated with DIN and DIA, respectively. While logistic regression analysis revealed that palonosetron and ganciclovir were associated with DIN and DIA, respectively. CONCLUSION: Palonosetron and ganciclovir were found to be correlated with drug-induced granulocytopenia. The results of this study provide an early warning of drug safety signals for drug-induced granulocytopenia, facilitating a quick and appropriate response for clinicians.

Effects of Aspirin Therapy on Bypass Efficacy and Survival of Patients Receiving Direct Cerebral Revascularization.

Background: Both patency maintenance and neoangiogenesis contribute to cerebrovascular bypass efficacy. However, the combined impact of the aforementioned two indicators on postoperative revascularization following superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass has been less well elucidated. Meanwhile, there is a paucity of evidence with conflicting results about postoperative aspirin therapy. Objective: The objective of the study was to investigate the correlation between aspirin use and STA-MCA bypass efficacy, including patency, postoperative neoangiogenesis, and follow-up outcomes. Methods: A total of 181 MMD patients (201 procedures) undergoing STA-MCA bypass at our institution (2017-2019) were retrospectively reviewed. The bypass efficacy level and postoperative complications were compared between aspirin and non-aspirin groups. Results: Among 95 PS-matched pairs, the aspirin group presented a significantly more favorable bypass efficacy than the non-aspirin group [odds ratio (OR) 2.23, 95% confidence interval (CI) 1.11-4.61; p = 0.026]. Multivariate logistic regression analysis confirmed the profound impact of aspirin as an independent predictor of bypass efficacy [adjusted OR 2.91, 95% CI 1.34-6.68; p = 0.009]. A remarkable negative correlation was found between bypass efficacy and the rate of ischemic complications (Phi = -0.521). Postoperative aspirin therapy was associated with a non-significant trend toward a lower incidence of ischemic events [OR 0.73, 95% CI 0.23-2.19; p = 0.580]. No significant difference in bleeding rates was observed between aspirin and control groups [OR 1.00, 95% CI 0.12-8.48; p = 1.000]. Conclusion: Among patients undergoing STA-MCA bypass procedures, bypass efficacy is a good predictor of follow-up outcomes. Postoperative aspirin therapy can improve patency, neoangiogenesis, and overall bypass efficacy, thereby protecting against postoperative ischemic complications. Clinical Trial Registration: http://www.chictr.org.cn/, identifier CTR2100046178.

LncRNA MEG3 targeting miR-424-5p via MAPK signaling pathway mediates neuronal apoptosis in ischemic stroke.

Emerging evidence suggests that long non-coding RNAs (lncRNAs) are significant regulators in the pathological process of ischemic stroke (IS). However, little is known about lncRNAs and their roles in IS. In this study, we aimed to screen out differentially expressed lncRNAs and revealed the underlying mechanisms in IS. The results of bioinformatic analysis showed that lncRNA MEG3 and Sema3A were over-expressed in IS samples, while miR-424-5p was lower-expressed. Correlation between MEG3/miR-424-5p, and miR-424-5p/Sema3A were predicted with miRanda and TargetScan, and verified by dual luciferase assay. Inhibition of MEG3 remarkably increased the expression of miR-424-5p and decreased the expression of Sema3A, which also led to in an increased cell viability and decreased cellular apoptosis in oxygen-glucose deprivation and reoxygenation (OGD/R) model, as well as an activated MAPK signaling pathways. Consistently, MEG3 was upregulated in MCAO mice, knockdown of MEG3 reduced the infarct volume and improved neurobehavioral outcomes in rats following MCAO. In conclusion, it was demonstrated that MEG3 accelerated the process of IS by suppressing miR-424-5p, which targeted Sema3A and the activated MAPK pathway. These results might provide useful information for exploring the potential therapeutic targets in IS.

NLRP3 inflammasome negatively regulates podocyte autophagy in diabetic nephropathy.

Inflammasome mechanisms are recognized as a key pathophysiology of diabetic nephropathy (DN). The nucleotide-oligomerization domain-like receptor 3 (NLRP3) inflammasome has attracted the most attention. Autophagy as a conserved intracellular catabolic pathway plays essential roles in the maintenance of podocytes. Although autophagy was involved in preventing excessive inflammatory responses in kidney diseases, a clear understanding of the regulation of NLRP3 inflammasome on autophagy in glomerular damage in DN is still lacking. In this study, we focused on the effect of the activation of NLRP3 inflammasome on the suppression of podocyte autophagy and aimed to investigate the role of autophagy in podocyte injury in DN. Podocyte autophagy has been confirmed to be inhibited in high-fat diet/streptozotocin (HFD/STZ)-induced DN mice, and NLRP3 has been found to be upregulated in both mice and human DN biopsies and in vitro. Activation of NLRP3 inflammasome exacerbated podocyte autophagy and reduced podocyte nephrin expression, while silencing of NLRP3 efficiently restored podocyte autophagy and ameliorated podocyte injury induced by high glucose. The results showed that NLRP3 was a negative regulator of autophagy and suggested that restoration of podocyte autophagy by inactivation of NLRP3 under high glucose could reduce podocyte injury. Proper modification of autophagy and inflammasome has the potential to benefit the kidney in DN.

ß-Arrestin-2-ERK1/2 cPLA2α axis mediates TLR4 signaling to influence eicosanoid induction in ischemic brain.

LPS has been shown to elicit neuroinflammation associated with the up-regulation of the eicosanoid pathway in animal models; however, the regulatory mechanisms of TLR4 in brain neuroinflammatory conditions remain elusive. ß-Arrestins are key regulators of the GPCR signaling pathway and are involved in the leukotriene B4-induced leukocyte migration to initiate inflammatory response. However, the roles of ß-arrestins in eicosanoid regulation and related diseases are not clear. To address this issue, we conducted a study to investigate the effect of TLR4 on the eicosanoid pathway in ischemic stroke brain and to explore the underlying molecular regulation mechanism. Cerebral ischemia was produced by occlusion of the middle cerebral artery, followed by reperfusion for 24 h. We demonstrated that knockout of TLR4 improves ischemic stroke brain associated with eicosanoid down-regulation. Interestingly, genetic disruption of ß-arrestin-2 failed to decrease neuroinflammation in the damaged brain of TLR4-/- mice, which indicates the requirement of ß-arrestin-2 for TLR4 knockdown protection. Further study showed that the negative regulation of phosphorylated (phospho-)ERK1/2 and phospho-cytosolic phospholipase A2 α (cPLA2α) by TLR4 deficiency was eliminated by genetic disruption of ß-arrestin-2. In addition, ß-arrestin-2 deficiency reversed the reduction of colocalization of phospho-ERK1/2 with phospho-cPLA2α in TLR4-/- mice following ischemic stroke. Mechanistic studies indicated that ß-arrestin-2 specifically colocalized and associated with ERK1/2 to prevent ERK1/2-dependent cPLA2α activation following ischemic injury, and ß-arrestin-2 deficiency blocked the negative regulation of phospho-ERK1/2, revived the association of phospho-ERK1/2 with phospho-cPLA2α, and subsequently increased the prostaglandin E2 and thromboxane A2 production remarkably. Our findings may provide novel insights that ß-arrestin-2 is responsible for ischemic brain improvement in TLR4-/- mice via negative regulation of eicosanoid production.-Xiang, Y., Wei, X., Du, P., Zhao, H., Liu, A., Chen, Y. ß-Arrestin-2-ERK1/2 cPLA2α axis mediates TLR4 signaling to influence eicosanoid induction in ischemic brain.

Cerebral dopamine neurotrophic factor protects microglia by combining with AKT and by regulating FoxO1/mTOR signaling during neuroinflammation.

BACKGROUND: The activation of microglia plays a crucial role in neuroinflammation. Previous studies have shown that cerebral dopamine neurotrophic factor (CDNF) has a protective effect on neuroinflammation, but the mechanisms involved have not been fully studied. AKT is a serine-threonine protein kinase widely expressed in mammals through which the downstream pathway FoxO1/mTOR is closely related to cell inflammation, apoptosis, metabolism, etc. Therefore, we examined whether CDNF regulates neuroinflammation through this pathway. METHODS: After pretreatment with CDNF and LPS, microglial cells were detected by laser confocal microscopy, coimmunoprecipitation and immunofluorescence to observe whether CDNF was colocalized with AKT. The expression of AKT and its downstream FoxO1/mTOR were determined by Western blot. The effect of CDNF on inflammatory cytokines was detected by ELISA, and the mRNA levels of AKT and FoxO1/mTOR were detected by qRT-PCR. RESULTS: Laser confocal and coimmunoprecipitation experiments significantly reveal the occurrence of interactions between AKT and CDNF in microglia. Western blot results show that CDNF incubation suppressed the activation of AKT/FoxO1/mTOR signaling. Moreover, CDNF clearly decreased the expression of inflammatory cytokines. In qRT-PCR, the expression of mRNA in AKT and its downstream FoxO1/mTOR gradually decreased due to CDNF intervention. CONCLUSIONS: CDNF combined with AKT and regulated the downstream pathway FoxO1/mTOR in microglia, eventually suppressing the secretion of inflammatory factors. Therefore, CDNF might play a protective role in the neuroinflammation of microglia via AKT/FoxO1/mTOR signaling.

Acetylpuerarin inhibits oxygen-glucose deprivation-induced neuroinflammation of rat primary astrocytes via the suppression of HIF-1 signaling.

In the central nervous system (CNS), ischemic injury induced by inflammation associated with astrocytes serves an important role in physiological and pathological processes. Neuroinflammation leads to the release of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß. The aim of the present study was to investigate whether acetylpuerarin attenuates oxygen-glucose deprivation (OGD)-induced astrocyte inflammation and secretion of pro-inflammatory cytokines via inhibiting hypoxia-inducible factor-1 (HIF-1) activation and suppressing downstream primary astrocyte signaling in rats. The results demonstrated that acetylpuerarin attenuates astrocyte viability and induces morphological changes following OGD stress. Furthermore, acetylpuerarin suppresses the stimulation of HIF-1α and nuclear factor (NF)-κB signaling pathways, while attenuating the expression and secretion of pro-inflammatory cytokines via HIF-1 suppression in OGD-induced astrocytes. These findings indicate that acetylpuerarin may attenuate OGD-induced astrocyte damage and inflammation in rat primary astrocytes via suppressing HIF-1 activation and NF-κB signaling. These results suggest that acetylpuerarin regulates inflammation associated with astrocytes and may represent a novel therapeutic agent for the treatment of neuroinflammation in the CNS.

Apocynin inhibited NLRP3/XIAP signalling to alleviate renal fibrotic injury in rat diabetic nephropathy.

AIMS: In this animal study, we tried to test the hypothesis that apocynin could play an anti-inflammation role by inhibiting NLRP3/X-linked inhibitor of apoptosis protein (XIAP) signalling and have an effect on antifibrosis in rats with diabetic nephropathy. MAIN METHODS: Diabetic nephropathy rats were induced by tail-vein injection of streptozotocin at 60 mg/kg body weight in sodium citrate buffer (0.01 M, pH 4.5) with unrestricted access to food/water for 12 weeks, and rats with blood glucose levels above 18.0 mM were considered diabetic; the damage index for glomerular mesangial cells damage index was calculated by morphological examinations; protein and mRNA changes were analysed by western blotting immunohistochemistry and real-time quantitative polymerase chain reaction; interstitial fibrosis was assessed and scored using Masson's staining. KEY FINDINGS: In rats with diabetic nephropathy, apocynin (1) reduced renal injury and improved renal function; (2) downregulated the expression of NLRP3 in renal cortex; (3) downregulated the expression of XIAP in renal cortex; and (4) attenuated renal fibrosis. SIGNIFICANCE: As an inhibitor of reactive oxygen species (ROS), apocynin could downregulate the expression of NLRP3 and XIAP, and alleviate renal fibrosis, which meant not only that ROS was one type of ligands of NLRP3, but also that ROS mechanism and NLRP3 activation might be therapeutic targets in the treatment of diabetic nephropathy in the future.

Anterior corpectomy comparing to posterior decompression surgery for the treatment of multi-level ossification of posterior longitudinal ligament: A meta-analysis.

BACKGROUND: Ossification of posterior longitudinal ligament (OPLL) can be treated by two surgical strategies, anterior decompression with fusion and posterior decompression with laminoplasty or laminectomy. It has been debated which surgical approach is more appropriate for the treatment of multilevel OPLL. The purpose of this study is to compare the outcomes of anterior corpectomy surgery to posterior decompression surgery for the treatment of multilevel ossification of OPLL. MATERIALS AND METHODS: The databases of Medline, Embase, Pubmed, Cochrane library, and Cochrane Central Register of Controlled Trials was searched and we included trials which comparing anterior to posterior surgery for multilevel OPLL. There was no language restrictions. Two authors independently assessed the methodological quality of included trials. The data of outcomes was extracted and analyzed by STATA 12.0. RESULTS: Six studies were included in this meta-analysis, and totally 123 patients were undergone anterior cervical corpectomy and fusion (ACCF) and 216 patients were decompressed by posterior approach. In this meta-analysis, the postoperative JOA score of anterior surgery was higher than posterior surgery at one year follow-up. Consistently, the recovery rate of anterior surgery was higher than posterior surgery. However, the anterior surgery (ACCF) showed significantly more complications comparing to posterior surgery for the treatment of multilevel OPLL. CONCLUSION: This meta-analysis indicates that the parameters of outcomes and functional recovery of patients performed with anterior surgery achieve better JOA scores and recovery rates to those with posterior surgery. Though the incidence of complications of anterior surgery are higher than posterior surgery, the anterior directly decompression is advised when the complications could be controlled by advanced surgical technique.

Inflammatory mechanisms involved in brain injury following cardiac arrest and cardiopulmonary resuscitation.

Cardiac arrest (CA) is a leading cause of fatality and long-term disability worldwide. Recent advances in cardiopulmonary resuscitation (CPR) have improved survival rates; however, the survivors are prone to severe neurological injury subsequent to successful CPR following CA. Effective therapeutic options to protect the brain from CA remain limited, due to the complexities of the injury cascades caused by global cerebral ischemia/reperfusion (I/R). Although the precise mechanisms of neurological impairment following CA-initiated I/R injury require further clarification, evidence supports that one of the key cellular pathways of cerebral injury is inflammation. The inflammatory response is orchestrated by activated glial cells in response to I/R injury. Increased release of danger-associated molecular pattern molecules and cellular dysfunction in activated microglia and astrocytes contribute to ischemia-induced cytotoxic and pro-inflammatory cytokines generation, and ultimately to delayed death of neurons. Furthermore, cytokines and adhesion molecules generated within activated microglia, as well as astrocytes, are involved in the innate immune response; modulate influx of peripheral immune and inflammatory cells into the brain, resulting in neurological injury. The present review discusses the molecular aspects of immune and inflammatory mechanisms in global cerebral I/R injury following CA and CPR, and the potential therapeutic strategies that target neuroinflammation and the innate immune system.

Inhibition of Toll-like receptor 9 attenuates sepsis-induced mortality through suppressing excessive inflammatory response.

Sepsis, a major clinical problem with high morbidity and mortality, is caused by overwhelming systemic host-inflammatory response. Toll-like receptors (TLRs) play a fundamental role in induction of hyperinflammation and tissue damage in sepsis. In this study, we demonstrate a protective role of TLR9 inhibition against the dysregulated inflammatory response and tissue injury in sepsis. TLR9 deficiency decreased the mortality of mice following cecal ligation and puncture (CLP)-induced sepsis. TLR9 knockout mice showed dampened p38 activation and augmented Akt phosphorylation in the spleen, lung and liver. In addition, TLR9 deficiency decreased the levels of inflammatory cytokines and attenuated splenic apoptosis after CLP. These results indicate that TLR9 inhibition might offer a novel therapeutic strategy for the management of sepsis.

The role of toll-like receptor 9 in chronic stress-induced apoptosis in macrophage.

Emerging evidence implied that chronic stress has been exerting detrimental impact on immune system functions in both humans and animals. Toll-like receptors (TLRs) have been shown to play an essential role in modulating immune responses and cell survival. We have recently shown that TLR9 deficiency protects against lymphocyte apoptosis induced by chronic stress. However, the exact role of TLR9 in stress-mediated change of macrophage function remains unclear. The results of the current study showed that when BALB/c mice were treated with restraint stress (12 h daily for 2 days), the number of macrophages recruited to the peritoneal cavity was obviously increased. Results also demonstrated that the sustained effects of stress elevated cytokine IL-1ß, TNF-α and IL-10 production yet diminished IFN-γ production from macrophage, which led to apoptotic cell death. However, TLR9 deficiency prevented the chronic stress-mediated accumulation of macrophages. In addition, knocking out TLR9 significantly abolished the chronic stress-induced imbalance of cytokine levels and apoptosis in macrophage. TLR9 deficiency was also found to reverse elevation of plasma IL-1ß, IL-10 and IL-17 levels and decrease of plasma IFN-γ level under the condition of chronic stress. These results indicated that TLR9-mediated macrophage responses were required for chronic stress-induced immunosuppression. Further exploration showed that TLR9 deficiency prevented the increment of p38 MAPK phosphorylation and reduction of Akt/Gsk-3ß phosphorylation; TLR9 deficiency also attenuated the release of mitochondrial cytochrome c into cytoplasm, caused upregulation of Bcl-2/Bax protein ratio, downregulation of cleavage of caspase-3 and PARP, as well as decreased TUNEL-positive cells in macrophage of stressed mice. Collectively, our studies demonstrated that deficiency of TLR9 maintained macrophage function by modulating macrophage accumulation and attenuating macrophage apoptosis, thus preventing immunosuppression in restraint-stressed mice.

Suppression of inflammatory response by flurbiprofen following focal cerebral ischemia involves the NF-κB signaling pathway.

Some studies of animal models of middle cerebral artery occlusion indicate that inflammation plays a key role in the pathogenesis of cerebral ischemia and secondary damage. Flurbiprofen has been suggested to alleviate cerebral ischemia/reperfusion injury in both focal and global cerebral ischemia models, but the mechanisms underlying the protective action are still incompletely understood. In this study we want to investigate the protective effect of flurbiprofen after transient middle cerebral artery occlusion (MCAO) in rats and the role of the NF-κB signaling pathway on this neuroprotective effect. Male Wistar rats were subjected to transient middle cerebral artery occlusion for 2 h, followed by 24 h reperfusion. Flurbiprofen was administrated via tail-vein injection at the onset of reperfusion. HE staining and Immunohistochemistry were carried out to detect the morphological changes in ischemic penumbra cortex. The expression of inflammatory cytokines genes (IL-1ß, IL-6 and TNF-α) and the levels of p-NF-κB (p65) in ischemic penumbra cortex were measured by RT-PCR and western blot. Administration of flurbiprofen at the doses of 5 mg/kg and 10 mg/kg significantly attenuated cerebral ischemia/reperfusion injury, as shown by a reduction in the morphological changes and inhibition of pro-inflammatory cytokine expression in ischemic penumbra cortex. Moreover, our findings further demonstrated that the inhibition of NF-κB activity was involved in the neuroprotective effect of flurbiprofen on inflammatory responses. Flurbiprofen protects against cerebral injury by reducing expression of inflammatory cytokines genes and this effect may be partly due to the inhibition of NF-κB signaling pathway.

Anti-inflammatory effect of acetylpuerarin on eicosanoid signaling pathway in primary rat astrocytes.

Astrocytes activation has been implicated in the inflammatory responses underlying brain injury and neurodegenerative diseases including bacterial infections, cerebral ischemia, and Parkinson's diseases. Acetylpuerarin is a newly modified isoflavone based on puerarin that has neuroprotective and antioxidant effects. In this study, we investigated the anti-inflammatory action of acetylpuerarin in regulating the eicosanoids generation and its underlying molecular mechanisms in lipopolysaccharide (LPS)-induced production of arachidonic acid (AA) metabolites in primary rat astrocytes. The results showed that acetylpuerarin concentration dependently inhibited the LPS-induced production of AA metabolites such as prostaglandin E2 (PGE2) and leukotriene C4 (LTC4), and acetylpuerarin significantly attenuated the expression and immunoreactivity of group V secretory phospholipase A2 (sPLA2) protein induced by LPS in astrocytes. Furthermore, in astrocytes pretreated with acetylpuerarin, the time course of phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and of cytosolic PLA2 alpha (cPLA2α) and expression of transcription factors, nuclear factor kappa B (NF-κB), was markedly truncated. Acetylpuerarin concentration dependently abolished the LPS-induced expressions of AA-metabolizing enzymes including cyclooxygenase-2 (COX-2) and lipooxygenase-5 (LOX-5). This study indicates that acetylpuerarin inhibited LPS-induced AA-metabolizing enzymes and AA metabolites in astrocytes via downregulation expression of group V sPLA2 and phosphorylation of ERK1/2, cPLA2α, and NF-κB. These findings reveal, in part, the molecular basis underlying the anti-inflammatory properties of acetylpuerarin.

Inhibition of sPLA2-IIA prevents LPS-induced neuroinflammation by suppressing ERK1/2-cPLA2α pathway in mice cerebral cortex.

Neuroinflammation is involved in various central nervous system (CNS) disorders, including brain infections, ischemia, trauma, stroke, and degenerative CNS diseases. In the CNS inflammation, secretory phospholipase A2-IIA (sPLA2-IIA) acts as a mediator, resulting in the generation of the precursors of pro-inflammatory lipid mediators, such as prostaglandins (PGs) and leukotrienes (LTs). However, the role of sPLA2-IIA in neuroinflammation is more complicated and remains unclear yet. In the present study, we investigated the effect of sPLA2-IIA inhibition by specific inhibitor SC-215 on the inflammation in LPS-induced mice cerebral cortex and primary astrocytes. Our results showed that the inhibition of sPLA2-IIA alleviated the release of PGE2 by suppressing the activation of ERK1/2, cPLA2α, COX-2 and mPGES-1. These findings demonstrated that sPLA2-IIA showed the potential to regulate the neuroinflammation in vivo and in vitro, indicating that sPLA2-IIA might be a novel target for the treatment of acute neuroinflammation.

Hydroxysafflor yellow A protects against cerebral ischemia-reperfusion injury by anti-apoptotic effect through PI3K/Akt/GSK3ß pathway in rat.

Hydroxysafflor yellow A (HSYA) is the major active chemical component of the flower of the safflower plant, Carthamus tinctorius L. Previously, its neuroprotection against cerebral ischemia-reperfusion (I/R) injury was reported by anti-oxidant action and suppression of thrombin generation. Here, we investigate the role of HSYA in cerebral I/R-mediated apoptosis and possible signaling pathways. Male Wistar rats were subjected to transient middle cerebral artery occlusion for 2 h, followed by 24 h reperfusion. HSYA was administered via tail-vein injection just 15 min after occlusion. The number of apoptotic cells was measured by TUNEL assay, apoptosis-related proteins Bcl-2, Bax and the phosphorylation levels of Akt and GSK3ß in ischemic penumbra were assayed by western blot. The results showed that administration of HSYA at the doses of 4 and 8 mg/kg significantly inhibited the apoptosis by decreasing the number of apoptotic cells and increasing the Bcl-2/Bax ratio in rats subjected to I/R injury. Simultaneously, HSYA treatment markedly increased the phosphorylations of Akt and GSK3ß. Blockade of PI3K activity by wortmannin dramatically abolished its anti-apoptotic effect and lowered both Akt and GSK3ß phosphorylation levels. Taken together, these results suggest that HSYA protects against cerebral I/R injury partly by reducing apoptosis via PI3K/Akt/GSK3ß signaling pathway.

Losartan, an angiotensin II type 1 receptor blocker, ameliorates cerebral ischemia-reperfusion injury via PI3K/Akt-mediated eNOS phosphorylation.

Angiotensin (Ang) II type 1 receptor blockers (ARBs) have been shown to protect against cerebral ischemia-reperfusion (I/R) injury. However, the mechanism by which ARBs protect brain ischemia injury is still unclear. The aims of this study were to investigate the effects of losartan, an ARB, on the phosphorylation of endothelial nitric oxide synthase (eNOS) in response to focal brain I/R and to determine whether the neuroprotective phosphatidylinositol-3-kinase (PI3K)-Akt signaling pathway is involved. Normotensive Wistar rats were pretreated for 14 days with 5mg/kg losartan, then subjected to middle cerebral artery occlusion for 2h followed by reperfusion (MCAO-R). Our results showed that losartan reduced infarct volumes and improved neurobehavioral outcomes in rats subjected to MCAO-R. Losartan pretreatment significantly suppressed an increase in inducible nitric oxide synthase (iNOS) and sustained normal levels of eNOS expression 24h after MCAO-R injury. Phosphorylated eNOS and Akt levels were much lower than those in the sham group at 24h after MCAO-R, suggesting that losartan pretreatment significantly preserved eNOS phosphorylation in response to the activated Akt. Moreover, blockade of PI3K activity by wortmannin, totally abolished losartan-induced eNOS phosphorylation, providing the first evidence that losartan stimulates eNOS phosphorylation through PI3K/Akt signaling in the MCAO-R rat model. Our findings provide a mechanistic basis underlying the benefits of using selective ARBs, such as losartan, in the treatment of cerebrovascular disease.