Background and purpose Lipoxin A4 (LXA4) has been reported to reduce inflammation in several neurological injury models. We studied the effects of LXA4 on neuroinflammation after subarachnoid hemorrhage (SAH) in a rat model. Methods Two hundred and thirty eight Sprague Dawley male rats, weight 280–320 g were used. Exogenous LXA4 (0.3 and 1.0 nmol) were injected intracerebroventricularly at 1.5 hours after SAH. Neurological scores, brain water content and blood-brain barrier were evaluated at 24 hours after SAH; Morris water maze and T-maze tests were examined at 21 days after SAH. The expression of endogenous LXA4 and its receptor formyl peptide receptor 2 (FPR2), as well as p38, IL-1β and IL-6 were studied either by ELISA or western blots. Neutrophil infiltration was observed by myeloperoxidase (MPO) staining. FPR2 siRNA was used to knock down LXA4 receptor. Results The expression of endogenous LXA4 decreased and the expression of FPR2 increased after SAH. Exogenous LXA4 decreased brain water content, reduced Evans blue extravasation, and improved neurological functions and improved the learning and memory ability after SAH. LXA4 reduced neutrophil infiltration and phosphorylation of p38, IL-1β and IL-6. These effects of LXA4 were abolished by FPR2 siRNA. Conclusion Exogenous LXA4 inhibited inflammation by activating FPR2 and inhibiting p38 after SAH. LXA4 may serve as an alternative treatment to relieve early brain injury after SAH.

BackgroundOur previous research and other studies with radiotracers showed evidence of a centripetal drainage pathway, separate from blood or lymphatic vessels, that can be visualized when a small amount of low molecular weight tracer is injected subcutaneously into a given region on skin of humans. In order to further characterize this interesting biological phenomenon, animal experiments are designed to elucidate histological and physiologic characteristics of these visualized pathways.MethodsMultiple tracers are injected subcutaneously into an acupuncture point of KI3 to visualize centripetal pathways by magnetic resonance imaging or fluorescein photography in 85 healthy rabbits. The pathways are compared with venography and indirect lymphangiography. Fluid flow through the pathways is observed by methods of altering their hydrated state, hydrolyzing by different collagenases, and histology is elucidated by optical, fluorescein and electron microscopy.ResultsHistological and magnetic imaging examinations of these visualized pathways show they consist of perivenous loose connective tissues. As evidenced by examinations of tracers’ uptake, they appear to function as a draining pathway for free interstitial fluid. Fluorescein sodium from KI3 is found in the pathways of hind limbs and segments of the small intestines, partial pulmonary veins and results in pericardial effusion, suggesting systematical involvement of this perivenous pathway. The hydraulic conductivity of these pathways can be compromised by the collapse of their fiber-rich beds hydrolyzed by either of collagenase type I, III, IV or V.ConclusionsThe identification of pathways comprising perivenous loose connective tissues with a high hydraulic conductivity draining interstitial fluid in hind limbs of a mammal suggests a potential drainage system complementary to vascular circulations. These findings may provide new insights into a systematically distributed collagenous connective tissue with a circulatory function and their potential relevance to the nature of acupuncture meridians.

Background and Purpose Mincle (macrophage-inducible C-type lectin, CLEC4E) receptor is reported involved in neuroinflammation in cerebral ischemia and traumatic brain injury. This study was designed to investigate the role of Mincle and its downstream Syk signal pathway in early brain injury after SAH in a rat model. Methods Two hundreds and fifteen (215) male Sprague-Dawley rats (280–320g) were subjected to endovascular perforation model of SAH. SAH grade, neurological score, and brain water content were measured at 24 h after SAH. Mincle/Syk as well as CARD9 (a member of the caspase-associated recruitment domain (CARD), involved in innate immune response), interleukin-1β (IL-1β) and myeloperoxidase (MPO) expressions were analyzed by western blot at 24 h after SAH. Specific cell types that expressed Mincle were detected with double immunofluorescence staining. Mincle siRNA, the endogenous ligand of Mincle receptor SAP130, and a selective Syk phosphorylation inhibitor piceatannol were used for intervention. Results Brain water content increased and neurological functions decreased in rats after SAH. The expression of SAP130, Mincle, Syk and p-Syk increased at 12h and peaked at 24h after SAH. Mincle siRNA reduced IL-1β and infiltration of MPO positive cells, decreased brain water content, and improved neurological functions at 24h after SAH. The endogenous ligand of Mincle receptor SAP130 up-regulated the expression of p-Syk and CARD9, and increased the levels of IL-1β and MPO, even though it did not increase brain water content nor it deteriorated neurological function at 24h after SAH. Syk inhibitor piceatannol reduced brain edema at 24h after SAH. Conclusion Mincle/Syk is involved in early brain injury after SAH, and they may serve as new targets for therapeutic intervention.

Sepsis‐induced myocardial dysfunction (SIMD) causes high mortality in seriously ill patients. Ginsenoside Rg1 has been proven to have effective anti‐inflammatory and antiapoptotic properties. However, the specific role of Rg1 in SIMD and the molecular mechanism remain unclear. Hence, we aimed to investigate the latent effects of ginsenoside Rg1 against SIMD and explore its underlying mechanisms. Male C57BL/6J mice and neonatal rat cardiomyocytes (NRCMs) were used as in vivo and in vitro models, respectively. Western blot analysis was used to detect the level of protein expression, and reverse transcription polymerase chain reaction was conducted to determine the messenger RNA expression of inflammatory factors. The terminal deoxynucleotidyl transferase‐mediated nick end labeling assay and flow cytometry were used to determine the apoptosis rate. Echocardiography was performed to assess cardiac function. The results showed that Rg1 improved cardiac function and attenuated lipopolysaccharide (LPS)‐induced apoptosis and inflammation in mice. In addition, in NRCMs, Rg1 downregulated the expression of LPS‐induced inflammatory cytokines and reversed the increased expression of Toll‐like receptor 4 (TLR4), nuclear factor‐κB (NF‐κB), and NOD‐like receptor 3 (NLRP3). In addition, treatment with TLR4 small interfering RNA (siRNA), a p‐NF‐κB inhibitor, or NLRP3 siRNA suppressed LPS‐induced apoptosis and inflammation. In conclusion, Rg1 can attenuate LPS‐induced inflammation and apoptosis both in NRCMs and septic mice and restore impaired cardiac function. Moreover, Rg1 may exert its effect via blocking the TLR4/NF‐κB/NLRP3 pathway.

Hypoxic-ischemic encephalopathy is a condition caused by reduced oxygen and cerebral blood flow to the brain resulting in neurological impairments. Effective therapeutic treatments to ameliorate these disabilities are still lacking. We sought to investigate the role of sestrin2, a highly conserved stress-inducible protein, in a neonatal rat hypoxic-ischemic encephalopathy model. Ten-day-old rat pups underwent right common carotid artery ligation followed by 2.5 h hypoxia. At 1 h post hypoxic-ischemic encephalopathy, rats were intranasally administered with recombinant human sestrin2 and sacrificed for brain infarct area measurement, Fluoro-Jade C, immunofluorescence staining, Western blot, and neurological function testing. rh-sestrin2 reduced brain infarct area, brain atrophy, apoptosis, ventricular area enlargement, and improved neurological function. Western blot showed that sestrin2 expression levels were increased after treatment with rh-sestrin2, and sestrin2 exerts neuroprotective effects via activation of the adenosine monophosphate-activated protein kinase pathway which in turn inhibits mammalian target of rapamycin signaling resulting in the attenuation of apoptosis. In conclusions: Sestrin2 plays an important neuroprotective role after hypoxic-ischemic encephalopathy via adenosine monophosphate-activated protein kinase signaling pathway and serves as a negative feedback regulator of mammalian target of rapamycin. Administration of rh-sestrin2 not only reduced infarct area and brain atrophy, but also significantly improved neurological function.

MicroRNAs (miRNAs) are a class of small non-coding RNAs, whose expression levels vary in different cell types and tissues. Emerging evidence indicates that tissue-specific and -enriched miRNAs are closely associated with cellular development and stress responses in their tissues. MiR-25 has been documented to be abundant in cardiomyocytes, but its function in the heart remains unknown. Here, we report that miR-25 can protect cardiomyocytes against oxidative damage by down-regulating mitochondrial calcium uniporter (MCU). MiR-25 was markedly elevated in response to oxidative stimulation in cardiomyocytes. Further overexpression of miR-25 protected cardiomyocytes against oxidative damage by inactivating the mitochondrial apoptosis pathway. MCU was identified as a potential target of miR-25 by bioinformatical analysis. MCU mRNA level was reversely correlated with miR-25 under the exposure of H2O2, and MCU protein level was largely decreased by miR-25 overexpression. The luciferase reporter assay confirmed that miR-25 bound directly to the 3' untranslated region (UTR) of MCU mRNA. MiR-25 significantly decreased H2O2-induced elevation of mitochondrial Ca2+ concentration, which is likely to be the result of decreased activity of MCU. We conclude that miR-25 targets MCU to protect cardiomyocytes against oxidative damages. This finding provides novel insights into the involvement of miRNAs in oxidative stress in cardiomyocytes.

Abstract-A class of dynamic fair scheduling schemes based on the generalized processor sharing (GPS) fair service discipline, under the generic name code-division GPS (CDGPS), is proposed for a wideband direct-sequence code-division multiple-access (CDMA) cellular network to support multimedia traffic. The CDGPS scheduler makes use of both the traffic characteristics in the link layer and the adaptivity of the wideband CDMA physical layer to perform fair scheduling on a time-slot by time-slot basis, by using a dynamic rate-scheduling approach rather than the conventional time-scheduling approach. Soft uplink capacity is characterized for designing efficient CDGPS resource allocation procedure. A credit-based CDGPS (C-CDGPS) scheme is proposed to further improve the utilization of the soft capacity by trading off the short-term fairness. Theoretical analysis shows that, with the C-CDGPS scheme, tight delay bounds can be provided to delay-sensitive traffic, and short-term unfairness can be bounded so that long-term weighted fairness for all users can still be satisfied. Simulation results show that bounded delays, increased throughput, and long-term fairness can be achieved for both homogeneous and heterogeneous traffic.Index Terms-Code-division multiple-access (CDMA), creditbased scheduling, dynamic fair scheduling, generalized processor sharing (GPS), quality-of-service (QoS), soft capacity.

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