Inhibition of phosphodiesterase 4 attenuates aquapo-rin 4 expression and astrocyte swelling following cerebral ischemia/reperfusion injury / 中国药理学与毒理学杂志

OBJECTIVE To investigate the role of PDE4 inhibition in astrocyte swelling caused by cerebral ischemic/reperfusion(I/R)injury and the molecular mech-anisms.METHODS SD rats were subjected to 2 h of focal cerebral ischemia induced by middle cerebral artery occlusion/reperfusion(MCAO/R).Roflumilast(Roflu)was intraperitoneally injected 2 h after MCAO.At 24 h after reperfusion,a high-resolution MRI was performed and using the wet-dry weighting method to measure the water content.The oxygen-glucose deprivation/reoxygenation(OGD/R)model was established in primary astrocytes for 2 h.After 24 h of reoxygenation,CellMask? plasma membrane stain was used to label the plasma membrane to calculate cell volume.The protein expressions insides astrocytes and penumbra were detected by Western blot-ting.To investigate the role of Akt/FoxO3a in mediating the effect of Roflu on the expression of AQP4.The astro-cytes were treated with an Akt inhibitor MK2206 before treatment with Roflu and the activation of Akt,the expres-sion of AQP4 and cell volume were determined as described above.In addition,an IL-1β-stimulated cell model was established in astrocytes,the expression of AQP4 and the activation of Akt/FoxO3a were detected by Western blotting.The change of AQP4 expression inside astrocytes and penumbra were visualized by immunofluo-rescence staining.RESULTS Roflu reduced MCAO/R-induced water contents,the expression of AQP4 and the phsophorylation of Akt and FoxO3a in the brains of MCAO/R rats.Inhibition of PDE4 decreased the cell volume and the expression of AQP4 in primary astro-cytes subjected to OGD/R.PDE4 inhibition activated Akt/FoxO3a,and inhibition of Akt by MK2206 blocked the protective effect of Roflu against OGD/R induced astro-cyte swelling.PDE4B knocking down reduced the expres-sion of AQP4,while PDE4B overexpression reversed the effect of PDE4B siRNA in astrocytes.Roflu exert-ed similar protective effect in IL-1β-cultured astrocytes,and importantly overexpression of FoxO3a remarkably increased the expression of AQP4 in IL-1β-stimulated astrocytes.CONCLUSION Our findings indicate that PDE4 inhibition limits I/R-induced brain edema and astro-cyte swelling via the Akt/FoxO3a/AQP4 pathway.PDE4 inhibition is a promising strategy for the treatment of brain edema after I/R injury.

Guiqi Baizhu Prescription Combined with Oxaliplatin Protects Intestinal Barrier of Tumor-bearing Mice with Gastric Cancer by Regulation of VIP/cAMP/PKA/AQP Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the protective effect of Guiqi Baizhu prescription combined with oxaliplatin on the intestinal barrier of tumor-bearing mice with gastric cancer by regulating downstream aquaporin 3 （AQP3） and aquaporin 4 （AQP4） through the vasoactive intestinal peptide （VIP）/cyclic adenosine monophosphate （cAMP）/protein kinase A （PKA） signaling pathway. MethodThe gastric cancer cell lines MFC with a density of 1×107/mL were prepared into cell suspension. The tumor-bearing mouse model of gastric cancer was established by inoculating 0.2 mL cell suspension under the right axilla of mice. After successful modeling， mice were randomly divided into 5 groups， namely， model group， oxaliplatin group （10 mg·kg-1）， and high， medium， and low-dose oxaliplatin + Guiqi Baizhu prescription groups （17.68， 8.84， 4.42 g·kg-1）， with 10 mice in each group， and the remaining 10 mice were set as a blank group. Mice in each group were treated with Chinese medicine， oxaliplatin， or normal saline by gavage or intraperitoneal injection for 14 d. The next day after the last dose， blood was taken from the eyeball to separate serum and take colonic samples. Hematoxylin-eosin （HE） staining was used to observe the changes in tissue morphology. The content of D-lactate acid （D-LA） and diamine oxidase （DAO） in the serum was determined by enzyme-linked immunosorbent assay （ELISA）. The mRNA and protein expressions of VIP， cAMP， PKA， AQP3， and AQP4 were detected by Real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. ResultCompared with the blank group， the model group showed edema in the colonic submucosa， disordered arrangement of intestinal glands in the mucosal layer， loss of goblet cells， infiltration of inflammatory cells， and villus shedding. However， there were different degrees of improvement in each administration group. As compared with the blank group， the serum levels of DAO and D-LA in the model group were significantly increased （P<0.01）. As compared with the model group， the levels of DAO and D-LA in the high-dose oxaliplatin + Guiqi Baizhu prescription group and the level of D-LA in the medium-dose oxaliplatin + Guiqi Baizhu prescription group were decreased （P<0.05， P<0.01）. As compared with the oxaliplatin group， the levels of D-LA in the high and medium-dose oxaliplatin + Guiqi Baizhu prescription groups were decreased （P<0.05）， and the levels of DAO and D-LA in other administration groups were decreased as well， but the difference had no statistical significance. As compared with the blank group， the mRNA and protein expression levels of VIP， cAMP， PKA， AQP3， and AQP4 in the model group were significantly decreased （P<0.05， P<0.01）. As compared with the model group， the mRNA and protein expression levels of VIP， cAMP， PKA， AQP3， and AQP4 in each administration group were increased， and those in the high-dose oxaliplatin + Guiqi Baizhu prescription group were significantly increased （P<0.05， P<0.01）， while the protein expression level of cAMP in the medium-dose oxaliplatin + Guiqi Baizhu prescription group were increased （P<0.05）. As compared with the oxaliplatin group， the protein expression levels of cAMP in the high-dose oxaliplatin + Guiqi Baizhu prescription group were increased （P<0.05）， and the mRNA and protein expressions of these indexes in the other groups were also increased but the differences were not statistically significant. ConclusionGuiqi Baizhu prescription combined with oxaliplatin can regulate AQP3 and AQP4 through the VIP/cAMP/PKA signaling pathway to protect the intestinal barrier of tumor-bearing mice with gastric cancer.

Peripheral origin exosomal microRNAs aggravate glymphatic system dysfunction in diabetic cognitive impairment

Cognitive dysfunction is one of the common central nervous systems (CNS) complications of diabetes mellitus, which seriously affects the quality of life of patients and results in a huge economic burden. The glymphatic system dysfunction mediated by aquaporin-4 (AQP4) loss or redistribution in perivascular astrocyte endfeet plays a crucial role in diabetes-induced cognitive impairment (DCI). However, the mechanism of AQP4 loss or redistribution in the diabetic states remains unclear. Accumulating evidence suggests that peripheral insulin resistance target tissues and CNS communication affect brain homeostasis and that exosomal miRNAs are key mediators. Glucose and lipid metabolism disorder is an important pathological feature of diabetes mellitus, and skeletal muscle, liver and adipose tissue are the key target insulin resistance organs. In this review, the changes in exosomal miRNAs induced by peripheral metabolism disorders in diabetes mellitus were systematically reviewed. We focused on exosomal miRNAs that could induce low AQP4 expression and redistribution in perivascular astrocyte endfeet, which could provide an interorgan communication pathway to illustrate the pathogenesis of DCI. Furthermore, the mechanisms of exosome secretion from peripheral insulin resistance target tissue and absorption to the CNS were summarized, which will be beneficial for proposing novel and feasible strategies to optimize DCI prevention and/or treatment in diabetic patients.

Optic neuromyelitis in relation with juvenile idiopathic arthritis: A case report

Optic neuromyelitis (ONM), also called neuromyelitis optica spectrum (Neuromyelitis Optica Spectrum Disorders, NMOSD) is recognized as an inflammatory autoimmune demyelinating disease of the central nervous system, mediated by autoantibodies against the aquaporin-4 receptor (AQP4-IgG). It predominantly affects the optic nerves and the spinal cord.1-3 It is known that patients with immune disorders are more likely to present other autoimmune diseases, but the relation between juvenile idiopathic arthritis and ONM has not been completely described.5 In this paper, we report a case of a patient with juvenile idiopathic arthritis, presenting with a rapidly progressive neurological condition, who is treated with biological drugs.1-4

La neuromielitis óptica (NMO), también llamada espectro de la neuromielitis óptica (neuromyelitis optica spectrum disorders) se reconoce como una enfermedad inflamatoria, autoinmune, desmielinizante del sistema nervioso central, mediada por autoanticuerpos contra el receptor de acuaporina 4 (AQP4-IgG) que afecta predominantemente a los nervios ópticos y la médula espinal1-3. Es conocido que los pacientes con trastornos inmunitarios tienen más probabilidades de presentar otras enfermedades autoinmunes; sin embargo, no está completamente descrita la asociación entre artritis idiopática juvenil y NMO5. En este escrito se reporta el caso de una paciente que cursa con artritis idiopática juvenil, inició con compromiso neurológico rápidamente progresivo, y es tratada con medicamentos biológicos1-4.

Baicalin treats cerebral ischemia reperfusion-induced brain edema in rats by inhibiting TRPV4 and AQP4 of astrocytes / 中国中药杂志

This study aims to explore the pharmacodynamic effect of baicalin on rat brain edema induced by cerebral ischemia reperfusion injury and discuss the mechanism from the perspective of inhibiting astrocyte swelling, which is expected to serve as a refe-rence for the treatment of cerebral ischemia with Chinese medicine. To be specific, middle cerebral artery occlusion(suture method) was used to induce cerebral ischemia in rats. Rats were randomized into normal group, model group, high-dose baicalin(20 mg·kg~(-1)) group, and low-dose baicalin(10 mg·kg~(-1)) group. The neurobehavior, brain index, brain water content, and cerebral infarction area of rats were measured 6 h and 24 h after cerebral ischemia. Brain slices were stained with hematoxylin and eosin(HE) for the observation of pathological morphology of cerebral cortex after baicalin treatment. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the content of total L-glutathione(GSH) and glutamic acid(Glu) in brain tissue, Western blot to measure the content of glial fibrillary acidic protein(GFAP), aquaporin-4(AQP4), and transient receptor potential vanilloid type 4(TRPV4), and immunohistochemical staining to observe the expression of GFAP. The low-dose baicalin was used for exploring the mechanism. The experimental results showed that the neurobehavioral scores(6 h and 24 h of cerebral ischemia), brain water content, and cerebral infarction area of the model group were increased, and both high-dose and low-dose baicalin can lower the above three indexes. The content of GSH dropped but the content of Glu raised in brain tissue of rats in the model group. Low-dose baicalin can elevate the content of GSH and lower the content of Glu. According to the immunohistochemical staining result, the model group demonstrated the increase in GFAP expression, and swelling and proliferation of astrocytes, and the low-dose baicalin can significantly improve this situation. The results of Western blot showed that the expression of GFAP, TRPV4, and AQP4 in the cerebral cortex of the model group increased, and the low-dose baicalin reduce their expression. The cerebral cortex of rats in the model group was severely damaged, and the low-dose baicalin can significantly alleviate the damage. The above results indicate that baicalin can effectively relieve the brain edema caused by cerebral ischemia reperfusion injury in rats, possibly by suppressing astrocyte swelling and TRPV4 and AQP4.

Monoclonal Antibody-Based Treatments for Neuromyelitis Optica Spectrum Disorders: From Bench to Bedside / 神经科学通报·英文版

Neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) is a chronic, recurrent, antibody-mediated, inflammatory demyelinating disease of the central nervous system, characterized by optic neuritis and transverse myelitis. The binding of NMO-IgG with astrocytic aquaporin-4 (AQP4) functions directly in the pathogenesis of >60% of NMOSD patients, and causes astrocyte loss, secondary inflammatory infiltration, demyelination, and neuron death, potentially leading to paralysis and blindness. Current treatment options, including immunosuppressive agents, plasma exchange, and B-cell depletion, are based on small retrospective case series and open-label studies. It is noteworthy that monoclonal antibody (mAb) therapy is a better option for autoimmune diseases due to its high efficacy and tolerability. Although the pathophysiological mechanisms of NMOSD remain unknown, increasingly, therapeutic studies have focused on mAbs, which target B cell depletion, complement and inflammation cascade inactivation, blood-brain-barrier protection, and blockade of NMO-IgG-AQP4 binding. Here, we review the targets, characteristics, mechanisms of action, development, and potential efficacy of mAb trials in NMOSD, including preclinical and experimental investigations.

Monoclonal Antibody-Based Treatments for Neuromyelitis Optica Spectrum Disorders: From Bench to Bedside / 神经科学通报·英文版

Neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) is a chronic, recurrent, antibody-mediated, inflammatory demyelinating disease of the central nervous system, characterized by optic neuritis and transverse myelitis. The binding of NMO-IgG with astrocytic aquaporin-4 (AQP4) functions directly in the pathogenesis of >60% of NMOSD patients, and causes astrocyte loss, secondary inflammatory infiltration, demyelination, and neuron death, potentially leading to paralysis and blindness. Current treatment options, including immunosuppressive agents, plasma exchange, and B-cell depletion, are based on small retrospective case series and open-label studies. It is noteworthy that monoclonal antibody (mAb) therapy is a better option for autoimmune diseases due to its high efficacy and tolerability. Although the pathophysiological mechanisms of NMOSD remain unknown, increasingly, therapeutic studies have focused on mAbs, which target B cell depletion, complement and inflammation cascade inactivation, blood-brain-barrier protection, and blockade of NMO-IgG-AQP4 binding. Here, we review the targets, characteristics, mechanisms of action, development, and potential efficacy of mAb trials in NMOSD, including preclinical and experimental investigations.

Effect of Plantaginis Semen on Inflammatory Cytokines and mRNA and Protein Expressions of AQP4 in Colon Tissue of Diarrhea Rats / 中国实验方剂学杂志

Objective:To observe Plantaginis Semen's mechanism in treating diarrhea by observing the effect on inflammatory factors in serum and mRNA and protein expressions of aquaporin4 (AQP4) in colon tissue of diarrhea rats. Method:Senne Folium was orally administered to duplicate diarrhea rats. Sixty male SD rats were randomly divided into normal group, model group, hydrochlorothiazide group (9 mg·kg-1), and low, middle, and high-dose Plantaginis Semen groups (0.95, 1.9, 3.8 g·kg-1). Senne Folium (20 mL·kg-1) was intragastrically administered in 5 groups in the morning, except for normal group that was orally given the same dose of distilled water. In the afternoon, each treatment group was orally given the corresponding drugs, while normal group and model group were orally given the same dose of distilled water. The loose stool rate, average degree of loose stool, and diarrhea index were compared according to fecal traits and stool times after 14 days of treatment. The serum and colon tissue were collected to detect the contents of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP) in serum. Hematoxylin-eosin (HE) staining was used to observe the pathological morphological changes of colon tissue, and quantiative Real-time fluorescent quantitative polymerase chain reaction (Real-time PCR) and Western blot were used to detect the mRNA and protein expressions of AQP4 in colon tissue. Result:In the model group, the loose stool rate, average degree of loose stool, and diarrhea index were significantly increased (P<0.01), apoptosis and necrosis were observed in the epidermal cells of colonic mucosa, telangiectasia and congestion in lamina propria were obvious, and a few neutrophils were infiltrated, and the contents of TNF-α, IL-6 and CRP in serum increased (P<0.05, P<0.01), the mRNA and protein expressions of AQP4 significantly decreased (P<0.01). Compared with the model group, the loose stool rate, average degree of loose stool, and diarrhea index were significantly decreased in low, middle, and high-dose Plantaginis Semen groups (P<0.01), the apoptosis and necrosis of epidermal cells, telangiectasia and hyperemia and neutrophil infiltration in colonic mucosa were obviously improved, and the contents of TNF-α and CRP in serum significantly decreased (P<0.05, P<0.01), the mRNA and protein expressions of AQP4 increased （P<0.05, P<0.01）. Conclusion:Plantaginis Semen has a better antidiarrheal effect, and its mechanism may be related to inhibition of inflammatory reaction, repair of pathological damage of colonic mucosa, up-regulation of AQP4 expression and promotion of water and fluid metabolism.

Effect of aquaporin 4 gene knockout on neuropathic pain and its possible mechanism / 国际药学研究杂志

Objective: To investigate the effect of aquaporin 4(AQP4)in neuropathic pain and explore the rela- tionship with the activation of spinal astrocytes and release of proinflammatory cytokines. Methods: The effect of AQP4 gene knockout(KO)on the pain-related behavior was investigated using the sciatic nerve branch injury model(SNI)of AQP4 KO and wild type(WT)mice. The expression of astrocyte activation-related protein,glial fibrillary acidic protein(GFAP),and the level of proinflammatory cytokines,TNF-α and IL-6,all in the mouse spinal cord samples,were detect- ed by Western blot(WB)and ELISA,respectively. Results: After SNI surgery,compared with the WT group,a signifi- cant attenuation in mechanical allodynia was found in the KO group(P<0.01),however,no difference was detected be- tween two sham groups(Sham)of WT and KO mice(P>0.05). These results indicated that the AQP4 gene knockout re- lieved neuropathic pain. Fouteen days after SNI surgery,WB results showed that the GFAP level in mouse spinal cord was significantly higher in the WT-SNI group than in the WT-Sham group(P<0.01),whereas the GFAP level in the KOSNI group was significantly lower than that in the WT-SNI group(P<0.01). These results indicated that AQP4 KO inhib- ited activation of spinal astrocytes in SNI model mice. In addition,14 days after SNI surgery,ELISA results showed that the levels of mouse spinal cord proinflammatory cytokines,TNF-α and IL-6 in the WT-SNI group were significantly high- er than those in the WT-Sham group(P<0.05 and P<0.01,respectively),whereas the levels of TNF-α and IL-6 in the KO-SNI group were significantly lower than those in the WT-SNI group(P<0.05 and P<0.01,respectively). These re- sults indicated that AQP4 KO inhibited the level of mouse spinal cord proinflammatory cytokines in SNI model mice. Conclusion: The AQP4 gene knockout may relieve the neuropathic pain via the inhibition of the astrocyte activation and proinflammatory cytokine release.

Effect of 13-Methyltetradecanoicacid on brain edema after cerebral ischemia in rats / 中国药理学通报

Aim To investigate the effect of 13-methyl- tetradecanoic acid (13-MTD) on brain edema after cerebral ischemia in rats and its mechanism. Methods The model of middle cerebral artery occlusion (MCAO) was prepared by suture embolization method. Thirty minutes prior to the insertion of the embolus, tail vein injection of 13-MTD 40, 80, 120 nig • kg"1 (M40, M80, M120) was respectively performed. The negative control group was given an equal volume of liposomes. 6, 12 and 24 h after ischemia, neurological deficits were observed with Ixmga neurological deficit scores; brain infarct volume was observed with TTC staining; brain edema was calculated with AutoCAD image analysis software; brain water content was measured with brain dry weight; the blood-brain barrier (KB). AQP4 mRNA expression in the injured brain tissue was detected by KT-PCR. The expression of AQP4 protein in the injured brain tissues was detected by immunohistochemistry. Results 13-MTD could significantly improve the symptoms of neurological deficits in rats with cerebral ischemia, reduce the volume of cerebral infarction, decrease brain water content and cerebral edema, and down-regulate EB leakage, and up-regulate the expression of AQP4 in the ischemic brain tissues. Conclusion 13-MTD can reduce brain edema after cerebral ischemia in rats by regulating AQP4 expression.

Expression of aquaporin 2, aquaporin 3 and aquaporin 4 in renal medulla of Bactrian camel ( Camelus bactrianus ) / Expresión de acuaporina 2, acuaporina 3 y acuaporina 4 en la médula renal del camello bactriano ( Camelus bactrianus )

SUMMARY: Aquaporins (AQPs) are members of the aquaporin water channel family that play an important role in reabsorption of water from the renal tubular fluid to concentrate urine. Using immunohistochemical staining on paraffin sections, We studied expression of AQP2, AQP3 and AQP4 in renal medulla of Bactrian camel (Camelus bactrianus). The renal medulla of cattle (Bos taurus) acted as the control. Compared with the control, strong expression of AQP2 was observed at the apical plasma membrane and intracellular vesicles, in both the outer medullary collecting duct (OMCD) and the inner medullary collecting duct (IMCD) of camel. Strong expression of AQP3 was observed at the basolateral plasma membrane of the IMCD of camel. Strong AQP4 expression, however, was observed at the basolateral plasma membrane in the OMCD of camel. Moreover, moderate AQP4 expression was detected in endothelium of capillary in medullary region of camels, whereas very weak/absent expression was detected in endothelium of capillary of cattle. We concluded that expression of AQP2, AQP3 and AQP4 in the camel kidney showed some differences from cattle in renal trans-epithelial water transport. It may enhance our better understanding of special water metabolism mechanisms that enable camels to survive in extreme environments.

RESUMEN: Las acuaporinas (AQP) son miembros de las proteínas de transporte que desempeñan un papel importante en la reabsorción de agua del líquido tubular renal para concentrar la orina. Estudiamos la expresión de AQP2, AQP3 y AQP4 en la médula renal del camello bactriano (Camelus bactrianus) usando tinción inmunohistoquímica en secciones de parafina. La médula renal del bovino (Bos taurus) se usó como control. En comparación con el control, se observó una fuerte expresión de AQP2 en la membrana plasmática apical y vesículas intracelulares tanto en el conducto colector medular externo (CCME) como en el conducto colector medular interno (CCMI) del camello. Se observó una fuerte expresión de AQP3 en la membrana plasmática basolateral del CCMI del camello. También se observó una expresión fuerte de AQP4 en la membrana plasmática basolateral en el CCME de camello. Además, se detectó una expresión moderada de AQP4 en el endotelio de los capilares en la región medular de los camellos, mientras que en el endotelio de los capilares del bovino se detectó una expresión muy débil. Concluimos que la expresión de AQP2, AQP3 y AQP4 en el riñón de camello mostró algunas diferencias con el bovino en el transporte trans-epitelial de agua renal. El estudio podría mejorar nuestra comprensión de los mecanismos especiales del metabolismo del agua que permiten a los camellos sobrevivir en ambientes extremos.

A characteristic analysis of longitudinally extensive transverse myelitis in South Indian population: A cohort study 145 – 151

This study described the clinical and paraclinical features of south Indian patients with longitudinally extensive transverse myelitis (LETM) and contrasted the findings betweenaquaporin-4 positive versus negative patients. The subjects were recruited between2010 and 2013.The distinctive features among71 LETM patients were compared and it was observed that 56% of the total subjects were found to be AQP4-Ab positive. The ratio of female tomale was found to be higher in the AQP4-Ab positive group. Magnetic resonance imaging showed holocord involvement more commonly in AQP4-Abnegative than positive group. The presence of hypointense lesions did not correlate with severity. The main distinctive features between AQP4-Abpositive and negative cases include older onset age, higher proportion of female, low frequency of conus involvement and higher prevalence of coexisting autoimmune disorders in AQP4-Ab positive cases. Therewas no difference in attack severity, onset of optic neuritis, and spasms between the two groups. Our results suggest that the clinical and spinal cord neuro-imaging information can aid in distinguishing between the positive and negative group of patients with LETM. The early detection of AQP4-Ab positive status predicts the recurrence of LETM or occurrence of optic neuritis duringthe study period.

The effect of high dose albumin on permeability of blood-brain barrier in brain of rats after ischemic-reperfusion / 中华急诊医学杂志

Objective To determine the effect of high dose albumin on permeability of blood brain barrier (BBB) in brain of rats after ischemic-reperfusion (IR) in order to explore its possible mechanism.Methods Establishment of brain ischemic reperfusion rat model by using middle cerebral artery occlusion (MCAO).Medicine treatment was given by caudal vein injection after 2 hours of MCAO.Thirty-six healthy male SD rats were then randomly (random number) divided into 6 groups (n =6 in each):6 h and 24 h sham-operation groups (Group Sham:operation without ischemia),6 h and 24 h normal saline groups (Group NS:NS injection 5 ml/kg) and 6 h and 24 h albumin group (Group Alb:25 ％ Alb injection 1.25 g/kg).Six hours and 24 hours after the end of reperfusion,rats were measured by Zea-Longa score (neural function deficit) separately.Serum concentration of S100B was examined by the ELISA kit and Evans blue in brain tissue was detected by spectrophotometer.The level of AQP4 was examined by Western blot and immunohistochemistry.All data were analyzed by one-way analysis of variance (ANOVA),The intergroup comparisons were analyzed by the least-significant-difference (LSD) test by using SPSS version 17.0 software.Differences were considered statistically significant if P ＜ 0.05.Results Zea-Longa score significantly increased in both group NS and group Alb at 6 h and 24 h (P =0.000).However,there was no significant difference in ZEA-LONGA score of 6 h and 24 h between group Alb and group NS (P =1.000).The serum concentration of S100B in group NS 6 h was significantly lower than that in group Alb at 6h (196.67±20.11 vs 160.04±14.00,P=0.000),and at24h (2.45±0.07 vs.2.23±0.07,P=0.000).Furthermore,concentration of Evans blue in brain tissue in group Alb was significantly higher than that in group NS at both 6 h (0.97 ± 0.08 vs.0.74 ± 0.06,P =0.000) and 24 h (2.45 ± 0.07 vs.2.23 ± 0.07,P =0.000).The expression of AQP4 in brain tissue was higher in group Alb than that in group NS at both 6 h (0.72 ±.0.11 vs.0.57 ± 0.06,P ＜ 0.01) and 24 h (0.80 ± 0.03 vs 0.61 ± 0.02,P ＜0.01).Conclusions High dose albumin contribute slightly in improvement of neural deficit in rats after IR.On the contrary,it can also aggravate the IR injury,which increases brain edema then increase the permeability of BBB.The mechanism may be associated with over-expression of AQP4 in brain tissue.

Analysis of Clinical Features of Patients with Neuromyelytis Opica and Spectrum of Neuromyelytis Opica / 医学研究杂志

Objective To discuss the clinical characteristics of patients withclinical features of patients with neuromyelytis opica and spectrum of neuromyelytis opica(NMOSD) and neuromyelitis optica (NMO).Methods With a retrospective study,From February 2013 to September 2016,a total of 72 NMO patients in Navy General Hospital for diagnosis and treatment were selected as the NMO the NMO group and the other 72 patients of NMOSD patients were selected as the NMOSD group.The results of two groups of patients with general demographic data,ocular symptoms,spinal cord and brain MRI,influence NMO-IgG were recorded.Results There were no significant differences in gender and age compared between the two groups (P ＞ 0.05).The clinical characteristics,frequency and duration in the NMOSD group compared to the NMO group were significantly different (P ＜ 0.05).In the NMOSD group,there were 8 patients who were decreased vision,4 patients were visual field defect,3 patients were discoloration,5 patients were diplopia.While in the NMO group,32 patients were decreased visual acuity,14 patients were visual field defect,12 patients were color vision,21 patients were diplopia.There were statistically significant difference between the two groups (P ＜ 0.05).In the NMOSD group,there were 8 patients were MRI of the spinal cord were normal,64 patients were abnormal and 32 patients of brain lesions in the head MRI.In the NMO group,MRI of the spinal cord were all abnormal,and there were 28 patients were brain lesions in the head MRI.The serum positive rate of NMO group was 41.7％,and the serum positive rate of NMOSD group was 59.7％.The sensitivity of AQP4-Ab antibody to NMO was 44.4％,the specificity was 75％,the sensitivity of AQP4-Ab was 61.1％,and the specificity of NMOSD was 75％.Conclusion The NMOSD is more with female patients,the first symptom is more with the spinal cord that the gray matter involvement in the spinal cord,and the performance of complex,NMO-IgG antibody can be used as a support for NMOSD diagnosis.

Effect of hypercapnia on blood brain barrier in rats with severe hypoxic-ischemic brain injury / 临床麻醉学杂志

Objective To investigate the effect of hypercapnia on hypoxic-ischemic brain injury in rats.Methods Forty-eight adult male SD rats were randomly divided into three groups: sham group (group S), hypoxic ischemic group (group HI) and hypercapnia group (group HP), n=16 in each group.Levine`s model was used to cause hypoxic-ischemic brain injury.In group S, the left common carotid artery was separated without ligation for 1 h, then ventilation with air maintaining the normal levels of PaO2 and PaCO2 for 3 h.In group HI, the left common carotid artery was separated and ligated for 1 h, PaO2 was maintained at 30-49 mm Hg by ventilating with low concentration (11%-13%) O2 for 3 hours.Based on group HI, PaCO2 in group HP was maintain at 60-80 mm Hg by inhalation of mixture gas containing (11%-13%) O2-8%CO2-N2 for 3 hours.FITC-dextran was used to measure the permeability of blood-brain barrier, TUNEL staining were used to observe the changes in the structure of the cerebral cortex.The expressions of aquaporin AQP4 and RECA-1 in cerebral cortex were detected by immunofluorescence and western blot.Results The level of brain water content, permeability of blood brain barrier and AQP4 expression were significantly increased in group HP as compared with group S and group HI (P<0.05).The histopathologic damage,as well as neuronal apoptotic index were aggravated in group HP as compared with group HI (P<0.05).Conclusion Hypercapnia may aggravate the brain damage during severe hypoxic-ischemic brain injury.This may associate with the increased expression AQP4 and the damage of blood-brain barrier.

Research progress of aquaporin 1 and 4 in diabetic retinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

Diabetic retinopathy(DR), one of the most common retinal vascular disease, is one of the causes of blindness for people over the age of 50.In the early stage of DR, microvascular cells are damaged, expand, start to leak, form micro hemangioma, then show occlusion, and non-perfusion area come into being, eventually form new blood vessels because of ischemia and hypoxia of retina.Illness develop into proliferative diabetic retinopathy(PDR).With the aggravation of the disease, PDR can cause the formation of fibrovascular membrane, the more serious fibrillation of epiretinal membrane, resulting in traction retinal detachment(tRD).Present studies suggest that aquaporins, the essential component of new blood vessels, including aquaporin 1 and aquaporin 4, play a significant pole in the development of diabetic retinopathy, causing the destruction of blood retinal barrier, inducing retinal edema, even macular edema, and participating in the formation of retinal angiogenesis.

Attenuation mechanism of gamboges during processing based on inflammatory toxicity and AQP3, AQP4 protein and mRNA expressions in rat gastric and duodenal tissues / 中国中药杂志

To expand the clinical application of gamboges, it is necessary to study crude gamboges' toxicity after oral administration and attenuation mechanism during processing. In this study, crude gamboges' toxicity was judged by multiple assays, including inflammatory mediums [such as nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6)] released by macrophage RAW264.7, and pathological manifestations of rat stomach and duodenal tissues after oral administration with crude and processed gamboges. The attenuation mechanism during processing was studied by detecting AQP3, AQP4 protein and mRNA expression in rat gastric and duodenal tissues using immunohistochemical assay and real-time fluorescent quantitative PCR technique. According to the results, crude gamboges group showed promotion in release of NO, TNF-α and IL-6 by macrophage RAW264.7 in a dose-dependent manner; Compared with crude gamboges group, processed gamboges group showed reduction in release of NO and IL-6, with increase in TNF-α. Crude gamboges could cause rat diarrhea, white blood cells increase, lymphocytes decrease, hyperemia and edema in rat gastric mucosa, duodenal mucosal necrosis and inflammatory cells infiltration. All of these results proved that gamboges had the inflammatory toxicity in gastric and duodenal tissues after oral administration in a dose-dependent manner, which however reduced after processing. In addition to the inflammatory toxicity, the mRNA and protein expressions of aquaporin 3 (AQP3), aquaporin 4 (AQP4) in gastric and duodenal tissues of high-dose crude gamboges group were increased significantly (P<0.05), while the protein and mRNA expressions of AQP3, AQP4 were weakened in processed gamboges group. The results showed that AQP3, AQP4 protein and mRNA expressions were positively correlated with the inflammatory toxicity. In conclusion, down-regulation of AQP3, AQP4 protein and mRNA expressions may be one of attenuation mechanisms in processing gamboges.

Dynamic expression of AQP4 in early stageof ischemia/reperfusion rats and cerebral edema / 中国药理学通报

Aim To make a research of rats with focal cerebral ischemia/reperfusion injury on pathological changes in brain and the changes of AQP4 and related proteins, in order to explore the relationship between AQP4 and brain edema. Methods Adult male SD rats, weighting 250~300 g, were randomly divided in-to Sham group and cerebral ischemia/reperfusion ( I/R) injury model group. The I/R model group was di-vided into the I/R-6 h, 12 h, 24 h, 48 h-four time point groups. The animal model of the right MCA is-chemia/reperfusion was established by suture method in mature SD rats. The nerve symptom score was con-ducted in the corresponding time points. Then, the permeability of brain tissue was detected by EB stai-ning;TTC staining was conducted to observe the cere-bral infarction volume;the dry wet weight method was used to detect the changes of brain water content; im-munohistochemical( IHC) , WB and RT-PCR were ap-plied to detect the expression of AQP4 , and the related factors at different time points of the model rats after is-chemia-reperfusion around infarcts. Results Com-pared with the Sham group, then ever function score of the rats in I/R model groups were much higher. With the increase of the reperfusion time, the cerebral in-farction volume, brain tissue permeability and the brain water content were also increased. IHC results showed that AQP4 expression gradually rose with widen distribution. WB and RT-PCR results verified the in-creasing level of AQP4 expression. The detection of the related proteins expression showed apparent changes. The expression of MMP-9 was increased, while the Oc-cludin and JAM-1 expression showed a decreasing trend. The I/R-48 h model group showed the most ob-vious differences in the expression of the related pro-teins and mRNA ( P <0. 01 vs Sham, respectively ) . Conclusion Accompanied with the aggravating cere-bral injury after cerebral ischemia/reperfusion, the ex-pression of AQP4 and MMP-9 level were activated, while the degradation of TJPs, Occludin and JAM-1, was increased. These factors are combined to make the formation of brain edema. This study makes a further research on the formation mechanism of the early stage for cerebral edema on I/R model and offers a potential for intervention in the filed of looking for a reliable drug therapy on cerebral edema.

Clinical features of late-onset neuromyelitis optica spectrum disorders / 天津医药

Objective To explore the clinical features of late-onset neuromyelitis optica spectrum disorders (LON?MOSD). Methods A retrospective analysis was performed to evaluate 61 patients with LONMOSD admitted to our hospital from January 2010 to May 2015. Results (1) The median age at onset was 57 (53, 63) years, male/female was 1∶3.7. Thirty-two patients (52.5%) had transverse myelitis (TM) and 16 patients (26.2%) had optic neuritis (ON) at the disease onset. Fifty-one patients (83.6%) experienced recurrent attacks. Forty patients (65.6%) showed abnormal brain magnetic resonance imag?ing (MRI). Spinal cord MRI showed more frequently present in thoracic regions (39.3%). (2) There were no significant differ?ences in clinical features between AQP-4 seropositive and seronegative groups. (3) By Spearman analysis, it was obvious that EDSS scores at acute phase and remission were positively correlated to AQP-4 antibody levels (rs=0.389, P0.05;rs=0.096, P>0.05). Conclusion LONMOSD patients are more prone to present with TM at onset and have more lesions in thoracic spinal cord and brain. The AQP-4 antibody titres can indicate the severity of disease in acute phase.

Effects of IL-1β on expression of AQP4 and its role in attack of seizure / 实用医学杂志

Objective To observe the effects of interleukin-1β (IL-1β) and pentylenetetrazol (PTZ) induced acute epilepsy and the dynamic expression of aquaporin-4 (AQP4) in hippocampus. To explore the role of IL-1β in the pathogenesis of epilepsy by regulating AQP4. Methods All rats were randomly divided into control group, IL-1β group, PTZ group, IL-1ra + PTZ group and dexamethasone + PTZ group. Observe the behavior of the rats within 60 minutes after injection and record seizure score in each group. Then immunohistochemistry and RT-qPCR were used to detect the expression of AQP4 at at 6 , 12, 24 and 36 h. Results Almost of rats in IL-1β group and PTZ group showed severe degree seizure. The rats in control group and dexamethasone + PTZ group showed no obvious seizure. The seizure of rats were more remarkable serious in PTZ group than that in the IL-1ra + pentylenetetrazole group (P < 0.05). Immunohistochemistry and RT-qPCR Show: the expression of AQP4 in hippocampus in PTZ group increased gradually after 12 h (P < 0.05), then reached in the peak after 24 h (P < 0.001). The expression of AQP4 in IL-1ra + PTZ group was lower compare with PTZ group in each time (P < 0.05). Although the expression of AQP4 in dexamethasone + PTZ group higher than the control group, it was not significantly different (P < 0.05). Conclusion The proinflammatory cytokine IL-1β break the balance of water in brain and increasing the concentration of extracellular excitatory amino acids or ions by upregulate the expression of AQP4 in order to promote the excitatory of neurons.