Neuron stem cell NLRP6 sustains hippocampal neurogenesis to resist stress-induced depression

Neurogenesis decline in hippocampal dentate gyrus (DG) participates in stress-induced depressive-like behaviors, but the underlying mechanism remains poorly understood. Here, we observed low-expression of NOD-like receptor family pyrin domain containing 6 (NLRP6) in hippocampus of stress-stimulated mice, being consistent with high corticosterone level. NLRP6 was found to be abundantly expressed in neural stem cells (NSCs) of DG. Both Nlrp6 knockout (Nlrp6-/-) and NSC-conditional Nlrp6 knockout (Nlrp6CKO) mice were susceptible to stress, being more likely to develop depressive-like behaviors. Interestingly, NLRP6 was required for NSC proliferation in sustaining hippocampal neurogenesis and reinforcing stress resilience during growing up. Nlrp6 deficiency promoted esophageal cancer-related gene 4 (ECRG4) expression and caused mitochondrial dysfunction. Corticosterone as a stress factor significantly down-regulated NLRP6 expression, damaged mitochondrial function and suppressed cell proliferation in NSCs, which were blocked by Nlrp6 overexpression. ECRG4 knockdown reversed corticosterone-induced NSC mitochondrial function and cell proliferation disorders. Pioglitazone, a well-known clinical drug, up-regulated NLRP6 expression to inhibit ECRG4 expression in its protection against corticosterone-induced NSC mitochondrial dysfunction and proliferation restriction. In conclusion, this study demonstrates that NLRP6 is essential to maintain mitochondrial homeostasis and proliferation in NSCs, and identifies NLRP6 as a promising therapeutic target for hippocampal neurogenesis decline linked to depression.

SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade

Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both and . However, whether SHP099-mediated SHP2 inhibition retards tumor growth anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8IFN- T cells and the upregulation of cytotoxic T-cell related genes including , which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.

Efficacy of periprocedural bivalirudin infusion in patients with chronic total occlusion lesion undergoing percutaneous coronary intervention / 中华心血管病杂志

Objective@#To investigate the efficacy of periprocedural use of bivalirudin for patients with chronic total occlusion(CTO) lesion undergoing percutaneous coronary intervention(PCI) therapy. @*Methods@#In this randomized controlled study, 74 patients with CTO lesions confirmed by coronary angiography or CT angiography, hospitalized in the general hospital of Shenyang military region from September 2015 to December 2016, were randomly divided into unfractionated heparin(UFH) group (n=38) and bivalirudin group (n=36) by the random number table.Patients in the UFH group were treated with injection of UFH 5 000 U through the artery sheath catheter before coronary angiography,and the UFH was intravenously administered at 100 U/kg before PCI. Patients in the bivalirudin group received intravenous injection of bivalirudin (0.75 mg/kg) before coronary angiography, followed by intravenous infusion of 1.75 mg·kg-1·h-1 until at least 2 hours after the PCI. The values of the activated coagulation time (ACT) were measured,and the value was remained at 250 to 350 seconds during the PCI. The incidence rate of adverse events including hemorrhage events, no-reflow/slow flow, and contact thrombus in perioperative period were observed in all patients. In addition, the incidence rate of the major adverse cardiovascular events (MACE) including recurrent angina, heart failure, target vessel revascularization, cardiac death, non-fatal myocardial infarction,and stroke within 1 year follow-up period were also observed in the 2 groups. @*Results@#Baseline clinical and PCI data were similar between the 2 groups (all P>0.05). During the perioperative period, the incidence of the bleeding was significantly lower in the bivalirudin group than in the UFH group(5.6% (2/36) vs. 23.7% (9/38) , P=0.028).The incidence of no-reflow/slow flow was also significantly lower in the bivalirudin group than in the UFH group(0 vs. 15.8% (6/38) , P=0.025). There was no significant difference in the incidence of contact thrombosis between bivalirudin group and UFH group(8.3% (3/36) vs. 0, P=0.110). There was no cardiac death or non-fatal myocardial infarction in the 2 groups within 1 year after PCI, and there was no significant difference in the incidence of MACE in 1 year follow-up after operation between bivalirudin group and UFH group (11.1% (4/36) vs. 21.1% (8/38) , P=0.246). @*Conclusion@#The application of the anticoagulant bivalirudin during PCI in patients with CTO lesion can reduce the incidence of perioperative bleeding and no-reflow/slow flow, and does not increase the risk of MACE within 1 year after PCI.

Retracted: Umbelliferone reverses depression-like behavior in chronic unpredictable mild stress-induced mice via RIP140/NF-κB pathway.

The above article from IUBMB Life, published online on October 5th, 2016 in Wiley Online Library (http://wileyonlinelibrary.com), has been retracted by agreement between the authors, the Journal Editors-in-Chief, Dr. Angelo Azzi and Dr. William Whelan, and Wiley Periodicals, Inc. The retraction has been agreed because the article was submitted and approved for publication by Chunhua Ma and Long Hongyan without consent in any form by the named Corresponding Author, Kong Lingdong. REFERENCE: Chunhua, M., Lingdong, K., Hongyan, L. and Zhangqiang, M. (2016), Umbelliferone reverses depression-like behavior in chronic unpredictable mild stress-induced mice via RIP140/NF-κB pathway. IUBMB Life. doi:10.1002/iub.1570 © 2017 IUBMB Life, 69(9):767-767, 2017.

Study on Renal Protection of Gui-Zhi Decoction in Hyperuricemic Mice / 世界科学技术-中医药现代化

This study was aimed to investigate renal protective effects and mechanism of Gui-Zhi(GZ) decoction in hyperuricemic mice.Potassium oxonate was used to induce hyperuricemia mouse model.Mice were randomly divided into 6 groups,which were the blank control group,model group,allopurinol group (5 mg·kg-1) and GZ decoction group (900,1 799 and 3 598 mg·kg-1).Hematoxylin eosin staining was used to observe the histopathological changes of renal tissues in mice.Commercial assay kits were used to measure levels of uric acid (UA),creatinine (Cr) and blood urea nitrogen (BUN) in serum and urine,as well as the xanthine oxidase (XOD) activity in liver.Renal protein levels of urate transporter 1 (URAT1),glucose transporter 9 (GLUT9),ATP-binding cassette G member 2 (ABCG2),organic cation transporter 1 (OCT1),OCT2,organic cation/carnitine transporter 1 (OCTN1) and OCTN2 were detected by western blot.The results showed that compared with the model group,GZ decoction can obviously decrease serum levels of UA,Cr and BUN,increase urine levels of UA and Cr,resulting in the elevation of fractional excretion of UA in hyperuricemic mice.Additionally,GZ decoction obviously inhibited hepatic XOD activity in hyperuricemic mice.Furthermore,GZ decoction downregulated renal URAT1 and GLUT9 protein levels,upregulated renal ABCG2,as well as OCT1,OCT2,OCTN1 and OCTN2 protein levels in hyperuricemic mice.It was concluded that GZ decoction had hypouricemic and renal protective effects in hyperuricemic mice,which might be associated with the reduction of UA production via inhibiting hepatic XOD activity,promoting UA and other organic ion excretion via regulating renal organic ion transporter protein levels.

Compatibility of Banxia Houpo decoction on hepatic CYP450 and renal organicion transporters in mice / 中国中药杂志

By analyzing the related indicators [hepatic CYP450 subtype and renal organic anion and cation transporters (OATs and OCTs)], the present study investigated the effects of formula Banxia Houpo decoction principal drug pinellia, assistant drug magnolia, their compatibility and the principle of the whole decoction on the metabolism ability in the liver and the transport change in the kidney of mice. Biochemical and molecular (RT-PCR and western blotting) results indicated that pinellia increased activity and expression of hepatic Cyp2e1 and Cyp3a11 in mice, respectively. Pinellia and magnolia increased expression of renal OAT1, OAT3, OCT1 and OCT2 in mice, respectively. The compatibility of pinellia and magnolia, as well as Banxia Houpo decoction synergistically restrained the activated effect of pinellia on hepatic Cyp2e1, therefore avoiding liver peroxidation and reducing toxicity potential. The compatibility of this drug pair and Banxia Houpo decoction not only reduced activity and expression of hepatic Cyp3a11 to control drug metabolism speed, but also balanced the expression of renal OAT1/3 and OCT1/2 to enhance drug efficacy. The effect of compatibility of Banxia Houpo decoction was better than that of pinellia and magnolia pair, and the normal dosage was better than the high dosage. The present study proved the advantage of the compatibility of pinellia combined with magnolia and the principle of Banxia Houpo decoction, which related to hepatic CYP450 and renal organic ion transporters, and guided the clinical use of Banxia Houpo decoction to exert its toxicity reduction and efficacy enhancement.

Mangiferin promotes uric acid excretion and kidney function improvement and modulates related renal transporters in hyperuricemic mice / 药学学报

The effects of mangiferin on uric acid excretion, kidney function and related renal transporters were investigated in hyperuricemic mice induced by potassium oxonate. Mice were divided into normal control group, and 5 hyperuricemic groups with model control, 50, 100, and 200 mg x kg(-1) mangiferin, and 5 mg x kg(-1) allopurinol. Mice were administered by gavage once daily with 250 mg x kg(-1) potassium oxonate for seven consecutive days to create the model. And 3 doses of mangiferin were orally initiated on the day 1 h after potassium oxonate was given, separately. Serum uric acid, creatinine and urea nitrogon levels, as well as urinary uric acid creatinine levels were measured. Mouse uromodulin (mUMOD) levels in serum, urine and kidney were determined by ELISA method. The mRNA and protein levels of related renal transporters were assayed by RT-PCR and Western blotting methods, respectively. Compared to model group, mangiferin significantly reduced serum uric acid, creatinine and urea nitrogon levels, increased 24 h uric acid and creatinine excretion, and fractional excretion of uric acid in hyperuricemic mice, exhibiting uric acid excretion enhancement and kidney function improvement. Mangiferin was found to down-regulate mRNA and protein levels of urate transporter 1 (mURAT1) and glucose transporter 9 (mGLUT9), as well as up-regulate organic anion transporter 1 (mOAT1) in the kidney of hyperuricemic mice. These findings suggested that mangiferin might enhance uric acid excretion and in turn reduce serum uric acid level through the decrease of uric acid reabsorption and the increase of uric acid secretion in hyperuricemic mice. Moreover, mangiferin remarkably up-regulated expression levels of renal organic cation and carnitine transporters (mOCT1, mOCT2, mOCTN1 and mOCTN2), increased urine mUMOD levels, as well as decreased serum and kidney mUMOD levels in hyperuricemic mice, which might be involved in mangiferin-mediated renal protective action.

Antidepressant effect of Epimedium brevicornum extracts / 中草药

Objective To study antidepressant effects of Epimedium brevicornum extracts.Methods(Behavioral) despair models of male mice,tails suspension test(TST),and forced swimming test(FST) were used to evaluate the effects of E.brevicornum extracts on behavioral,monoamine oxidas(MAOA) and monoamine oxidase B(MAO-B) activities in brain and liver tissue,and MDA level in liver tissue of mouse.Reserpine antagonistic model was also used to investigate possible antidepressant mechanisms of E.brevicornum extracts.Results The extracts of E.brevicornum(25,50, 100,and 200 mg/kg) significantly reduced the duration of murine immobility in TST and FST,inhibited MAO-A and MAO-B activities in brain and liver of mice,and reversed the elevated liver MDA level in mice in TST.There was no significant amelioration in the decreases of body temperature in mice of Reserpine antagonistic model.Conclusion(E.brevicornum) extracts possesses the definite antidepressant properties.

Oxygen Free Radical Clearing Activity and Anti-lipid Peroxidation of Shengyaling Injection in Vitro / 中药新药与临床药理

Objective: To observe oxygen-free-radical clearing activity and anti-lipid peroxidation of Shengyaling injection in vitro. Method: In-vitro oxygen free radical generation system (OFRGS) and lipid peroxidation induced by OFRGS in the supernatant fluid of mice heart tissue homogenate were used to evaluate the anti-oxidation activity of Shengyaling injection. Result:Shengyaling injection cleared superoxidase anion free radical induced by hypoxanthine-xanthine oxidase system and hydroxyl free radical induced by fenton reaction system, and inhibited mice heart tissue lipid peroxidation induced by FRGS at a dose-dependent manner. Conclusion:Shengyaling injection possesses an anti-oxidation effect.

Effects of Processing on Antioxidation of Ramulus Cinnamomi / 中成药

Objective: To investigate the effects of processing on antioxidation of Ramulus Cinnamomi .Method: The oxygen free radicals generation system in vitro and mouse liver homogenate lipid peroxidation reaction induced by hydroxy free radicals were used to estimate the effects. Results: Aqueous extracts of different processed products of Ramulus Cinnamomi were stronger than the alcohol extracts in the scavenging superoxide anion (O 2 -), but weaker in the scavenging hydroxyl free radical (?OH) and the anti lipid peroxidation. There were some existed differences among the different processed products. Conclusion: The processing affected the anti oxidation of Ramulus Cinnamomi .