Methamphetamine (METH) addiction is a chronic brain disorder characterized by intense drug cravings and high relapse rates. Traditional Chinese medicines (TCM) have shown efficacy in treating METH addiction via TrkB/ERK signaling. However, the role of Polygalae Radix (PR), a neuropharmacological active TCM, in METH addiction remains unclear. This study examined the effects of PR (25, 50, and 100 mg/kg) on locomotor activity in mice and its impact on METH-induced behavioral sensitization (BS) at different stages. Western blotting (WB) assessed TrkB and ERK expression across brain regions. PR (25 and 50 mg/kg) alone had no effect on locomotor activity in mice, whereas 100 mg/kg significantly reduced locomotor activity. PR (25 and 50 mg/kg) administered during the development phase inhibited METH-induced locomotor activity, but its administration during the expression phase had no impact. Continuous PR (25 and 50 mg/kg) administration throughout the entire process prevented METH-induced BS in mice. WB analysis revealed that PR alone elevated ERK in the prefrontal cortex, nucleus accumbens (NAc), caudate putamen (CPu), and TrkB in the CPu. During the development phase, PR inhibited METH-induced TrkB/ERK increases in the CPu, whereas, during the expression phase, ERK elevation in the CPu was mitigated. Continuous PR administration blocked METH-induced TrkB/ERK increases in the CPu and ERK levels in the NAc. These findings indicate that PR attenuates METH-induced BS and locomotor activity during the developmental phase through the TrkB/ERK pathway in the CPu, highlighting its therapeutic potential for METH addiction.

Drug addiction is a chronic and recurrent brain disease. Our previous research demonstrated that the B subunit of phosphatase 2A (PP2A/B) increased in the dorsal striatum (DS) of methamphetamine (METH)-sensitized mice. Interestingly, studies indicate that PP2A/B can also interplay with microRNA (miRNA). In this study, we investigated seven miRNAs that have been reported to potentially interplay with PP2A/B, and our results showed that miR-222-3p significantly decreased in the DS of METH-sensitized mice. We further used dual-luciferase reporter assay to clarify the regulatory relationship between miR-222-3p and PP2A/B mRNA, and we also constructed adeno-associated virus (AAV) to overexpress miR-222-3p in the DS to further examine the influence of miR-222-3p on METH-induced behavioral sensitization. Our results demonstrated that miR-222-3p did interplay with PP2A/B mRNA and overexpressed miR-222-3p could significant attenuate METH-induced behavioral sensitization. At the same time, overexpressed miR-222-3p could reverse the change in the PP2A-AKT signaling pathway in the DS of METH-sensitized mice. Our results indicate that overexpression of miR-222-3p in the DS might attenuate METH-induced behavioral sensitization through the PP2A-AKT signaling pathway.

Drug addiction, including methamphetamine (METH) addiction, is a significant public health and social issue. Perturbations in intracellular Ca2+ homeostasis are associated with drug addiction. K+-dependent Na+/Ca2+ exchanger 2 (NCKX2) is located on neuronal cell membranes and constitutes a Ca2+ clearance mechanism, with key roles in synaptic plasticity. NCKX2 is associated with motor learning, memory, and cognitive functions. However, the role of NCKX2 in METH addiction remains unclear. In this study, we investigated the expression levels of NCKX2 in four addiction-related brain regions: the prefrontal cortex (PFc), nucleus accumbens (NAc), dorsal striatum (DS), and hippocampus (Hip) in a C57/BL6 mouse model of METH-induced conditioned place preference (CPP) and behavioral sensitization. Levels of NCKX2 were unchanged in these brain regions in mice with METH-induced CPP but were decreased in the PFc and NAc of mice with METH-induced behavioral sensitization. Adeno-associated virus (AAV)-mediated overexpression of NCKX2 in the PFc attenuated the expression phase of METH-induced behavioral sensitization in mice, whereas AAV-mediated knockdown of NCKX2 enhanced the effects of METH. Collectively, our results suggest that NCKX2 is involved in METH-induced behavioral sensitization but does not affect conditioned reward-related memory, highlighting the potential of NCKX2 as a molecular target for studying the mechanisms underscoring METH addiction.

Drug addiction can be described as a chronic and relapsing brain disease. Behavioral sensitization is common animal model in the study of addiction and N-Methyl-D-aspartate subtype of glutamate receptor (NMDAR) is believed play key role in this process. LY235959 is a competitive NMDAR antagonist, however, its effect on methamphetamine (METH)-induced behavioral sensitization is not been reported yet. In this study, we choose three doses (0.33 mg/kg, 1.0 mg/kg, and 3.0 mg/kg) of LY235959 to investigate its effect on locomotor activity, METH-induced behavioral sensitization and different phases of it in C57/BL6 mice. We also used western blotting to examine the PP2A/B - AKT cascade which had been proved involved in METH-induced behavioral sensitization in the dorsal striatum (DS). The results showed that only 0.33 mg/kg LY235959 increased locomotor activity dramatically, however, 1.0 mg/kg and 3.0 mg/kg of LY235959 could attenuate METH-induced behavioral sensitization markedly. We also found that LY235959 only disrupted the development phase of METH-induced behavioral sensitization and the following western blotting results further indicated that PP2A/B - AKT cascade might involve in this process. Taken together, these results indicated that LY235959 attenuates development phase of METH-induced behavioral sensitization through the PP2A/B - AKT cascade in the DS.

Four undescribed sulfoxide-containing derivatives, sinkiangenoxides A and B, (2 Z , 4 E )-sinkiangenoxide C, and (2 E , 4 E )-sinkiangenoxide C ( 1 - 4 ), and one known compound, 1-(methylthio)propyl ( E )-1-propenyl disulfide ( 5 ), were isolated from the resin of Ferula sinkiangensis . Their structures were determined based on spectroscopic methods, including IR, UV, HRESIMS, NMR, and CD analysis. Compounds 2 - 4 showed moderate cytotoxic activities against four human cancer cell lines with IC (50) values ranging from 15.0 to 40.3 mu M. Sinkiangenoxide B ( 2 ) was shown to induce apoptosis in HepG2 cells. In addition, compound 5 effectively attenuated lipopolysaccharide-induced nitric oxide release and TNF- alpha , IL-1 beta , IL-6, and IL-10 expression.

Drug addiction is a chronic recurrent brain disease characterized by compulsive drug use and a high tendency to relapse. We previously reported that the Ras-extracellular signal-regulated kinase (ERK)-ΔFosB pathway in the caudate putamen (CPu) was involved in methamphetamine-induced behavioral sensitization. Rap1, as an antagonist of Ras originally, was found to participate in neuronal synaptic plasticity recently, but the role of Rap1 in methamphetamine addiction is unclear. First, in this study, we constructed the acquisition, extinction and reinstatement of methamphetamine-induced conditioned place preference (CPP) in mice, respectively. Then, protein levels of Rap1, Ras and pERK/ERK in the prefrontal cortex (PFc), CPu and hippocampus of CPP mice on three phases were detected. We found that protein levels of Rap1, Ras and pERK/ERK in the CPu were significantly increased after repeated methamphetamine administration, as well as Rap1 and pERK/ERK in the hippocampus. However, protein levels of Rap1 and pERK/ERK in the CPu were decreased on the reinstatement of CPP mice. Therefore, Rap1 and Ras in the CPu and Rap1 in the hippocampus may participate in the regulation of the acquisition of methamphetamine-induced CPP in mice by activating ERK. Moreover, Rap1-ERK cascade in the CPu contributes to both the acquisition and reinstatement of methamphetamine-induced CPP in mice.

Morphine is one of the most abused drugs in the world, which has resulted in serious social problems. The frontal association cortex (FrA) has been shown to play a key role in memory formation and drug addiction. N-Methyl-d-aspartate receptors (NMDARs) are abundant in the prefrontal cortex (PFc) and much evidence indicates that GluN2B-containing NMDARs are involved in morphine-induced conditioned place preference (CPP). However, the function of GluN2B in the FrA during morphine-induced CPP has yet to be fully investigated. In the present work, a CPP animal model was employed to measure the expression of phosphorylated (p-) GluN2B (Serine; Ser 1303) in the FrA and NAc in different phases of morphine-induced CPP. We found that p-GluN2B (Ser 1303) was increased in the FrA during the development and reinstatement phases but unchanged in the extinction phase. The use of ifenprodil, a GluN2B-specific antagonist, to block the activity of GluN2B in the two phases attenuated morphine-induced CPP and reinstatement. Furthermore, ifenprodil also blocked morphine-induced upregulation of p-GluN2B (Ser 1303) in the FrA in both phases. These results indicate that GluN2B-containing NMDARs in the FrA may be involved in the regulation of morphine-induced CPP and reinstatement.

Two new components, stelltian A (1) and stelltian B (2), along with two known compounds, neoboutomannin (3) and 6,9-O-dedimethyltrigonostemone (4), were isolated from the aerial parts of Stelleropsis tianschanica. Their structures were clarified using 1D and 2D NMR spectroscopic methods and the HRESIMS spectra. All the isolated compounds were profiled for their antitumor activities against human breast cancer cells (MCF-7) and HeLa cells. Among them, compounds 2?4 have a moderate cytotoxic activity.

Mycoplasma pneumoniae infection may induce a systemic hypercoagulable abnormality, like organ embolism and infarction. Indexes of blood coagulation and C-reactive protein (CRP) have been reported different between healthy people and mycoplasma pneumoniae pneumonia (MPP) patients, but this difference in MPP patients with different chest imaging findings has rarely been reported. We performed a retrospective study of 101 children with MPP and 119 controls, combined with radiological examination and blood tests, to compare the blood coagulation and CRP level among MPP children with different chest imaging findings. For the MPP children with different chest imaging findings, there were significant differences in CRP, fibrinogen (FIB) and D-dimer (D-D) levels among subgroups (P = .004, P = .008 and P < .001 respectively). The CRP level in group of interstitial pneumonia was significantly higher than that in groups of bronchopneumonia and hilar shadow thickening (P = .003 and P = .001 respectively). And the FIB and D-D values in group of lung consolidation were significantly higher than that in the other 3 groups (all P < .05). When compared with controls, the white blood cell, CRP, FIB, and D-D levels in MPP children were significantly higher, and the activated partial thromboplastin time and thrombin time levels were significantly lower (all P < .05). Our results showed that CRP level changed most significantly in group of interstitial pneumonia, whereas FIB, D-D levels changed most significantly in the lung consolidation group.

Methamphetamine (METH) abuse has become a serious social problem. Behavioral sensitization is a common behavioral paradigm used to study the neurobiological mechanism that underlies drug addiction. Our previous study demonstrated that the activity of protein phosphatase 2A (PP2A) and the level of phosphorylated extracellular signal-related kinase 1/2 (p-ERK 1/2) are increased in the caudate putamen (CPu) of METH-sensitive mice. However, the relationship between PP2A and ERK 1/2 in METH-induced behavioral sensitization remains unknown. Some studies have indicated that Raf1 may be involved in this process. In this study, LB100, a PP2A inhibitor for treating solid tumors, was first used to clarify the relationship between PP2A and ERK 1/2. In addition, Western blot was used to examine the levels of p-Raf1 (Ser 259) and p-ERK 1/2 (Thr 202/Tyr 204) in the CPu, hippocampus (Hip) and nucleus accumbens (NAc). Our results showed that 2 mg/kg LB100 significantly attenuated METH-induced behavioral sensitization. Furthermore, Western blot analysis revealed that pretreatment with 2 mg/kg LB100 remarkably reversed METH-induced reduction of p-Raf1, as well as upregulation of p-ERK 1/2 in the CPu. Taken together, these results indicate that PP2A plays an important role in METH-induced behavioral sensitization and phosphorylates ERK 1/2 by dephosphorylating p-Raf1 in the CPu to further regulate METH-induced behavioral sensitization.

Corrosion continues to be a major challenge in developing supercritical water-cooled reactor and supercritical water oxidation systems. Corrosion behaviors of candidate alloy materials used in these environments are significantly affected by the properties of oxides formed on alloy surfaces. This work presents a comprehensive review of the oxidation processes and involved chemical reactions of corrosion-resistant alloys in supercritical water. The oxidation process of an alloy in supercritical water is proposed to have two stages, and chemical reactions at these two stages are described in detail. The transitions of Cr/Ni/Fe oxides and the formation mechanism of oxide film are analyzed comprehensively. Moreover, the diffusion property, protection effect, and stability of oxides in supercritical water are summarized systematically.

Protein phosphatase 2A (PP2A) is an evolutionarily conserved serine/threonine phosphatase abundant in mammalian brains. Although recent research has revealed that PP2A plays important roles in cocaine and morphine addictions, the mechanism of action of PP2A in methamphetamine (METH) addiction is unclear. LB100 is a PP2A inhibitor able to penetrate the blood-brain barrier (BBB); the role of LB100 in METH-induced conditioned place preference (CPP) has not yet been reported. Here, we explored the roles of LB100 in distinct phases of METH-induced CPP. Our findings indicate that LB100 inhibits the acquisition and reinstatement of METH-induced CPP and promotes the extinction of METH-induced CPP. Moreover, LB100 alone did not affect the natural preference of mice. Intriguingly, repeated administration of LB100 in the extinction phase did not inhibit the reinstatement of METH-induced CPP, but LB100 injection prior to METH administration could significantly block it. Taken together, we found that LB100 has significant effects on different phases of METH-induced CPP, and is therefore, a potentially promising therapeutic for METH addiction.

Drug addiction can be described as a chronic and relapsing brain disease. Behavioral sensitization is believed to share similar mechanisms with relapse. Our previous studies have demonstrated that ifenprodil could attenuate methamphetamine (METH)-induced behavioral sensitization. However, the mechanism underlying this process has not been fully investigated. Protein phosphatase 2A (PP2A) is a conserved serine/threonine protein phosphatase that has been linked to many neurological diseases; however, there are few reports about PP2A in the context of drug addiction. In this study, we measured the level of phosphorylated (p-) GluN2B (Serine; Ser 1303), PP2A/B (a regulatory subunit of PP2A), and PP2A/C (a catalytic subunit of PP2A) in different brain regions such as the prefrontal cortex (PFc), nucleus accumbens (NAc), dorsal striatum (DS), and hippocampus (Hip). We also used ifenprodil, a selective antagonist of GluN2B to clarify the relationship between GluN2B and PP2A. The results showed that METH increased the level of p-GluN2B (Ser 1303) and PP2A/B in the DS and ifenprodil blocked this increase. We further examined the interaction between PP2A/B and PP2A/C in the DS and found that METH treatment increased the interaction between PP2A/B and PP2A/C, which was also blocked by ifenprodil. Then, we explored the pathway downstream of PP2A in the DS and found that p-AKT (Threonine; Thr 308) but not p-AKT (Ser 473) was dephosphorylated by PP2A. Taken together, these results indicated that the GluN2B-PP2A-AKT cascade was involved in METH-induced behavioral sensitization.

Five undescribed sesquiterpene coumarins, one undescribed coumarin derivative, and twenty-five known analogues, were isolated from the resin of Ferula sinkiangensis K.M.Shen. The planar structures and relative configurations of the undescribed compounds were determined by NMR experiment and HRESIMS data. The absolute configurations were established by Electrostatic Circular Dichroism method. Among these analogues, Sinkiangenol E showed the best cytotoxic activity against HeLa cervical cancer cells. Annexin V-FITC/PI staining indicated that Sinkiangenol E induced apoptosis in HeLa cells. Cell cycle analysis showed Sinkiangenol E arrested cell cycle at G0/G1 phase. Western blot results proved that Sinkiangenol E affected apoptosis-related and cell cycle regulation-related protein expression by activating the MAPK pathway.

The SNAP25 gene is involved in the development of antipsychotic-induced weight gain (AIWG) or metabolic syndrome during antipsychotics use in Americans and Europeans, but its role in Asians remains unknown. To identify common variants in SNAP25 associated with schizophrenia and evaluate their effects on AIWG and antipsychotic responses in Han Chinese individuals with schizophrenia, we conducted a two-stage case-control study of 3,243 patients and 6,154 healthy controls. 2128 inpatients in the replication stage have received conventional treatment with an antipsychotic monotherapy (Haloperidol, Olanzapine or Risperidone) for 10 weeks at least. Weight change, antipsychotic responses and metabolic indices change were assessed during treatments. Three SNPs were significantly associated with schizophrenia in samples (rs6039769, P = 6.64 × 10-7; rs3787283, P = 0.004283; rs3746544, P = 2.51 × 10-6). Of these, rs6039769 is a novel schizophrenia-associated SNP and is uncorrelated with the other two variants, which have previously been associated with schizophrenia in European-ancestry samples. Rs6039769 was significantly associated with AIWG (P < 0.001), but not with antipsychotic responses or metabolic indices. Another two SNPs were not associated with AIWG or antipsychotic responses or metabolic indices. Overall, there were significant differences in antipsychotic responses and metabolic indices among the three treatment groups. Our findings suggest that SNAP25 gene may contribute to the susceptibility of AIWG and even metabolic disturbances. A prior identification of high-risk of patients with rs6039769 would contribute to a better precision of the pharmacological treatment.

PURPOSE:To assess the efficacy and safety of tigecycline in treating complicated intra-abdominal infections (cIAIs) in hospitalized patients in China.PATIENTS AND METHODS:A Phase IV, multicenter, randomized, double-blinded, active-controlled, non-inferiority study was conducted. Hospitalized cIAI patients ≥18 years of age were randomized (1:1) to receive intravenous tigecycline (initial dose 100 mg, then 50 mg q12h) or imipenem/cilastatin (500 mg/500 mg or adjusted for renal dysfunction, q6h) for 5-14 days. The primary end point was clinical response for clinically evaluable (CE) subjects at test-of-cure (TOC) assessment.RESULTS:Four hundred and seventy subjects were randomized; 232 in the tigecycline and 231 in the imipenem/cilastatin group were treated. Tigecycline was non-inferior to imipenem/cilastatin with respect to clinical response at TOC for all CE subjects, ie, the lower bound of the two-sided 95% CI (-12.0%, -1.4%) for the treatment difference in cure rate, tigecycline (89.9%) minus imipenem/cilastatin (96.6%), was >-15%. As non-inferiority was concluded in the CE population, superiority of tigecycline over imipenem/cilastatin and superiority of imipenem/cilastatin over tigecycline were tested on the CE and the modified intent-to-treat (mITT) populations according to pre-specified statistical criteria, and neither could be demonstrated (the cure rate was 82.8% vs 88.7%, difference -6.0% [-12.8%, 0.8%], for the mITT population). The subject-level microbiological response rate at TOC for the microbiologically evaluable population was 88.0% (110/125) vs 95.3% (102/107, difference -7.3% [-15.2%, 0.5%]). Nausea, drug ineffectiveness, postoperative wound infection, vomiting, and pyrexia were the most common adverse events in tigecycline-treated subjects; pyrexia, nausea, vomiting, and increased alanine aminotransferase and aspartate aminotransferase levels were most common in imipenem/cilastatin-treated subjects; none were unanticipated.CONCLUSION:Tigecycline was non-inferior to imipenem/cilastatin in treating hospitalized adult patients with cIAI. Superiority of tigecycline over imipenem/cilastatin or imipenem/cilastatin over tigecycline could not be demonstrated. Safety was consistent with the known profile for tigecycline.CLINICALTRIALSGOV IDENTIFIER:NCT01721408.

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is reported as a promising anti-cancer therapeutic agent. Nevertheless, a variety of cancer cells, including human malignant glioma cells, are resistant to TRAIL treatment, indicating that it is necessary to find effective strategies to overcome the TRAIL resistance. Linarin (LIN), a natural flavonoid compound in Flos Chrysanthemi Indici (FCI), has been exhibited to exert various pharmacological activities, including anti-cancer. Here in our study, we found that non-cytotoxic doses of LIN (5μM) dramatically potentiated TRAIL (80ng/ml)-induced cytotoxicity (52.36±1.58%) and apoptosis (68.50±1.23%) using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and flow cytometry assays, respectively, in human glioma cells of U87MG. Apoptosis was evidenced by enhanced cleavage of Caspase-8/-9/-3 and poly (ADP-ribose) polymerase (PARP), and reduced anti-apoptotic proteins, including B-cell leukemia/lymphoma 2 (Bcl-2), mantle cell lymphoma (Mcl)-1, and Survivin. Moreover, both intrinsic and extrinsic apoptosis pathways were included in apoptosis induced by LIN and TRAIL co-treatment, along with high release of Cyto-c into cytoplasm and enhancement of fas-associated protein with death domain (FADD), death-inducing signaling complex (DISC), death receptor 4 (DR) 4 and DR5, respectively. Reactive oxygen species (ROS) generation, up to 39.86±2.32%, was also highly triggered by TRAIL and LIN combinational treatment, which was accompanied with high phosphorylation of c-Jun-N-terminal kinase (JNK). In vivo, TRAIL and LIN double treatment significantly reduced the tumor growth using xenograft tumor model through inducing apoptosis. We demonstrated that combining LIN with TRAIL treatments might be effective against TRAIL-resistant glioma cells through inducing apoptosis regulated by ROS generation.

Malignant glioma are linked to a high mortality rate. Therefore, it is necessary to explore and develop effective therapeutic strategy. Oroxyloside is a metabolite of oroxylin A. However, its inhibitory effects on cancer are little to be known. In the present study, we investigated the effects of oroxyloside on cell proliferation, migration, and apoptosis in vitro and in vivo in human glioma. The results indicated that oroxyloside significantly suppressed the proliferation of human glioma cells through inducing cell cycle arrest at G0/G1 phase through reducing Cyclin D1 and cyclin-dependent kinase 2 (CDK2) while enhancing p53 and p21 expressions. In addition, the migration of glioma cells was dramatically inhibited by oroxyloside in a dose-dependent manner, which was related to its modulation on extracellular matrix (ECM), as evidenced by up-regulated E-cadherin, and metastasis-associated protein 3 (MTA3), whereas down-regulated N-cadherin, Vimentin, Twist, alpha-smooth muscle actin (α-SMA) and Syndecan-2. Furthermore, oroxyloside treatment markedly induced apoptosis in glioma cells through improving Caspase-9, Caspase-3 and PARP cleavage, accompanied with high release of cytochrome c (Cyto-c) into cytoplasm and subsequently increase of apoptotic protease-activating factor 1 (Apaf-1). In vivo, oroxyloside administration significantly inhibited the glioma cell xenograft tumorigenesis through various signaling pathways, including suppression of Cyclin D1/CDK2 and ECM pathways, as well as potentiation of p53/p21 and Caspases pathways. Together, the findings above illustrated that oroxyloside, for the first time, was used as a promising candidate against human glioma.

Voltage-gated L-type calcium channels (VLCC) are distributed widely throughout the brain. Among the genes involved in schizophrenia (SCZ), genes encoding VLCC subunits have attracted widespread attention. Among the four subunits comprising the VLCC (α − 1, α −2/δ, β and γ), the γ subunit that comprises an eight-member protein family is the least well understood. In our study, to further investigate the risk susceptibility by the γ subunit gene family to SCZ, we conducted a large-scale association study in Han Chinese individuals. The SNP rs17645023 located in the intergenic region of CACNG4 and CACNG5 was identified to be significantly associated with SCZ (OR = 0.856, P = 5.43 × 10−5). Similar results were obtained in the meta-analysis with the current SCZ PGC data (OR = 0.8853). We also identified a two-SNP haplotype (rs10420331-rs11084307, P = 1.4 × 10−6) covering the intronic region of CACNG8 to be significantly associated with SCZ. Epistasis analyses were conducted and significant statistical interaction (OR = 0.622, P = 2.93 × 10−6, Pperm < 0.001) was observed between rs192808 (CACNG6) and rs2048137 (CACNG5). Our results indicate that CACNG4, CACNG5, CACNG6 and CACNG8 may contribute to the risk of SCZ. The statistical epistasis identified between CACNG5 and CACNG6 suggests that there may be an underlying biological interaction between the two genes.