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The discovery of the robust antidepressant actions of ketamine is regarded as one of the greatest advancements in depression treatment in the past 60 years. Recent findings have provided strong evidence for the presence of bidirectional communication networks between the gastrointestinal tract and the brain in depression. Moreover, increasing evidence supports the antidepressant role of ketamine in regulating the gut microbiome and microbiota-derived molecules; however, the mechanisms underpinning such effects are still ambiguous. This review summarizes the current understanding of the anti-depressant mechanisms of ketamine and its metabolites regarding the bidirectional regulation by microbiota-gut-brain axis. We review the relationship between gut microbiota and the antidepressant mechanisms of ketamine, and discuss the role of stress response, brain-derived neurotrophic factor (BDNF)-mediated neurogenesis, anti-inflammatory effect and neurotransmitters.

N-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na+ and Ca2+-permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure-activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound 32h caused a significant increase in NMDAR excitability in vitro and impressive activity in the forced swimming test. Moreover, compound 32h showed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.

Anesthetic ketamine is a racemic mixture containing equal amount of (R)-ketamine and (S)-ketamine. Increasing preclinical data show that (R)-ketamine has a rapid-onset and sustained antidepressant without significant side effects. There are currently many studies on (R)-ketamine, however, the quantity and quality of these studies are unknown. Therefore, we conducted a bibliometric analysis of research on (R)-ketamine from January 2002 to December 2021. We obtained the publications on (R)-ketamine from the Web of Science database during the period. A variety of bibliographic elements were collected, including annual publications, authors, countries/regions, institutions, journals, and keywords. A total of 922 publications were included in this study. Professor Kenji Hashimoto of Chiba University in Japan was the most productively influential author in the field of (R)-ketamine and the authors from United States were the leader in this field. In addition, we found that the antidepressant effect of (R)-ketamine has been a hotspot in very recent years. This study provided a comprehensive analysis of research on (R)-ketamine and highlighted the growing interest in (R)-ketamine and its antidepressant effects.

Neuropathic pain is mainly triggered after nerve injury and associated with plasticity of the nociceptive pathway in primary sensory neurons. Currently, the treatment remains a challenge. In order to identify specific therapeutic targets, it is necessary to clarify the underlying mechanisms of neuropathic pain. It is well established that primary sensory neuron sensitization (peripheral sensitization) is one of the main components of neuropathic pain. Calcium channels act as key mediators in peripheral sensitization. As the target of gabapentin, the calcium channel subunit α2δ1 (Cavα2δ1) is a potential entry point in neuropathic pain research. Numerous studies have demonstrated that the upstream and downstream targets of Cavα2δ1 of the peripheral primary neurons, including thrombospondins, N-methyl-D-aspartate receptors, transient receptor potential ankyrin 1 (TRPA1), transient receptor potential vanilloid family 1 (TRPV1), and protein kinase C (PKC), are involved in neuropathic pain. Thus, we reviewed and discussed the role of Cavα2δ1 and the associated signaling axis in neuropathic pain conditions.

Summary A crescentic lesion in renal biopsy could be segmental or circumferential, but the distribution and clinical implication of the circumferential crescents in immunoglobulin A nephropathy (IgAN) remains unknown. A total of 384 crescentic IgAN patients between 2011 and 2019 were included. The subjects were classified as the circumferential crescent who have at least one crescent involving ≥50% circumference of Bowman’s capsule, otherwise as to the segmental crescent. Clinical, pathological, and prognostic relationships were analyzed. The primary endpoint was a 30% decline in eGFR, and the secondary endpoint was more than 3.5 g/d proteinuria during follow-up. Of the 384 patients, 72 (18.8%) patients had more than one circumferential crescent. 52 (17.6%) Oxford C1 patients have circumferential crescent. During a mean follow-up of 32.3 months, both the primary and secondary endpoints have occurred more in the circumferential crescent patients. Kaplan–Meier analysis showed the patient with the circumferential crescent had significantly lower renal survival than those without. In multivariable Cox analyses, having the circumferential crescents in at least one-fifth of glomeruli was independently associated with primary endpoint (hazard ratio:3.60, 95% CI:1.46–8.83), after adjusting for Oxford-score, eGFR, systolic blood pressure, and proteinuria. Furthermore, those patients who scored C1 in Oxford and presenting with circumferential crescents, had better renal survival if they received the other immunosuppressants therapy. The circumferential crescents lesion was associated with adverse outcomes in IgAN, and more than one-fifth of glomeruli circumferential crescents is an independent predictor of 30% eGFR decline after adjusting for clinical and histological parameters.

Anoctamin 1 (ANO1) is a kind of calcium-activated chloride channel involved in nerve depolarization. ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration. In this study, several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening, among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed, synthesized and compound 42 (IC50 = 0.79 μmol/L) was finally obtained. Compound 42 selectively inhibited ANO1 without affecting ANO2 and intracellular Ca2+ concentration. Subsequently, the analgesic effect was investigated by intragastric administration in pain models. Compound 42 significantly attenuated allodynia which was induced by formalin and chronic constriction injury. Through homology modeling and molecular dynamics, the binding site was predicted to be located near the calcium-binding region between α6 and α8. Our study validates ANO1 inhibitors having a significant analgesic effect by intragastric administration and also provides selective molecular tools for ANO1-related research., Graphical abstract Calcium-activated chloride channel anoctamin 1 (ANO1) is a potential target for pain treatment. A novel series of 4-arylthiophene-3-carboxylic acid compounds are discovered to intensely and selectively suppress the ANO1 channel and orally attenuate allodynia which was induced by formalin and chronic constriction injury.Image 1

To evaluate the value of thrombospond in Type I domain-containing 7A (THSD7A) and M-type phospholipase A2 receptor (PLA2R) in primary membranous nephropathy (PMN) and to explore the relationship between their antibody levels and prognosis.Renal tissues in 128 patients with membranous nephropathy in the Second Xiangya Hospital of Central South University were collected from February 2015 to August 2017, including 108 patients with primary membranous nephropathy (PMN group) and 20 patients with secondary membranous nephropathy (SMN) (SMN group). Indirect immunofluorescence method was used to detect the expression of PLA2R antigen in kidney tissues,and the glomerular expression of THSD7A antigen was examined by immunohistochemistry and indirect immunofluorescence. The serum levels of anti-PLA2R antibodies and THSD7A antibodies were also detected by ELISA. According to the results of PMN examination,the patients were also divided into a PLA2R-related membranous nephropathy group and a THSD7A-related membranous nephropathy group.The positive rate of PLA2R in the renal tissues in the PMN group was higher than that in the SMN group (78% in the PMN group, 35% in the SMN group,PLA2R and THSD7A are the target antigen of PMN, and the associated autoantibodies are helpful for the differential diagnosis of PMN. The anti-PLA2R antibody levels can reflect the severity of the disease and evaluate the effect of treatment. The incidence of THSD7A membranous nephropathy is low, and monitoring the serum anti-THSD7A antibody levels can assess patients' condition and predict disease outcome.

In this paper, 2 cases of collagen Type Ⅲ glomerulopathy were analyzed. The clinical manifestations mainly included nephrotic syndrome, proteinuria, hypertension and renal dysfunction. One patient showed that the complement factor H-related protein 5 (CFHR5) gene was likely a disease-causing mutation. The pathological examination of renal tissues showed hyperplasia of mesangial matrix, sub-endothelial insertion, and double-track formation. Immunohistochemistry of Type III collagen was positive. Electron microscopy revealed that massive collagen fibers (40-70 nm in diameter) deposited in the mesangial matrix and basement membrane. As for the follow-up results, the normal renal function had kept steady and the proteinuria was moderate in 1 case treated with angiotensin Ⅱ receptor blocker. Due to other system disease, another case developed into acute kidney injury and then received hemodialysis. The clinical manifestations of collagen Type Ⅲ glomerulopathy was atypical, the light microscope pathological features were various, and the disease was mainly diagnosed by electron microscopy and immunohistochemistry.回顾性分析2例Ⅲ型胶原肾小球病患者，临床表现为肾病综合征、蛋白尿、高血压及肾功能减退。1例患者行基因检测，结果显示补体因子H相关蛋白5(complement factor H-related protein 5，CFHR5)基因疑似发生致病突变。肾组织病理检查显示系膜基质增生、内皮插入伴基底膜双轨形成。免疫组织化学显示Ⅲ型胶原阳性。电子显微镜显示大量40~70 nm胶原沉积。1例应用血管紧张素Ⅱ受体阻滞剂(angiotensin Ⅱ receptor blocker，ARB)治疗，肾功能维持正常，尿蛋白稳定在轻到中度水平；1例因其他系统疾病并发急性肾损伤后行血液透析。Ⅲ型胶原肾小球病临床表现不典型，光镜病理表现多样，主要通过电子显微镜及免疫组织化学检查确诊。.

Herein, a novel series of multireceptor ligands was developed as polypharmacological antipsychotic agents using the designed multiple ligand approach between dopamine receptors and serotonin receptors. Among them, compound 47 possessed unique pharmacological features, exhibiting high affinities for D2, D3, 5-HT1A, 5-HT2A, and 5-HT6 receptors and low efficacy at the off-target receptors (5-HT2C, histamine H1, and adrenergic α1 receptor). Compound 47 showed dose-dependent inhibition of apomorphine- and MK-801-induced motor behavior, and the conditioned avoidance response with low cataleptic effect. Moreover, compound 47 resulted nonsignificantly serum prolactin levels and weight gain change compared with risperidone. Additionally, compound 47 possessed a favorable pharmacokinetic profile with oral bioavailability of 58.8% in rats. Furthermore, compound 47 displayed procognition properties in a novel object recognition task in rats. Taken together, compound 47 may constitute a novel class of atypical antipsychotic drugs for schizophrenia.

Multitarget antidepressants selectively inhibiting monoaminergic transporters and 5-hydroxytryptamine (5-HT) 2A receptor have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors. In the present study, we synthesized a series of novel 3-(benzo[d][1,3]dioxol-4-yloxy)-3-arylpropyl amine derivatives, among which compound H05 was identified as a lead, exhibiting potent inhibitory effects on both serotonin (Ki = 4.81 nM) and norepinephrine (NE) (Ki = 6.72 nM) transporters and moderate 5-HT2A antagonist activity (IC50 = 60.37 nM). H05 was able to dose-dependently reduce the immobility duration in mouse forced swimming test and tail suspension test, with the minimal effective doses lower than those of duloxetine, and showed no stimulatory effect on locomotor activity. The administration of H05 (5, 10, and 20 mg/kg, by mouth) significantly shortened the immobility time of adrenocorticotropin-treated rats that serve as a model of treatment-resistant depression, whereas imipramine (30 mg/kg, by mouth) and duloxetine (30 mg/kg, by mouth) showed no obvious effects. Chronic treatment with H05 reversed the depressive-like behaviors in a rat model of chronic unpredictable mild stress and a mouse model of corticosterone-induced depression. Microdialysis analysis revealed that the administration of H05 at either 10 or 20 mg/kg increased the release of 5-HT and NE from the frontal cortex. The pharmacokinetic (PK) and brain penetration analyses suggest that H05 has favorable PK properties with good blood-brain penetration ability. Therefore, it can be concluded that H05, a novel serotonin and NE reuptake inhibitor with 5-HT2A antagonist activity, possesses efficacious activity in the preclinical models of depression and treatment-resistant depression, and it may warrant further evaluation for clinical development.

Ginkgo biloba extract EGb 761 possesses a variety of biological effects and has been proved to be beneficial in Alzheimer's disease. This study aimed to explore the anti-inflammatory mechanisms of EGb 761 on the Aβ1-42-induced BV-2 microglial cells. We analyzed the production and gene expression of proinflammatory cytokines by enzyme-linked immunosorbent assay and qRT-PCR, examined phosphorylation of MAPKs by western blot and measured nuclear factor-κB nuclear translocation. Compared with Aβ1-42-treated group, EGb 761 inhibited release and gene expression of tumor necrosis factor-α and interleukin-1β, suppressed nuclear translocation of nuclear factor-κB and attenuated phosphorylation of p38 MAPK in a concentration-dependent manner, but not ERK and JNK. In summary, the results suggested that EGb 761 could attenuate Aβ1-42-induced neuroinflammatory response.

By use of the 6-hydroxypyridazinone framework, a new series of potent σ1 receptor ligands associated with pharmacological antineuropathic pain activity was synthesized and is described in this article. In vitro receptor binding studies revealed high σ1 receptor affinity (Ki σ1 = 1.4 nM) and excellent selectivity over not only σ2 receptor (1366-fold) but also other CNS targets (adrenergic, μ-opioid, sertonerigic receptors, etc.) for 2-(3,4-dichlorophenyl)-6-(3-(piperidin-1-yl)propoxy)pyridazin-3(2H)-one (compound 54). Compound 54 exhibited dose-dependent antiallodynic properties in mouse formalin model and rats chronic constriction injury (CCI) model of neuropathic pain. In addition, functional activity of compound 54 was evaluated using phenytoin and indicated that the compound was a σ1 receptor antagonist. Moreover, no motor impairments were found in rotarod tests at antiallodynic doses and no sedative side effect was evident in locomotor activity tests. Last but not least, good safety and favorable pharmacokinetic properties were also noted. These profiles suggest that compound 54 may be a member of a novel class of candidate drugs for treatment of neuropathic pain.

Tong Wu,1 Xianghua Qi,1 Yuan Su,2 Jing Teng,1 Xiangqing Xu11Internal Medicine-Neurology, Shandong Provincial Traditional Chinese Medical Hospital, 2School of Mathematic and Quantitative Economics, Shandong University of Finance and Economics, Jinan, People’s Republic of ChinaObjective: To explore the electroencephalogram (EEG) characteristics in patients with chronic fatigue syndrome (CFS) using brain electrical activity mapping (BEAM) and EEG nonlinear dynamical analysis.Methods: Forty-seven outpatients were selected over a 3-month period and divided into an observation group (24 outpatients) and a control group (23 outpatients) by using the non-probability sampling method. All the patients were given a routine EEG. The BEAM and the correlation dimension changes were analyzed to characterize the EEG features.Results: 1) BEAM results indicated that the energy values of δ, θ, and α1 waves significantly increased in the observation group, compared with the control group (P

Multitarget antidepressants selectively inhibiting monoaminergic transporters and 5-hydroxytryptamine (5-HT) 2A receptor have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors. In the present study, we synthesized a series of novel 3-(benzo[d][1,3]dioxol-4-yloxy)-3-arylpropyl amine derivatives, among which compound H05 was identified as a lead, exhibiting potent inhibitory effects on both serotonin (

In this paper, we report the optimization of a series of novel, potential antipsychotic derivatives combining potent dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptor affinities. The pharmacological features of compound 27 are a high affinity for dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptors. Moreover it possesses low affinity for 5-HT2C and H1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). Furthermore, compound 27 inhibited apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitch without observable catalepsy at the highest dose tested in mice. Taken together, among the amide derivatives, we identified compound 27 as a potential antipsychotic lead candidate.

To examine the expression of phospholipase A2 receptor (PLA2R) in renal tissues and the level of anti-PLA2R antibody in serum in patients with idiopathic membranous nephropathy (IMN) and secondary membranous nephropathy (SMN), and to evaluate their diagnostic value in IMN. Methods: A total of 73 patients, who were diagnosed between May, 2014 and February, 2015 in the Department of Nephrology of the Second Xiangya Hospital, Central South University, were divided into three groups: an IMN group (n=48), an SMN group (n=17) and a minimal change disease group (n=8) according to the renal biopsy. PLA2R expression in renal tissues and the level of anti-PLA2R antibody in serum were detected by indirect immunofluorescence technique. Results: The positive rate and fluorescence intensity for PLA2R in the renal tissues in the IMN group were higher than those in the SMN group (91.7% in the IMN group vs 29.4% in the SMN group, P0.05), while the positive rate and serum level for anti-PLA2R antibody in the IMN group were higher than those in the SMN group (85.4% in the IMN group vs 29.4% in the SMN group, P0.05); the expression of PLA2R in renal tissues and the serum level for anti-PLA2R antibody were not detected in the minimal change disease group. The serum level of anti-PLA2R antibody was positively correlated with 24 h urine protein (r=0.432, P0.01) and negatively correlated with serum albumin (r=-0.307, P0.05). Conclusion: The expression of PLA2R in renal tissues and the serum level of anti-PLA2R antibody might be potential markers for diagnosis of IMN.目的：检测特发性膜性肾病(idiopathic membranous nephropathy，IMN)、继发性膜性肾病(secondary membranous nephropathy，SMN)患者肾组织中磷脂酶A2受体(phospholipase A2 receptor，PLA2R)的表达及血清抗PLA2R抗体滴度，分析其在诊断IMN中的价值。方法：2014年5月至2015年2月中南大学湘雅二医院肾内科肾活检患者73例，分为IMN组(n=48)、SMN组(n=17)和微小病变性肾病组(n=8)。采用间接免疫荧光法检测各组肾组织PLA2R及血清抗PLA2R抗体的表达。结果：IMN组肾组织PLA2R阳性率为91.7%，SMN组阳性率为29.4%，IMN组阳性率、荧光强度明显高于SMN组(均P0.05)；IMN组血清PLA2R抗体阳性率为85.4%，SMN组阳性率为29.4%，IMN组抗体阳性率及滴度明显高于SMN组(均P0.05)；微小病变性肾病组肾组织PLA2R抗原及血清抗体均呈阴性。IMN组血清PLA2R抗体滴度与24 h尿蛋白呈正相关(r=0.432，P0.01)，与血清白蛋白呈负相关(r=–0.307，P0.05)。结论：检测肾组织PLA2R和血清PLA2R抗体的表达有助于IMN的诊断及鉴别诊断，监测血清PLA2R抗体滴度有助于评估疾病活跃程度和治疗效果。.

The discovery and synthesis of a new series of pyrimidines as potent sigma-1 receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 receptor binding assays. The nature of the pyrimidine scaffold was crucial for activity, and a basic amine was shown to be necessary according to the known pharmacophoric model. The most promising derivative was 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine (137), which exhibited a high binding affinity to σ1R receptor (Ki σ1 = 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivo tests, compound 137 exerted dose-dependent antinociceptive effects in mice formalin model and rats CCI models of neuropathic pain. In addition, no motor impairments were found in rotarod tests; acceptable pharmacokinetic properties were also noted. These data suggest compound 137 may constitute a novel class of drugs for the treatment of neuropathic pain.

In this study, a series of phenyl-1,2,4-oxadiazole derivatives were synthesized and evaluated for anti-allodynic activity. Structure-activity relationship studies identified 1-{4-[3-(2,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl]butyl}piperidine (39) with excellent affinity for the σ1 receptor and selectivity for the σ2 receptor, with poor activity to other central nervous system neurotransmitter receptors and transporters associated with pain. Compound 39 exhibited dose-dependent efficacy in suppressing the formalin-induced flinching and attenuating mechanical allodynia in chronic constriction injury-induced neuropathic rats. These results suggest that compound 39 exerts potent antihyperalgesic activity and could be considered as a promising candidate for treating neuropathic pain.

A series of 2,3-dihydrobenzo[b][1,4]dioxin- and indolealkylamine derivatives were synthesized and the target compounds were evaluated for their binding affinities at the 5-HT1A receptor and serotonin transporter. Antidepressant-like activities of the compounds were screened using the tail suspension and forced swim tests in mice. Preliminary results indicated that the target compounds exhibited high binding affinities at the 5-HT1A receptor and serotonin transporter, and produced marked antidepressant-like effects. The best example from this study, compound 5, exhibited high binding affinities for the 5-HT1A receptor (Ki = 96 nM) and serotonin transporter (Ki = 9.8 nM). The intrinsic activity of compound 5 showed agonistic property to the 5-HT1A receptor and inhibition of the 5-HT transporter. Furthermore, compound 5 exhibited greater antidepressant efficacy than fluoxetine and showed acceptable pharmacokinetic properties.

In the present study, the effects of tanshinone IIA (TSN) on the prevention of left ventricular hypertrophy (LVH) and apoptotic processes were observed in spontaneously hypertensive rats (SHRs). A total of 18 SHRs (age, 8 weeks) were randomly divided into three groups. The SHRs in the control group (group S8) were sacrificed at week 8 of the experiment. The SHRs in the treatment group (group D18) and the placebo group (group S18) were injected with TSN and distilled water (1 ml/kg body weight/day), respectively, for 10 weeks, commencing at week 8, and were subsequently sacrificed at week 18. The systolic blood pressure (SBP) and left ventricular mass index (LVMI) were determined. Using hematoxylin and eosin and van Gieson staining, together with immunohistological methods, cardiomyocyte size and diameter, collagen volume fraction (CVF) and perivascular circumferential area (PVCA) were measured. Evaluation of Bcl-2, Bax and p53 expression levels for apoptosis analysis was performed using western blotting. It was observed that the SBP, LVMI, cardiomyocyte size and diameter, CVF, PCVA and cardiomyocyte apoptosis index (Bax and p53 expression) were increased significantly in group S18 compared with group S8. However, Bcl-2 expression levels were decreased in group S18 compared with group S8. The administration of TSN in group D18 resulted in higher Bcl-2 expression levels and significantly decreased LVMI, cardiomyocyte size and diameter, CVF, PCVA, Bax and p53 expression levels compared with group S18. LVH and apoptosis of the cardiac tissues increased with the increasing age of the SHRs. TSN may inhibit the development of LVH and decrease the level of apoptosis in SHRs, possibly via the upregulation of Bcl-2 and the downregulation of Bax and p53 expression.

EGb 761 is main active ingredient of the popular and standardized natural extract Ginkgo biloba, which is known to benefit ischemic stroke. In this study we investigated the potential neuroprotective effect of EGb 761 on the hippocampus in the ischemic/reperfusion rat model. Significant recovery of motor function was seen in EGb 761 treated group compared to vehicle treated group. Infarct volume, as revealed by 1% 2,3,5-triphenyltetrazolium chloride (TTC) staining, was significantly reduced, coupled with conspicuous suppression of neurons apoptosis and significant increments in the cell proliferation and migration in hippocampus. This study reports the therapeutic potential of EGb 761 in stroke animals, which could be related to the attenuation of apoptosis and enhancement of neurogenesis.

The objective of this study is to evaluate the effect and mechanism of mitochondria-targeted peptides (MTP131 and SPI20) on contrast-induced acute kidney injury (CI-AKI) in rats with hypercholesterolemia.Forty SD rats were randomly divided into normal diet group (NN, n = 8) and high cholesterol supplemented dietary group (HN, n = 32). At the end of 8 weeks, the group HN was divided into four subgroups. All Rats were given injection of either diatrizoate (10 mL/kg) or equal volume of normal saline, the rats pretreated with MTP131 or SPI20 were given injection with MTP131 or SPI 20 (3 mg/kg) by peritoneal cavity for 3 times. Blood, urine and renal tissue samples were prepared to determine biochemical parameters. The renal pathological changes were evaluated by hematoxylin and eosin staining and scored semiquantitatively, The protein expression of renal NOX4 was also measured by Western blotting.In diatrizoate-injected rats, Serum creatinine (Scr), fractional excretion of sodium (FeNa%), fractional excretion of potassium (FeK%), pathological scores, renal malondialdehyde (MDA) content, the NADPH oxidase activity and the expression of NOX4 in kidney tissue were significantly increased (p 0.01). In the groups pretreated with MTP131 or SPI20, the levels of Scr, FeNa%, FeK%, MDA content and NADPH oxidase activity in renal tissue decreased (p 0.01), the levels of renal super oxygen dehydrogenises and ATPase activity increased (p 0.01). The renal injuries induced by contrast media (CM) were alleviated.MTP131 and SPI20 might protect acute kidney injury induced by CM in rats with hypercholesterolemia.

The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine D2, D3, and serotonin 5-HT1A and 5-HT2A receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for 5-HT2C and H1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound 17m inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia.

To examine levels of M-type phospholipase A2 receptor (PLA2R) and its antibody in the patients with hepatitis B virus-associated membranous nephropathy (HBV-MN), and to explore the correlation of PLA2R with laboratory parameters and pathological characteristics. Methods: A total of 49 adult patients with biopsy-proved HBV-MN were enrolled in this study. Levels of anti-PLA2R antibody in serum and PLA2R in renal tissue were detected. Patients were assigned into two groups: a positive PLA2R group and a negative PLA2R group. Differences in laboratory parameters and pathological characteristics were compared between the two groups. Results: Of 49 patients with HBV-MN, 17 had positive PLA2R expression in renal tissues. In the positive PLA2R group, 10 patients were positive for serum anti-PLA2R antibody. Patients with positive PLA2R expression in renal tissues showed higher levels of 24 hour urinary protein [(4.6±3.9) g/d], serum HbsAg (70.5%) and renal HbsAg expression (71%), while lower level of serum albumin [(24.1±7.5) g/L] than those of the negative group. Conclusion: PLA2R is expressed in the renal tissues and serum anti-PLA2R antibody can be detected in some HBV-MN patients. Positive PLA2R expression in renal tissue might be related to HbsAg deposition in serum and renal tissues. Patients with positive PLA2R expression in renal tissue have more severe glomerular sclerosis.目的：研究M型磷脂酶A2受体(phospholipase A2 receptor，PLA2R)在乙肝病毒相关性膜性肾病(hepatitis B virus-associated membranous nephropathy，HBV-MN)患者血液及肾组织中的表达情况，并探讨肾组织PLA2R阳性表达在乙型肝炎相关性肾小球肾炎(hepatitis B virus associated glomerulone nephritis，HBV-GN)患者中的临床和病理特点。 方法： 选取经肾活检确诊的49例HBV-MN患者。检测血清抗PLA2R抗体以及肾组织PLA2R的表达，将患者分为肾组织PLA2R表达阳性组和阴性组，比较两组间临床指标、病理改变、血抗PLA2R抗体表达水平的差异。结果：17例患者存在肾组织PLA2R阳性表达，其中10例患者血清抗PLA2R抗体阳性。肾组织阳性组较阴性组24 h尿蛋白水平升高，血白蛋白水平下降，血清HbsAg阳性比例更高(70.5%)，肾组织HbsAg表达比例更高(71%)。结论：肾组织PLA2R以及血清抗PLA2R抗体在HBV-MN患者中有一定表达，其表达可能与HBV-MN患者血清以及肾组织中HbsAg沉积有关。肾组织PLA2R阳性患者肾小球慢性损伤可能相对更重。.

In recent years, multi-targeting directed ligands have attracted great interest as possible new atypical antipsychotics. Combinations of dopamine and serotonin receptor ligands within single molecules might afford new therapeutic opportunities. Herein, we describe the synthesis of a novel series of 6-hydroxypyridazinone benzisoxazoles and their binding behaviors to different receptors in terms of atypical antipsychotic behaviors. The most potent compound (46) exhibited excellent affinities for certain receptors (D2, Ki = 0.5 ± 0.07 nM; 5-HT1A, Ki = 5.9 ± 0.8 nM; 5-HT2A, Ki = 0.3 ± 0.01 nM; 5-HT6, Ki = 0.5 ± 0.04 nM) and combined with low affinities for the H1, 5-HT2C, and adrenergic α1 receptors. In contrast to risperidone, compound 46 exhibited a high cataleptic threshold; this may be useful in the development of a novel class of drugs treating schizophrenia.

In this paper, we report the discovery and the synthesis of novel, potential antipsychotic piperidine-2,6-dione derivatives combining potent dopamine D(2) , D(3) and serotonin 5-HT(1A) , 5-HT(2A) , 5-HT(2C) receptor properties. We describe the structure-activity relationships that led us to the promising derivative: 1-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butyl)-4-(4-chlorophenyl)-piperidine-2,6-dione 5. The unique pharmacological features of compound 5 are a high affinity for dopamine D(2) , D(3) and serotonin 5-HT(1A) , 5-HT(2A) , 5-HT(2C) receptors, together with a low affinity for the H(1) receptor (to reduce the risk of obesity under chronic treatment). In a behavioral model predictive of positive symptoms, compound 5 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. In particular, compound 5 was more potent than clozapine.

To explore the association of urinary podocyte excretion and renal expression of podocyte-specific marker podocalyxin (PCX) with clinicopathological changes in immunoglobulin A nephropathy (IgAN).Morning urine samples from IgAN patients and healthy controls were collected. The expression of glomerular PCX was quantified in 50 IgAN patients diagnosed by renal biopsy. IgAN was classified based on the Lee's Grading system and scored according to the Katafuchi semiquantitative criteria. Morphological evaluation of podocyte was determined by electron microscopy.The amount of urinary podocytes in the IgAN patients was significantly higher than that in the healthy controls (p0.01). Pairwise comparison among Lee's grades of IgAN showed that the median of urinary podocytes in Lee's I-II group was lower than that in Lee's III, IV, and V groups (p0.05); group III lower than group V (p0.05). The positive rate of urinary podocytes was the highest in Lee's IV and V groups (100%), and lowest in Lee's I-II group (55%). Multiple comparison among groups of Lee's grades of IgAN showed that the glomerular PCX expression in Lee's I-II group was higher than that in Lee's III, IV, and V groups (p0.05); groups III and IV higher than group V (p0.05). The amount of urinary podocytes in IgAN patients was negatively correlated with PCX expression (r = -0.702, p0.01), but positively correlated with 24-h urinary protein (r = 0.465, p0.01) and glomerular (r = 0.233, p0.01) and renal tubular pathological scores (r = 0.307, p0.05). The glomerular PCX expression was negatively correlated with 24-h urinary protein (r = -0.367, p0.05) and glomerular (r = -0.560, p0.05) and tubular pathological scores (r = -0.377, p0.05). Electron microscopy showed significant changes in podocytes of IgAN, especially in the foot process.The amount of urinary podocyte can reflect the loss of podocytes in renal tissue, which may be a marker of IgAN progression.

To elucidate the role of mast cells (MCs) in the pathogenesis of tubulointerstitial lesions in IgA nephropathy (IgAN), we investigated the number of MCs, serum stem cell factor (SCF), protease-activated receptor-2 (PAR-2) and alpha-smooth-muscle actin (alpha-SMA) in the kidney and the correlation between MC number, SCF, PAR-2, alpha-SMA and tubulointerstitial lesions in biopsy specimens and serum creatinine levels, urinary protein excretion in patients with IgA nephropathy.Thirty-five patients with IgA nephropathy were enrolled in this study. Clinical parameters, such as serum creatinine and urinary protein excretion, were obtained from each patient at the time of biopsy. Paraffin-embedded sections were used for immunohistochemical staining. Monoclonal antibodies to human tryptase, alpha-SMA, and SCF and polyclonal antibody to PAR-2 were used as primary antibodies. Ten cortical interstitial fields were randomly selected and assessed using a computer-assisted color image analyzer. Tubulointerstitial fibrosis was assessed as the percentage of the area stained with Masson trichrome in ten cortical interstitial fields.In all of the control subjects, few tryptase-positive MCs were observed in the glomeruli and interstitium. In contrast, sparse MCs were observed in the interstitium, but not in the glomeruli of diseased kidneys. The number of interstitial MCs in the tubulointerstitial lesions, the expression of SCF, PAR-2 and alpha-SMA were positively correlated with the degree of interstitial fibrosis. A close correlation between MCs, alpha-SMA, PAR-2 and SCF was found (r = 0.887 for alpha-SMA, r = 0.844 for PAR-2, r = 0.853 for SCF, P0.01). Also a close correlation between alpha-SMA, PAR-2 and SCF was found (r = 0.874 for PAR-2, r = 0.862 for SCF, P0.01). PAR-2 was correlated with SCF (r = 0.893, P0.01). Moreover, a significant positive correlation was observed between the number of interstitial MCs, the expression of SCF, PAR-2 and alpha-SMA and the serum creatinine level (r = 0.738 for MCs, r = 0.658 for alpha-SMA, r = 0.692 for PAR-2, r = 0.754 for SCF, P0.05).Our findings suggest that MC infiltration possibly induced by SCF in renal interstitial tissues seems to be associated with tubulointerstitial fibrosis through PAR-2 in IgA nephropathy.

A 38-year-old Chinese man was admitted to the Second Xiangya Hospital of the Central South University (Changsha, China) with heavy proteinuria and rapidly progressing renal failure with nephrotic syndrome. An initial renal biopsy identified collapsing glomerulopathy (CG) with characteristic segmental collapse of the glomerular tuft and marked hypertrophy and hyperplasia of the visceral epithelial cells. A second renal biopsy showed dilation of glomerular capillary loops as a result of effective treatment with rapamycin and anti-viral therapy. Serology for the coxsackie virus antibody was positive when the collapsing lesion was present, and became negative following treatment, which indicated a strong association between the development of CG and coxsackie virus infection. To the best of our knowledge, this is the first case report of CG associated with coxsackie virus infection.

To investigate whether a sudden temperature change between neighboring days has significant impact on mortality. A Poisson generalized linear regression model combined with a distributed lag non-linear models was used to estimate the association of temperature change between neighboring days with mortality in a subtropical Chinese city during 2008–2012. Temperature change was calculated as the current day’s temperature minus the previous day’s temperature. A significant effect of temperature change between neighboring days on mortality was observed. Temperature increase was significantly associated with elevated mortality from non-accidental and cardiovascular diseases, while temperature decrease had a protective effect on non-accidental mortality and cardiovascular mortality. Males and people aged 65 years or older appeared to be more vulnerable to the impact of temperature change. Temperature increase between neighboring days has a significant adverse impact on mortality. Further health mitigation strategies as a response to climate change should take into account temperature variation between neighboring days.

To explore tubulointerstitial nephritis antigen (TIN-ag) expression of chronic kidney disease (CKD) patients' renal tissue and the correlation to clinical phenotype.Through digital drawing lots, a total of 77 CKD patients from October 2012 to February 2013 at our department were randomly selected. All of them underwent biopsy. Based upon their pathological findings, they were divided into 2 groups of minimal change disease (MCD) and non-minimal change disease (NMCD). The stains of hematoxylin and eosin and Masson were used to observe renal pathological changes and immunofluorescence for detecting the TIN-ag expression of kidney tissue. The serum levels of creatinine, blood urea nitrogen, estimated glomerular filtration rate (eGFR), 24-hour urine output, 24-hour urine protein, α1-microglobulin, β2-microglobulin, pathological casts, N-acetyl-beta-glucosaminidase (NAG), specific gravity and other clinical parameters were monitored to examine their relationship between renal tissue TIN-ag expression.TIN-ag expression was distinct in renal tubular basement membrane of MCD patients while weak in primary focal segmental glomerulosclerosis (FSGS)(n = 16), IgA nephropathy (n = 23), MN (n = 14) and LN (n = 15) renal tissue. Immunofluorescence quantitative analysis showed that tubular TIN-ag fluorescence intensity of NMCD group was significantly lower than that of MCD group (4.84(3.02, 10.73) vs 20.79(8.19, 37.00), P0.01). In addition, TIN-ag expression in renal interstitial collagen area deposition of 0 grade group was higher than that of collagen area deposition 1-3 grades group (all P0.05). Serum α1-microglobulin and pathological urine cast, 24-hour urine protein of CKD patients were negatively correlated with kidney tubules TIN-ag expression (r = -0.312, -0.298, -0.214, all P0.05). Serum creatinine, blood urea nitrogen, serum β2-microglobulin and eGFR of CKD patients had no significant correlations with TIN-ag expression (P0.05). TIN-ag expression of CKD patients with lower expression levels of NAG was significantly higher than that of normal levels of NAG expression. TIN-ag expression of low urine specific gravity group was lower than that of normal urine specific gravity group (P0.05).TIN-ag expression of renal tissue tubule basement membrane in NMCD group is significantly lower than that in MCD group. TIN-ag expression is negatively correlated with renal tissue fibrosis. Expression of serum α1-microglobulin and concentrations of urinary pathology tube, 24-hour urine protein, NAG expression and urine specific gravity are negatively correlated with renal tissue TIN-ag expression in CKD patients.

The synthesis and sigma-1 receptor (σ1R) antagonist activity of a new series of 3,4-dihydro-2(1H)-quinolinone derivatives are reported. The new compounds were evaluated in vitro in sigma-1 and sigma-2 receptor-binding assays in guinea pig brain membranes. The structure–activity relationship led us to the promising derivative 7-(3-(piperidin-1-yl)propoxy)-1-(4-fluorobenzyl)-3,4-dihydro-2(1H)-quinolinone (35). The compounds with highest affinity and greatest selectivity were further profiled, and compound 35 had a high binding constant for sigma-1 receptor (Kiσ1 = 1.22 nM) and high sigma-1/2 selectivity (1066-fold). Thus, compound 35, which proved to be an antagonist of sigma-1 receptor, emerged as the most interesting candidate. In addition, compound 35 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 35 could be a potent candidate for pain treatment.

To investigate the mechanism of mitochondrial oxidative injury induced by high glucose peritoneal dialysis solution (PDS) and the protective effect of peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1α) in the mitochondria of human peritoneal mesothelial cells (HPMC) in the high glucose ambience.HPMC was cultured in a PDS containing 1.5%, 2.5% and 4.25% glucose for 24 hours. Western blot analysis was used to detect PGC-1α expression. MitoSOX? Red staining, respiratory chain complexes and antioxidant enzyme activities were determined.The activities of respiratory chain complex III and antioxidant enzymes decreased significantly in a concentration- and time-dependent manner, along with the increased production of mitochondrial reactive oxygen species (ROS) and cellular apoptosis. In addition, protein expression of PGC-1α was also decreased in the high glucose PDS ambience.High glucose PDS might inhibit PGC-1α expression, resulting in the inhibition of mitochondrial function and increase of mitochondrial ROS and cellular apoptosis.

A series of benzoxazole/benzothiazole-2,3-dihydrobenzo[b][1,4]dioxine derivatives (5a-5d and 8a-8j) was synthesized. Compounds were evaluated for binding affinities at the 5-HT1A and 5-HT2A receptors. Antidepressant activities of the compounds were screened using the forced swimming test (FST) and the tail suspension test (TST). The results indicated that the compounds exhibited high affinities for the 5-HT1A and 5-HT2A receptors and showed a marked antidepressant-like activity. Compound 8g exhibited high affinities for the 5-HT1A (Ki=17 nM) and 5-HT2A (Ki=0.71 nM) receptors; it also produced a decrease of the immobility time and exhibited potent antidepressant-like effects in the FST and TST in mice.

In this paper, we report the synthesis of novel, potential antipsychotic coumarin derivatives combining potent dopamine D₂, D₃ and serotonin 5-HT(1A), 5-HT(2A) receptors properties. We describe the structure activity relationship that leads us to the promising derivative: 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-6-methyl-2,3-dihydrocyclopenta[c]chromen-4(1H)-one 27. The unique pharmacological features of compound 27 are a high affinity for dopamine D₂, D₃ and serotonin 5-HT(1A), 5-HT(2A) receptors, together with a low affinity for H₁ receptor (to reduce the risk of obesity under chronic treatment). In animal models, compound 27 inhibited apomorphine-induced climbing and MK-801-induced hyperactivity without observable catalepsy at the highest dose tested. In particular, compound 27 was more potent than clozapine.

To investigate the effect of plasminogen activator inhibitor-1 (PAI-1), tissue type plasminogen activator (t-PA), and endothelin-1 (ET-1) on the atherosclerosis progress in the maintenance hemodialysis patients.We enrolled 19 patients with maintenance hemodialysis (MHD) and 11 healthy people as control. Patients were divided into 2 groups according to their age above or below 40 years old (11 and 8 in each, respectively), whereas the subjects in control group were below 40 years old. All the clinical information of the research subjects was collected: including age, gender, time of hemodialysis, blood pressure, blood urea nitrogen (BUN), and serum creatinine (SCr). Immunohistochemistry and pathological image analysis were used to investigate the pathological changes, calcification and the expression of PAI-1, t-PA, and ET-1 on the blood vessel.Compared with the age-matched healthy control group, there were higher blood vascular media thickness, blood vascular media thickness/diagmeter ratio, blood vascular media thickness area/vascular inter-wall area ratio (P0.05) and more calcification (P0.05) in the the internal iliac artery in the chronic renal failure MHD patients. All the results were similar when compared the above 40 years old group with the below 40 years old one in the chronic renal failure MHD patients. There were positive correlation of blood vascular media thickness with age and blood pressure (P0.05). Expression of PAI-1, ET-1, t-PA on the internal iliac artery vessel was elevated in the chronic renal failure MHD patients compared with the health control (P0.05). The level of PAI-1 or ET-1 was much higher in the above 40 years old group than the below 40 years old one in the chronic renal failure MHD patients, whereas there was no significant difference in the t-PA expression between the 2 groups (P0.05). There were positive correlation of PAI-1 or ET-1 expression with age and blood pressure (P0.05). There were positive correlation of PAI-1 or ET-1 expression with blood vascular media thickness and calcification (P0.05 or P0.01). There was no correlation of hemodialysis time with blood vascular media thickness, calcification, PAI-1, t-PA, or ET-1 expressions.MHD patients accompany with atherosclerosis which is severer in the patients above 40 years old than the patients below 40 years old. The higher of the blood pressure, the severer of the atherosclerosis. Abnormal expression of PAI-1 plays an important role in the progress of the atherosclerosis in the chronic renal failure MHD patients, whereas t-PA has no function in this process. The level of PAI-1 and ET-1 would be helpful to evaluating the degree of atherosclerosis in the chronic renal failure MHD patients. Hemodialysis time may not be a potential accelerator for atherosclerosis progression.

Compound (I) shows high affinity for dopamine D2 and D3, serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors with a low affinity for the H1 receptor.