Carbazole and tetrahydro-carboline derivatives as dopamine D3 receptor antagonists with the multiple antipsychotic-like properties

Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

Ketamine for depression treatment: past, present, and future / 中国临床药理学与治疗学

Depression has become a serious global public health problem due to its high incidence and great harm, and has aroused the attention of the society. Ketamine, a commonly used intravenous anesthetic and analgesic in clinical practice, has been found to have unique advantages in antidepressant therapy in recent years. With the development of research, the enantiomeric isomers of ketamine, (S)-ketamine and (R)ketamine have entered the research field of antidepressant therapy. In this paper, we reviewed the progress of research on the antidepressant effects and mechanisms of ketamine, (S )-ketamine and (R)-ketamine, and provide a brief overview of the antidepressant effects of metabolites of ketamine, thereby deepening the understanding of the readers in the field of antidepressant effects of ketamine.

Discovery of 4-arylthiophene-3-carboxylic acid as inhibitor of ANO1 and its effect as analgesic agent

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

Two cases of Type Ⅲ collagen glomerulopathy and literature review / 中南大学学报(医学版)

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.

Clinical significance of Mtype phospholipase A2 receptor and thrombospondin Type 1 domaincontaining 7A in primary membranous nephropathy / 中南大学学报(医学版)

OBJECTIVES@#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.@*METHODS@#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.@*RESULTS@#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, <0.01),while the positive rate of anti-PLA2R antibody in the PMN group was also higher than that in the SMN group (50% in the PMN group, 25% in the SMN group, <0.05).The serum level of anti-PLA2R antibody was positively correlated with 24 h urine protein (=0.254, <0.05) and negatively correlated with serum albumin (=-0.236, <0.05). The expression of THSD7A was positive in glomeruli in 7 cases of the PMN group (6%) by immuno-histochemistry, and which was positive in 1case of the SMN group (5%).The serum levels of anti-THSD7A antibody in the PMN group were higher than those in the SMN group [(0.49±0.26) pg/mL in the PMN group,(0.34±0.27) pg/mL in the SMN group, <0.05]. There was no difference in the clinical characteristics between the PLA2R-related membranous nephropathy group and the THSD7A-related membranous nephropathy group.@*CONCLUSIONS@#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.

Diagnostic value of renal phospholipase A2 receptor and serum anti-phospholipase A2 receptor antibody in membranous nephropathy / 中南大学学报(医学版)

Objective:To examine the expression ofphospholipase 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 antiPLA2R 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,P＜0.05),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,P＜0.05);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,P＜0.01) and negatively correlated with serum albumin (r=-0.307,P＜0.05).Conclusion:The expression of PLA2R in renal tissues and the serum level of anti-PLA2R antibody might be potential markers for diagnosis oflMN.

Role of M-type phospholipase A2 receptor and its antibody in hepatitis B virus-associated membranous nephropathy / 中南大学学报(医学版)

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.

Efffect of plasminogen activator inhibitor-1 and endothelin-1 on the atherosclerosis in the maintenance hemodialysis patients / 中南大学学报(医学版)

OBJECTIVE@#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.@*METHODS@#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.@*RESULTS@#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 (P<0.05) and more calcification (P<0.05) 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 (P<0.05). 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 (P<0.05). 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 (P<0.05). There were positive correlation of PAI-1 or ET-1 expression with age and blood pressure (P<0.05). There were positive correlation of PAI-1 or ET-1 expression with blood vascular media thickness and calcification (P<0.05 or P<0.01). There was no correlation of hemodialysis time with blood vascular media thickness, calcification, PAI-1, t-PA, or ET-1 expressions.@*CONCLUSION@#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.

Effect of high glucose peritoneal dialysis solution on PGC-1α expression and mitochondria related oxidative injury in human peritoneal mesothelial cells / 中南大学学报(医学版)

OBJECTIVE@#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.@*METHODS@#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.@*RESULTS@#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.@*CONCLUSION@#High glucose PDS might inhibit PGC-1α expression, resulting in the inhibition of mitochondrial function and increase of mitochondrial ROS and cellular apoptosis.

New pathologic classification of diabetic nephropathy (retrospective study of 37 cases) / 中南大学学报(医学版)

OBJECTIVE@#To investigate the new pathological classification of diabetic nephropathy (DN) published by Research Committee of the Renal Pathology Society in 2010.@*METHODS@#Renal biopsy specimens were obtained from 37 patients with type 2 diabetes mellitus with micro-albuminuria (MAU) or clinical albuminuria (CAU). These samples were classified according to new pathological classification for DN and new standard scores for interstitial vascular injury.@*RESULTS@#Before the classification, DN was seen in 26 palients. After re-analysis according to the new pathological classification, the patients diagnosed with DN increased to 32. In these 32 DN patients, 1 was classified as type I, 3 as type IIa, 2 as type IIb, 23 as type III and 3 as type IV; 12 patients had mild interstitial injury, 15 had midrange interstitial injury, while 5 had severe interstitial injury.@*CONCLUSION@#The new pathological classification of DN can increase the diagnosis rate and attract more attention to tubular and interstitial damage in DN, contributing to the early diagnosis and treatment of DN.

Effect of norcantharidin on the expression of FN, Col IV and TGF-β1 mRNA and protein in HK-2 cells induced by high glucose / 中南大学学报(医学版)

OBJECTIVE@#To observe the effect of norcantharidin (NCTD) on the expression of mRNA and protein of fibronectin (FN), collagen IV(Col IV) and transforming growth factor-β1(TGF-β1) in human kidney proximal tubular epithelial (HK)-2 cells induced by high glucose.@*METHODS@#HK-2 cells were incubated with serum-free DMEM for 24 h to synchronize cell growth, and then the cells were divided into 4 groups: Group C (5.5 mmol/L D-glucose), Group M (5.5 mmol/L D-glucose + 24.5 mmol/L-mannitol), Group HG (30 mmol/L D-glucose), and Group HG + NCTD (30 mmol/L D-glucose + 0.5-40 mg/L NCTD). Cytotoxicity of HK-2 cells induced by high glucose of NCTD was detected by Trypan blue dye exclusive assay. The effect of NCTD on the proliferation of HK-2 cells in high glucose was determined by MTT. The cells were collected to extract total RNA and protein at 6, 24 and 48 h after the incubation. The expression of FN, Col IV and TGF-β1 mRNA was examined by RT-PCR, and FN, Col IV and TGF-β1 protein was analyzed by Western blot.@*RESULTS@#Trypan blue dye exclusive assay showed NCTD concentrations over 5 mg/L were rather toxic in HK-2 cells. The proliferation of HK-2 cells in high glucose was interrupted by interfered with 5 mg/L NCTD as measured by MTT (P0.05).@*CONCLUSION@#NCTD can downregulate FN, collagen IV and TGF-β1 mRNA and protein expression in HK-2 cells stimulated by 30 mmol/L D-glucose.

Synthesis and analgesic activities of phenyl piperazinyl aralkyl ketone derivatives / 药学学报

To explore novel non-opioid analgesic agents, 16 compounds were synthesized and their structures were confirmed by 1H NMR and HR-MS. YX0611-1 was treated as the leading compound. The results of mice writhing model and hot plate model showed that compounds 2, 7, 8, 9, 11 and 15 had obvious analgesic activities in vivo. The test of affinity to mu, delta, kappa receptor displayed that active compounds didn't act on opioid receptor. The results of preliminary toxicity and pharmacokinetic tests showed that compound 7 had better safety and pharmacokinetic properties than that of YX0611-1, and it deserved further development.

Expression of B1a cells and IgA1 positive cells in tonsil of IgA nephropathy patients and analysis of associated clinicopathological factors / 中华肾脏病杂志

Objective To examine the expression of IgA1 and B1a positive cells in palatine tonsils of IgA nephropathy (IgAN) patients, and to analyze the association between B1a cells and clinicopathological changes. Methods Eight patients diagnosed as IgAN by renal biopsy and 8 chronic tonsillitis patients without nephritis as control were enrolled in the study.Immunofluorescence and laser scanning confocal microscope (LSCM) were applied to observe the localization and quantitative calculation of Bla and IgA1 positive cells. Statistic analysis of the association of B1a cells with proteinuria and pathological Lee's grading was performed. Results Bla cells were mainly localized in germinal center of tonsil, and IgA1 positive cells were mainly localized in subepithelium of tonsil. Compared to control group, the percent of B1a cells and IgA1 positive cells was significantly higher in IgAN (P＜0.01). There was a positive correlation between Bla cells and IgA1 cells (P＜0.05). In IgAN, the percent of B1a cells in patients with hematuria and proteinuria was obviously higher than that of patients with hematuria only (P＜0.05). The number of Bla cells in IgAN patients with≥Lee's grade Ⅲ was significantly higher than that of those ＜ grade Ⅲ (P＜0.05). Conclusions IgA1 may be secreted by Bla cells in the tonsil of IgAN patients. The number of B1a cells is correlated with exacerbation of proteinuria and pathological severity, which may play an important role in pathogenesis of IgAN.

Correlation of urinary podocyte number and glomerular podocalyxin expression with clinicopathology in IgA nephropathy patients / 中华肾脏病杂志

Objective To examine the correlation of urinary podocyte number and giomerular podocalyxin expression with clinicopathology in IgA nephropathy(IgAN)patients. Methods Morning urinary specimens(100 ml)3 days before renal biopsy from 50 patients with IgAN diagnosed by renal biopsy and from 20 healthy volunteers as control were collected. After centrifugation, 300 μI sediment was used for smear. Immunohistochemical staining with monoclonal anti-podocalyxin antibody was performed to detect urinary podocytes and the number of podocyte was counted under optical microscope. Computer image analysis system was used to examine glomerular PCX expression. Renal pathology and classification were investigated based on Lee's grading and Katafuchi semi-quantitative integration method. Relevance analysis was carried out on urinary podocyte number, glomerular PCX expression with pathological score and clinical data. Results The amount of urinary podocytes in IgAN was obviously higher than that in healthy controls(P<0.01). Significant differences were found in multiple comparison of the median of urinary podocytes among Lee's grade groups. I - II group was lower as compared to Ⅲ , Ⅳ, Ⅴ groups(all P<0.05). Ⅲ group was lower as compared to V group(P<0.05). The positive rate of urinary podocyte was the highest in Ⅳ and V groups(100%), while the lowest in Ⅰ - Ⅱ group(55%). Glomerular PCX expression in IgAN decreased with the aggravation of renal pathology. Significant differences were found in multiple comparison of the glomerular PCX expression with the pathological score. Lee's Ⅰ - Ⅱ group was higher as compared to Ⅲ, Ⅳ, Ⅴ groups(all P<0.05). Ⅳ and Ⅳ groups were higher as compared to V group(P<0.05). In IgAN, urinary podocyte excretion was negatively correlated with glomerular PCX expression(r=-0.702, P<0.01), positively correlated with 24-hour urinary protein(r=0.465, P<0.01)and positively correlated with glomerular and tubular scores(r=0.233, 0.307, P<0.05). Glomerular PCX expression was negatively correlated with 24-hour urinary protein(r=-0.367,P<0.05)and negatively correlated with glomerular and tubular scores(r =-0.560, -0.377, P <0.05). Conclusions Injury and desquamation of glomerular podocytes may involve in the development of IgAN. The number of urinary podocyte can reflect the loss of podocytes in renal tissue, which may be used as a marker of disease progression of IgAN.

Expression of MCP-1 in renal tissues of patients with IgA nephropathy / 中南大学学报(医学版)

Objective To investigate the differential expression of monocyte ehemoattraetant protein-1 (MCP-1) in renal biopsy tissues of patients with IgA nephropathy, and to analyse the association between these 2 markers and their effect on various pathologic types of IgA nephropathy. Methods According to pathologic type, 88 renal biopsy tissues of patients with IgA nephropathy were divided into 4 groups: a minimal change group, a mesangial proliferative glomerulonephritis group, a focal sclerosing glomerulonephritis group, and a diffused sclerosing glomerulonephritis group. Immunohistochemical staining was used to detect the in situ expression of MCP-1 and CD68 on renal biopsy tissues. The expression levels were semi-quantified by image analysis and clinical data were collected from the patients. Results The differences in glomerular MCP-1 expressions were not statistically significant among all groups, while the tubulointerstitial MCP-1 expressions were statistically different among the 4 groups, with the average scores of 1.43 ± 0. 60, 5.98 ±0.92, 10. 60 ± 0.76 and 11.65 ±0.39 for minimal change group, mesangial proliferative glomerulonephritis group, focal sclerotic glomerulonephritis, and diffused sclerotic glomerulonephritis group, respectively. The tubular and interstitial CD68 scores were 0. 75 ± 0. 71, 5. 87 ± 0. 96, 10. 42 ± 0. 61, and 11.40 ±0.49 for the 4 groups, with significant differences in both MCP-1 and CD68 among the 4 groups. Correlation analysis indicated a positive correlation between tubulointerstitial MCP-1 and CD68 (r = 0. 688, P ＜ 0. 01) . MCP-1 in tubulointerstitial was significantly correlated with 24 h urinary protein excretion (r=0.531, P＜0.01). Conclusion MCP-1 plays a critical role in mac-rophage infiltration in the kidney. MCP-1 is associated with the severity of tubulointerstitial damage and clinical prognosis.

Mast cell infiltration is involved in renal interstitial fibrosis of rat models with protein overload nephropathy / 中华肾脏病杂志

Objective To investigate the correlation of infiltration of mast cells in kidney with renal interstitial fibrosis, expression of TGF-β1 and stem eel] factor (SCF) in rat models withprotein-overload nephropathy. Methods Sixty uninephrectomized SD rats were randomly divided into model group [intraperitoneal injections of bovine serum albumin (BSA)] and control group (intraperitoneal injections of equal volume of saline). Ten rats from both groups were sacrificed respectively at week 3, 7 and 11 after injection. 24 h urinary protein and serum biochemistry of these SD rats at the time of sacrifice were measured. The intensity of mast cell infiltration was examined by toluidine blue (TB) staining and immunohistochemistry using a monoclonal anti-MC chymase antibody. The expression of TGF-β1 and SCF was detected byimmunohistochemistry, using a monoclonal mouse anti-rat TGF-β1 antibody and a polyclonal rabbstanti-rat SCF antibody. Results Severe proteinuria was induced in the rats by BSA injectionpeaked at week 7 [(199.1±98.4) mg/d] after the BSA injection and gradually decreased until week11 [(133.7±67.8) mg/d]. Renal injury was accompanied with chymase-postitive and TB-postitive mast cell infiltration, in close proximity to areas of interstitial fibrosis. With aggravation oflesions degree, the number of mast cells increased,the difference between the modal rats and control rats was significant (P<0.05). Immunostainahle expression of SCIF and TGF-β1 was detected in tubular as well as interstitial cells, and increased with the BSA injection. The difference between the model rats and control rats was significant (P<0.05). Mast cells were positively correlated with interstitial fibrosis (r=0.772, P<0.01), expression of TGF-β1 (r=0.521, P<0.01) and SCF(r=0.916,P<0.01). Conclusions Increased infiltration of mast cells is involved in interstitial fibrosis of rats with protein-overload nephropathy. Proteinuria may attract mast cells to kidney by chemot actions of SCF,and mast cells may contribute to the development of renal fibrosis by secreting chymase and increasing expression of TGF-β1.