The role of CD38 in inflammation-induced depression-like behavior and the antidepressant effect of (R)-ketamine.

CD38 is involved in immune responses, cell proliferation, and has been identified in the brain, where it is implicated in inflammation processes and psychiatric disorders. We hypothesized that dysfunctional CD38 activity in the brain may contribute to the pathogenesis of depression. To investigate the underlying mechanisms, we used a lipopolysaccharide (LPS)-induced depression-like model and conducted behavioral tests, molecular and morphological methods, along with optogenetic techniques. We microinjected adeno-associated virus into the hippocampal CA3 region with stereotaxic instrumentation. Our results showed a marked increase in CD38 expression in both the hippocampus and cortex of LPS-treated mice. Additionally, pharmacological inhibition and genetic knockout of CD38 effectively alleviated neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, subsequently improving depression-like behaviors. Moreover, optogenetic activation of glutamatergic neurons of hippocampal CA3 reduced the susceptibility of mice to depression-like behaviors, accompanied by reduced CD38 expression. We also found that (R)-ketamine, which displayed antidepressant effects, was linked to its anti-inflammatory properties by suppressing increased CD38 expression and reversing synaptic defects. In conclusion, hippocampal CD38 is closely linked to depression-like behaviors in an inflammation model, highlighting its potential as a therapeutic target for antidepressant development.

Myelin-associated oligodendrocytic basic protein-dependent myelin repair confers the long-lasting antidepressant effect of ketamine.

Ketamine exhibits rapid and sustained antidepressant effects. As decreased myelination has been linked to depression pathology, changes in myelination may be a pivotal mechanism underlying ketamine's long-lasting antidepressant effects. Although ketamine has a long-lasting facilitating effect on myelination, the precise roles of myelination in ketamine's sustained antidepressant effects remain unknown. In this study, we employed spatial transcriptomics (ST) to examine ketamine's lasting effects in the medial prefrontal cortex (mPFC) and hippocampus of mice subjected to chronic social defeat stress and identified several differentially expressed myelin-related genes. Ketamine's ability to restore impaired myelination in the brain by promoting the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes was demonstrated. Moreover, we showed that inhibiting the expression of myelin-associated oligodendrocytic basic protein (Mobp) blocked ketamine's long-lasting antidepressant effects. We also illustrated that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) signaling mediated ketamine's facilitation on myelination. In addition, we found that the (R)-stereoisomer of ketamine showed stronger effects on myelination than (S)-ketamine, which may explain its longer-lasting antidepressant effects. These findings reveal novel mechanisms underlying the sustained antidepressant effects of ketamine and the differences in antidepressant effects between (R)-ketamine and (S)-ketamine, providing new insights into the role of myelination in antidepressant mechanisms.

Changes in spectrum of biopsy-proven kidney diseases within decade: an analysis based on 10 199 cases from South China.

PURPOSE: To assess the regional epidemiological trends of kidney diseases over time in the South China using renal biopsy-proven cases. METHODS: This retrospective observational cohort study was conducted at the Institute of Nephrology, Second Xiangya Hospital of Central South University, and encompasses all patients diagnosed with kidney disease via biopsy from 2012 to 2021. RESULTS: The study sample consisted of 10 199 native kidneys, with a male-to-female ratio of 0.91:1 and an average age of 38.74 (±14.53) years. Primary glomerular nephropathy, systemic glomerular nephropathy (SGN), tubulointerstitial disease, and hereditary renal diseases accounted for 66.92 (6825)%, 24.49 (2498)%, 8.06 (822)%, and 0.53 (54)%, respectively. The leading pathologies of primary glomerular nephropathy remained the IgA nephropathy. The frequencies of IgA nephropathy and membranous nephropathy increased significantly, whereas the frequencies of minimal change disease and focal segmental glomerulosclerosis decreased (P < .001) between 2017 and 2021 than in the years 2012 and 2016. An earlier onset of membranous nephropathy was observed in the age group of 45-59 years compared to previous studies. The leading pathologies of SGN were found to be lupus nephritis (758 cases, 30.45%) and hypertension nephropathy (527 cases, 21.17%). The frequencies of hypertension nephropathy and diabetic nephropathy increased between 2017 and 2021 compared to 2012 and 2016 (P < .001), gradually becoming the leading pathological types of SGN. In elderly patients diagnosed with nephrotic syndrome, the frequencies of amyloidosis significantly increased (P < .01). CONCLUSION: Our study may provide insights for kidney disease prevention and public health strategies. What is already known on this topic The pathological spectrum of kidney diseases has undergone significant transformations in the past decade, driven by the escalating incidence of chronic diseases. Although there are studies exploring the renal biopsy findings from various regions in China which present both similarities and differences in epidemiology, few large-scale reports from the South China in recent decades were published. What this study adds Our findings reveal the following key observations: (i) increased proportion of middle-aged patients leading to the increasing average age at the time of biopsy；(ii) the frequencies of IgA nephropathy and membranous nephropathy (MN) increased significantly, whereas the frequencies of minimal change disease and focal segmental glomerulosclerosis decreased (P < .001) between 2017 and 2021 than in the years 2012 and 2016; (iii) earlier onset of MN in the age group of 45-59 years old was found in our study; and (iv) a higher frequency of hypertension nephropathy and DN presented over time, and frequency of amyloidosis increased in elderly patients diagnosed with NS. How this study might affect research, practice, or policy This single-center yet a large-scale study of the kidney disease spectrum in South China may provide a reference point for the diagnosis, treatment, and prevention of chronic kidney disease.

A Resting-State Functional Magnetic Resonance Imaging Study of Abnormal Frontoparietal Network Function in Migraine without Aura.

BACKGROUND This study aimed to investigate frontoparietal network (FPN) dysfunction in participants with migraine without aura (MwoA). MATERIAL AND METHODS We selected 48 age-, sex-, and education level-matched graduate students (24 participants with MwoA [MwoA group] and 24 healthy controls). RS-fMRI and independent component analysis were used to examine the FPN and to compare abnormal encephalic regional homogeneity values. The Mindful Attention Awareness Scale (MAAS), Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), and Self-Rating Scale of Sleep (SRSS) were used to evaluate attention, anxiety, depression, and sleep, respectively. Pearson's correlation was applied to evaluate the association between abnormal brain areas and the scores for each scale. RESULTS Neural function activity in encephalic regions of FPN showed abnormal changes in the MwoA group. The MwoA group had significantly lower MAAS scores (P<0.001), higher SAS scores (P<0.001), and higher SDS (P=0.06) and SRSS scores (P=0.26). In the MwoA group, functional activity of the right parietal lobule in the left FPN was positively correlated with MAAS scores (P=0.01) and negatively correlated with SAS (P=0.02). The orbital part of left inferior frontal gyrus activity in the right FPN was positively correlated with SDS (P=0.04) and SRSS (P<0.001). Right superior marginal gyrus activity in the right FPN was positively correlated with SDS (P=0.02). CONCLUSIONS Abnormal FPN function was correlated with attention, anxiety, depression, and sleep status in the MwoA group. These results offer further insights into the evaluation and treatment of MwoA.

A Novel Etomidate Analog EL-0052 Retains Potent Hypnotic Effect and Stable Hemodynamics without Suppressing Adrenocortical Function.

Etomidate is a potent and rapidly acting anesthetic with high therapeutic index (TI) and superior hemodynamic stability. However, side effect of suppressing adrenocortical function limits its clinical use. To overcome this side effect, we designed a novel etomidate analog, EL-0052, aiming to retain beneficial properties of etomidate and avoid its disadvantage of suppressing adrenocortical steroid synthesis. Results exhibited that EL-0052 enhanced GABAA receptors currents with a concentration for EC50 of 0.98 ± 0.02 µM, which was about three times more potent than etomidate (3.07 ± 1.67 µM). Similar to hypnotic potency of etomidate, EL-0052 exhibited loss of righting reflex with ED50s of 1.02 (0.93-1.20) mg/kg in rats and 0.5 (0.45-0.56) mg/kg in dogs. The TI of EL-0052 in rats was 28, which was higher than 22 of etomidate. There was no significant difference in hypnotic onset time, recovery time, and walking time between EL-0052 and etomidate in rats. Both of them had minor effects on mean arterial pressure in dogs. EL-0052 had no significant effect on adrenocortical function in dogs even at a high dose (4.3 × ED50), whereas etomidate significantly inhibited corticosteroid secretion. The inhibition of cortisol synthesis assay showed that EL-0052 had a weak inhibition on cortisol biosynthesis in human H259 cells with an IC50 of 1050 ± 100 nM, which was 2.09 ± 0.27 nM for etomidate. EL-0052 retains the favorable properties of etomidate, including potent hypnotic effect, rapid onset and recovery, stable hemodynamics, and high therapeutic index without suppression of adrenocortical function. SIGNIFICANCE STATEMENT: The novel etomidate analog EL-0052 retains the favorable properties of etomidate without suppressing adrenocortical function and provides a new strategy to optimize the structure of etomidate.

LncRNA NEAT1 accelerates renal tubular epithelial cell damage by modulating mitophagy via miR-150-5p-DRP1 axis in diabetic nephropathy.

NEW FINDINGS: What is the central question of this study? Diabetic nephropathy (DN) is a severe complication of diabetes correlated with a higher mortality rate in diabetic patients. Renal tubular injury participates in the pathogenesis of DN. We aimed to uncover the biological function of the NEAT1-miR-150-5p-DRP1 axis in an in vitro model of DN and elaborate the potential mechanisms. What is the main finding and its importance? NEAT1 facilitated high glucose-induced damage in HK-2 cells by reducing mitophagy via the miR-150-5p-DRP1 axis, which sheds light on DN pathogenesis and reveals a potential treatment for DN. ABSTRACT: Diabetic nephropathy (DN) is a severe complication in diabetic patients, with a high mortality rate. Renal tubular injury is involved in the pathogenesis of DN. In this study, we aimed to uncover the regulatory roles of the NEAT1-miR-150-5p-DRP1 axis in an in vitro model of DN and its possible mechanisms. High glucose-challenged HK-2 cells were used as an in vitro DN model. NEAT1, miR-150-5p and DRP1 levels were assessed by RT-qPCR. Cell viability was determined by the MTT assay. MitoSOX Red and JC-1 were used to evaluate intracellular production of reactive oxygen species and mitochondrial membrane potential, respectively. Lactate dehydrogenase release and superoxide dismutase activity were assessed with commercial kits. The protein levels of DRP1, p62, BECN1(beclin 1) and BNIP3 were determined by western blotting. The interaction between NEAT1 (DRP1) and miR-150-5p was verified by a dual-luciferase reporter assay and an RNA immunoprecipitation assay. Our results showed that in response to high glucose the NEAT1 and DRP1 levels were upregulated, whereas the miR-150-5p level was downregulated in HK-2 cells. Knockdown of NEAT1 or DRP1 in high glucose-challenged HK-2 cells inhibited excessive reactive oxygen species production and lactate dehydrogenase release, increased cell viability, mitochondrial membrane potential and superoxide dismutase activity and enhanced mitophagy. Inhibition of miR-150-5p resulted in the opposite results. Mechanistically, NEAT1 sponged miR-150-5p to increase the DRP1 level. Moreover, silencing of NEAT1 or DRP1 could counteract miR-150-5p inhibition-induced deleterious effects. Collectively, our findings indicate that NEAT1 facilitates high glucose-induced damage in HK-2 cells by suppressing mitophagy via the miR-150-5p-DRP 1 axis, which sheds light on a novel mechanism of DN.

Two cases of Type â ¢ collagen glomerulopathy and literature review. / â ¢åž‹èƒ¶åŽŸè‚¾å°çƒç— 2ä¾‹æŠ¥é“åŠæ–‡çŒ®å¤ä¹ .

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 M-type phospholipase A2 receptor and thrombospondin Type 1 domain-containing 7A in primary membranous nephropathy. / Måž‹ç£·è„‚é ¶A2受体及1型血小板反应蛋白7AåŸŸåœ¨ç‰¹å‘è†œæ€§è‚¾ç— ä¸­çš„ä¸´åºŠæ„ä¹‰.

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, P<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, P<0.05).The serum level of anti-PLA2R antibody was positively correlated with 24 h urine protein (r=0.254, P<0.05) and negatively correlated with serum albumin (r=-0.236, P<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, P<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.

Synthesis and Biological Evaluation of Sigma-1 (σ1 ) Receptor Ligands Based on Phenyl-1,2,4-oxadiazole Derivatives.

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.

Pharmacological Characterization of H05, a Novel Serotonin and Noradrenaline Reuptake Inhibitor with Moderate 5-HT2A Antagonist Activity for the Treatment of Depression.

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.

[Diagnostic value of renal phospholipase A2 receptor and serum anti-phospholipase A2 receptor antibody in membranous nephropathy].

OBJECTIVE: 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, 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 of IMN.

[Role of M-type phospholipase A2 receptor and its antibody in hepatitis B virus-associated membranous nephropathy].

OBJECTIVE: 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.

Synthesis and biological evaluation of a series of benzoxazole/benzothiazole-containing 2,3-dihydrobenzo[b][1,4]dioxine derivatives as potential antidepressants.

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.

Synthesis and evaluation of novel 2,3-dihydrobenzo[b][1,4]dioxin- and indolealkylamine derivatives as potential antidepressants.

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.

[Tubulointerstitial nephritis antigen expression in chronic kidney disease and its clinical significance].

OBJECTIVE: To explore tubulointerstitial nephritis antigen (TIN-ag) expression of chronic kidney disease (CKD) patients' renal tissue and the correlation to clinical phenotype. METHODS: 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, ß2-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. RESULTS: 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), P < 0.01). 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 P < 0.05). 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 P < 0.05). Serum creatinine, blood urea nitrogen, serum ß2-microglobulin and eGFR of CKD patients had no significant correlations with TIN-ag expression (P > 0.05). 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 (P < 0.05). CONCLUSIONS: 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.

A novel dual serotonin transporter and M-channel inhibitor D01 for antidepression and cognitive improvement.

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition. In this study, we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01 (a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative) that exhibits both anti-depression effects and improvements in cognition. D01 inhibits serotonin transporters (Ki = 30.1 ± 6.9 nmol/L) and M channels (IC50 = 10.1 ± 2.4 µmol/L). D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on locomotion. Intragastric administrations of D01 (20 and 40 mg/kg) can significantly shorten the immobility time in a mouse model of chronic restraint stress (CRS)-induced depression-like behavior. Additionally, D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice, but not fluoxetine. Furthermore, D01 reverses the long-term potentiation (LTP) inhibition induced by scopolamine. Taken together, our findings demonstrate that D01, a dual-target serotonin reuptake and M channel inhibitor, is highly effective in the treatment-resistant depression and cognitive deficits, thus holding potential for development as therapy of depression with cognitive deficits.

Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia.

Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia. Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT7, H1, M1, Alpha1A, D2L, D2S, Alpha2A, D3 receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical. Results: In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT2A receptor (5-HT2A IC50 = 0.47 nM) than dopamine receptors (D2L IC50 = 1.04 nM; D2S IC50 = 11.71 nM; D3 IC50 = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED50/ Mice MK-801 model ED50 = 104.6-fold; for Risperidone, mice catalepsy model ED50/ Mice MK-801 model ED50 = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094. Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.

High-expression of FABP4 in Tubules is a Risk Factor for Poor Prognosis in DKD Patients.

BACKGROUND: Lipid metabolism imbalance is involved in the mechanism of renal tubular injury in diabetic kidney disease (DKD). Fatty acid binding protein 4 (FABP4) has been reported to participate in cellular lipid toxicity. However, the expression of FABP4 in renal tissues of DKD and its correlation with clinical/ pathological parameters and prognosis have not been studied. METHODS: A retrospective cohort study was conducted in 108 hospitalized Type 2 diabetes (T2D) patients with renal injury, including 70 with DKD and 38 with NDKD (non-DKD). Clinical features, pathological findings, and follow-up parameters were collected. Serum and urine FABP4 were detected by ELISA. An immunohistochemistry stain was used to determine FABP4 in renal tubulointerstitium. A double immunofluorescence stain was employed to assess FABP4- and CD68-positive macrophages. Correlation analysis, logistic regression models, receiver operating characteristic (ROC), and Kaplan-Meier survival curve were performed for statistical analysis. RESULTS: DKD patients had increased expression of FABP4 and ectopic fat deposition in tubules. As shown by correlation analyses, FABP4 expression in renal tubules was positively correlated with UNAG (r=0.589, p=0.044) and ESRD (r=0.740, p=0.004). Multivariate regression analysis revealed that UNAG level was correlated with FABP4 expression level above median value (odds ratio:1.154, 95% confidence interval:1.009-1.321, p=0.037). High-expression of FABP4 in renal tubules of DKD was at an increased risk of ESRD. Increased FABP4 expression in inflammatory cells was also associated with ESRD in DKD. CONCLUSION: High-expression of FABP4 is involved in the pathogenesis of renal tubular lipid injury and is a risk factor for poor prognosis in DKD patients.

Aged rats are susceptible to nephrotoxicity induced by iodinated contrast media.

OBJECTIVE: The objective of this study is to evaluate the effect and mechanism of aging on iodinated-contrast-media-induced nephropathy in male rats. METHODS: Twenty-four healthy male rats were initially divided into 12-month-old and 24-month-old age groups (adult and older age groups, respectively; n = 12/group); subsequently, each age group was randomly divided into saline control (NS) and contrast media (CM) groups (n = 6/group). CM (76% diatrizoate, 10 mL/kg b.w.) was given through the caudal vein. Urinary creatinine (Ucr) and serum creatinine (Scr) were detected by an automatic biochemical analyzer. The activities of renal malondialdehyde (MDA), superoxide dismutase (SOD), angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and reduced form of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) were determined by spectrophotometric assays with commercially available kits according to the manufacturers' protocols. Renal histological changes were observed by hematoxylin and eosin staining and scored semiquantitatively. RESULTS: In diatrizoate-injected aged rats, Scr, the activities of ACE, Ang II, MDA, and NADPH oxidase in renal tissues were significantly increased (p < 0.01). The histologic scores were higher in the aged animals with CM treatment than those of control or adult rats (p < 0.01). There was an increasing trend but no significant statistical difference in renal ACE, Ang II, MDA, and NADPH oxidase or histologic scores in adult CM-injected rats compared with control animals (p > 0.05). CONCLUSIONS: Older age is an aggravating factor of iodinated-contrast-media-induced nephropathy in male rats. Oxidative stress and the renin-angiotensin system (RAS) may play an important role in nephrotoxicity induced by iodinated contrast media, especially in aged male rats.

Mitochondria-targeted peptides prevent on contrast-induced acute kidney injury in the rats with hypercholesterolemia.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: MTP131 and SPI20 might protect acute kidney injury induced by CM in rats with hypercholesterolemia.