ABSTRACT
The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) in depression is a topic of debate, and the underlying mechanisms remain largely unclear. We now elucidate hippocampal excitation-inhibition (E/I) balance underlies the regulatory effects of 5-HT2CR in depression. Molecular biological analyses showed that chronic mild stress (CMS) reduced the expression of 5-HT2CR in hippocampus. We revealed that inhibition of 5-HT2CR induced depressive-like behaviors, reduced GABA release and shifted the E/I balance towards excitation in CA3 pyramidal neurons by using behavioral analyses, microdialysis coupled with mass spectrum, and electrophysiological recording. Moreover, 5-HT2CR modulated neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction through influencing intracellular Ca2+ release, as determined by fiber photometry and coimmunoprecipitation. Notably, disruption of nNOS-CAPON by specific small molecule compound ZLc-002 or AAV-CMV-CAPON-125C-GFP, abolished 5-HT2CR inhibition-induced depressive-like behaviors, as well as the impairment in soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly-mediated GABA vesicle release and a consequent E/I imbalance. Importantly, optogenetic inhibition of CA3 GABAergic neurons prevented the effects of AAV-CMV-CAPON-125C-GFP on depressive behaviors in the presence of 5-HT2CR antagonist. Conclusively, our findings disclose the regulatory role of 5-HT2CR in depressive-like behaviors and highlight the hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioral consequences of 5-HT2CR inhibition.
ABSTRACT
BACKGROUND: A referenced MRI-based classification associated with focused ultrasound ablation surgery (FUAS) outcomes is lacking in adenomyosis. PURPOSE: To identify an MRI-based classification system for informing the FUAS outcomes. STUDY TYPE: Retrospective. POPULATION: Patients with FUAS for adenomyosis, were divided into a training set (N = 643; 355 with post-FUAS gonadotropin-releasing hormone/levonorgestrel, 288 without post-FUAS therapy) and an external validation set (N = 135; all without post-FUAS therapy). FIELD STRENGTH/SEQUENCE: 1.5 T, turbo spin-echo T2-weighted imaging and single-shot echo-planar diffusion-weighted imaging sequences. ASSESSMENT: Five MRI-based adenomyosis classifications: classification 1 (C1) (diffuse, focal, and mild), C2 (intrinsic, extrinsic, intramural, and indeterminate), C3 (internal, adenomyomas, and external), C4 (six subtypes on areas [internal or external] and volumes [<1/3 or ≥2/3]), and C5 (internal [asymmetric or symmetric], external, intramural, full thickness [asymmetric or symmetric]) for FUAS outcomes (symptom relief and recurrence). STATISTICAL TESTS: The optimal classification was significantly associated with the most subtypes of FUAS outcomes. Relating to the timing of recurrence was measured using Cox regression analysis and median recurrence time was estimated by a Kaplan-Meier curve. A P value <0.05 was considered statistically significant. RESULTS: Dysmenorrhea relief and recurrence were only associated with C2 in training patients undergoing FUAS alone. Compared with other subtypes, the extrinsic subtype of C2 was significantly associated with dysmenorrhea recurrence in the FUAS group. Besides, the median dysmenorrhea recurrence time of extrinsic subtype was significantly shorter than that of other subtypes (42.0 months vs. 50.3 months). In the validation cohort, C2 was confirmed as the optimal system and its extrinsic subtype was confirmed to have a significantly shorter dysmenorrhea recurrence time than other subtypes. DATA CONCLUSION: Classification 2 can inform dysmenorrhea relief and recurrence in patients with adenomyosis undergoing FAUS only. Itsextrinsic subtype was associated with an earlier onset of dysmenorrhea recurrence after treatment. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 5.
Subject(s)
Adenomyosis , High-Intensity Focused Ultrasound Ablation , Female , Humans , Adenomyosis/diagnostic imaging , Adenomyosis/surgery , Dysmenorrhea/diagnostic imaging , Dysmenorrhea/complications , Dysmenorrhea/surgery , Treatment Outcome , Retrospective Studies , High-Intensity Focused Ultrasound Ablation/methods , Magnetic Resonance Imaging/methods , Ultrasonography, Interventional/methodsABSTRACT
Asari Radix et Rhizoma is a common drug for relieving exterior syndrome in clinics, but its toxicity limits its use. In this study, the mechanism of hepatic damage of Asari Radix et Rhizoma was studied by network pharmacology and metabolomics. The hepatic damage-related dataset, namely GSE54257 was downloaded from the GEO database. The Limma package was used to analyze the differentially expressed genes in the dataset GSE54257. Toxic components and target genes of Asari Radix et Rhizoma were screened by TCMSP, ECTM, and TOXNET. The hepatic damage target genes of Asari Radix et Rhizoma were obtained by mapping with the differentially expressed gene of GSE54257, and a PPI network was constructed. GO and KEGG enrichment analysis of target genes were performed, and a "miRNA-target gene-signal pathway" network was drawn with upstream miRNA information. Thirty rats were divided into a blank group, a high-dose Asari Radix et Rhizoma group, and a low-dose Asari Radix et Rhizoma group, which were administered once a day. After continuous administration for 28 days, liver function indexes and liver pathological changes were detected. Five liver tissue samples were randomly collected from the blank group and high-dose Asari Radix et Rhizoma group, and small molecule metabolites were analyzed by ultra-high performance liquid chromatography-mass spectrometry(UHPLC-MS). The orthogonal partial least squares-discriminant analysis(OPLS-DA) method was used to screen differential metabolites, and enrichment analysis, correlation analysis, and cluster analysis were conducted for differential metabolites. Finally, the MetaboAnalyst platform was used to conduct pathway enrichment analysis for differential metabolites. It was found that there were 14 toxic components in Asari Radix et Rhizoma, corresponding to 37 target genes, and 12 genes related to liver toxicity of Asari Radix et Rhizoma were obtained by mapping to differentially expressed genes of GSE54257. The animal test results showed that Asari Radix et Rhizoma could significantly increase the liver function index, reduce the activity of the free radical scavenging enzyme, change the liver oxidative stress level, and induce lipid peroxidation damage in rats. The results of untargeted metabolomics analysis showed that compared with the blank group, nine metabolites were up-regulated, and 16 metabolites were down-regulated in the liver tissue of the Asari Radix et Rhizoma group. These 25 metabolites had strong correlations and good clustering. Pathway enrichment analysis showed that these differential metabolites and the 12 hepatotoxic target genes of Asari Radix et Rhizoma were mainly involved in purine metabolism, as well as the biosynthesis and metabolism of valine, leucine, glycine, serine, and threonine. The study confirmed that the hepatica damage effect of Asari Radix et Rhizoma was the result of multi-component, multi-target, and multi-signaling pathways, and its mechanism may be related to inhibiting nucleotide synthesis and affecting protein metabolism.
Subject(s)
Drugs, Chinese Herbal , Liver , Metabolomics , Animals , Rats , Drugs, Chinese Herbal/administration & dosage , Liver/metabolism , Liver/drug effects , Male , Network Pharmacology , Rats, Sprague-Dawley , Asarum/chemistry , Asarum/genetics , Asarum/metabolism , Rhizome/chemistry , Humans , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/geneticsABSTRACT
Hypertension is the leading cause of morbidity and mortality globally among all cardiovascular diseases. Purinergic signalling plays a crucial role in hypertension through the sympathetic nerve system, neurons in the brain stem, carotid body, endothelium, immune system, renin-angiotensin system, sodium excretion, epithelial sodium channel activity (ENaC), and renal autoregulation. Under hypertension, adenosine triphosphate (ATP) is released as a cotransmitter from the sympathetic nerve. It mediates vascular tone mainly through P2X1R activation on smooth muscle cells and activation of P2X4R and P2YR on endothelial cells and also via interaction with other purinoceptors, showing dual effects. P2Y1R is linked to neurogenic hypertension. P2X7R and P2Y11R are potential targets for immune-related hypertension. P2X3R located on the carotid body is the most promising novel therapeutic target for hypertension. A1R, A2AR, A2BR, and P2X7R are all related to renal autoregulation, which contribute to both renal damage and hypertension. The main focus is on the evidence addressing the involvement of purinoceptors in hypertension and therapeutic interventions.
Subject(s)
Endothelial Cells , Hypertension , Humans , Receptors, Purinergic/physiology , Synaptic Transmission , Signal Transduction , Adenosine Triphosphate/physiologyABSTRACT
BACKGROUND: Neuroinflammation after aneurysmal subarachnoid hemorrhage (aSAH) leads to poor outcome of patients. High mobility group box 1 (HMGB1) contributes to inflammation through binding to receptors for advanced glycation end-products (RAGE) in various diseases. We aimed to determine the production of these two factors after aSAH and their relationship with clinical features. METHODS: HMGB1 and soluble RAGE (sRAGE) levels in cerebrospinal fluid (CSF) of aSAH patients and controls were measured, and their temporal courses were observed. The correlation between early concentrations (days 1-3) and clinical symptoms assessed by disease severity scores, neuroinflammation estimated by CSF IL-6 levels, as well as prognosis evidenced by delayed cerebral ischemia (DCI) and 6-month adverse outcome was investigated. Finally, combined analysis of early levels for predicting prognosis was confirmed. RESULTS: CSF HMGB1 and sRAGE levels were higher in aSAH patients than in controls (P < 0.05), and the levels decreased from higher early to lower over time. Their early concentrations were positively associated with disease severity scores, IL-6 levels, DCI and 6-month poor outcome (P < 0.05). HMGB1 ≥ 6045.5 pg/ml (OR = 14.291, P = 0.046) and sRAGE ≥ 572.0 pg/ml (OR = 13.988, P = 0.043) emerged as independent predictors for DCI, while HMGB1 ≥ 5163.2 pg/ml (OR = 7.483, P = 0.043) and sRAGE ≥ 537.3 pg/ml (OR = 12.653, P = 0.042) were predictors for 6-month poor outcome. Combined analysis of them improved predictive values of adverse prognosis. CONCLUSION: CSF HMGB1 and sRAGE levels of aSAH patients were increased early and then varied dynamically, which might act as potential biomarkers for poor outcome, especially when co-analyzed.
Subject(s)
Brain Ischemia , HMGB1 Protein , Subarachnoid Hemorrhage , Humans , Subarachnoid Hemorrhage/complications , Interleukin-6 , Neuroinflammatory Diseases , Prognosis , Biomarkers/cerebrospinal fluid , Receptor for Advanced Glycation End Products/metabolism , Brain Ischemia/etiology , Brain Ischemia/complications , Cerebral Infarction/complicationsABSTRACT
Manganese chloride (MnCl2) has been shown to inhibit the Yes-associated protein (YAP) in high-fat diet-fed ApoE-/- mice. Although YAP has been implicated in atherogenesis, there are limited data on the effects of MnCl2 on cardiac remodeling. In this study, we discovered, by electrocardiography, that hyperlipidemia led to spontaneous supraventricular arrhythmia (SVA) in ApoE-/- (KO) mice, with 3 of 9 KO + MnCl2 mice (33%) exhibiting lower incidence of spontaneous SVA than KO mice (6 of 10 mice, 60%). Echocardiography revealed that reduced systolic function in KO mice was reversed by MnCl2 treatment. Oil Red O staining of the aortas and biochemical analysis of lipid levels showed that MnCl2 inhibited plaque formation in a lipid metabolism-independent manner. MnCl2 inhibited inflammatory cell infiltration and reduced fibrosis, as evidenced by hematoxylin and eosin, immunohistochemical and Masson's trichrome staining, respectively. Our findings demonstrate that spontaneous SVA and reduced systolic function were blocked by MnCl2. Our findings show that MnCl2 was useful in delaying cardiac remodeling and reducing susceptibility to spontaneous SVA in a mouse model of hyperlipidemia.
Subject(s)
Chlorides/administration & dosage , Hyperlipidemias/drug therapy , Manganese Compounds/administration & dosage , Tachycardia, Supraventricular/prevention & control , Tachycardia, Supraventricular/physiopathology , Ventricular Remodeling , Administration, Oral , Animals , Chlorides/pharmacology , Disease Models, Animal , Hyperlipidemias/complications , Male , Manganese Compounds/pharmacology , Mice, Inbred C57BL , Mice, Knockout , Tachycardia, Supraventricular/etiology , Ventricular Remodeling/drug effectsABSTRACT
Neurons are special polarized cells whose synaptic vesicles release neurotransmitters into the synaptic cleft, acting on postsynaptic receptors and thus transmitting information from presynaptic to postsynaptic states. The integrity of the vesicle cycle is critical to the transmission of neural signals in the brain. According to the molecular mechanism of calcium-triggered release, the assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) is required in the process of synaptic vesicle fusion and vesicle exocytosis. Many delicate steps are required to maintain the dynamic process of 'release-recycle', including intermediate processes and the dynamic balance of neurotransmission. Various neurodegenerative and neuropsychiatric diseases result from synaptic cycle dysfunction. This review of the relationships between the structure and function of synaptic vesicles in physiological and pathological conditions provides a theoretical basis for synaptic transmission and a novel avenue for the study of synaptic plasticity associated with mood disorders, highlighting potential targets for treating diseases.
Subject(s)
Exocytosis/physiology , Nervous System Diseases/physiopathology , Synaptic Transmission/physiology , Animals , Calcium/metabolism , Humans , Neuronal Plasticity/physiology , Neurons/physiology , Synapses/physiology , Synaptic Vesicles/physiologyABSTRACT
Anxiety is recognized as primary clinical phenotype of psychiatric disorders. However, many patients with anxiety have not yet received effective treatment. Our previous study demonstrated that hippocampal nNOS-CAPON interaction is implicated in anxiety-related behaviors, and blocking nNOS-CAPON interaction in the hippocampus produces anxiolytic-like effects. Here, ZLc-002, a small molecule inhibitor of nNOS-CAPON coupling, was evaluated for anxiolytic-like properties after systemic administered using anxiety behavioral tests, including open-field (OF), elevated plus maze (EPM), novelty-suppressed feeding (NSF) and light-dark (LD) tests. We reported that ZLc-002 when administered intraperitoneally at the dose of 40 or 80 mg/kg/d for 14 days produces anxiolytic-like effects. Furthermore, the similar effects of ZLc-002 were observed when administered intravenously at the dose of 10, 20 or 40 mg/kg/d for 7 days. More importantly, the mice dosing with 80 mg/kg/d ZLc-002 intraperitoneally or 40 mg/kg/d ZLc-002 intravenously for 3 days exerted significant behavioral effects. However, intragastric administration with ZLc-002 was devoid of effect on anxiety behaviors, even at high doses. Furthermore, intraperitoneal or intravenous treatment of ZLc-002 significantly disrupted the interaction between nNOS and CAPON in the hippocampus of adult mice, and there was a significant anxiolytic-like effect of ZLc-002 at day 3 after intrahippocampal microinjection. Our results verified that systemic administration of putative small molecule inhibitor of nNOS-CAPON can be used for the treatment of anxiety disorders.
Subject(s)
Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Anti-Anxiety Agents/administration & dosage , Nitric Oxide Synthase Type I/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/metabolism , Animals , Anxiety Disorders/drug therapy , Anxiety Disorders/metabolism , Behavior, Animal/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Hippocampus/drug effects , Hippocampus/metabolism , Injections, Intraperitoneal , Male , Maze Learning/drug effects , Mice , Mice, Inbred ICR , Nitric Oxide Synthase Type I/metabolismABSTRACT
Anxiety disorders are associated with a high social burden worldwide. Recently, increasing evidence suggests that nuclear factor kappa B (NF-κB) has significant implications for psychiatric diseases, including anxiety and depressive disorders. However, the molecular mechanisms underlying the role of NF-κB in stress-induced anxiety behaviors are poorly understood. In this study, we show that chronic mild stress (CMS) and glucocorticoids dramatically increased the expression of NF-κB subunits p50 and p65, phosphorylation and acetylation of p65, and the level of nuclear p65 in vivo and in vitro, implicating activation of NF-κB signaling in chronic stress-induced pathological processes. Using the novelty-suppressed feeding (NSF) and elevated-plus maze (EPM) tests, we found that treatment with pyrrolidine dithiocarbamate (PDTC; intra-hippocampal infusion), an inhibitor of NF-κB, rescued the CMS- or glucocorticoid-induced anxiogenic behaviors in mice. Microinjection of PDTC into the hippocampus reversed CMS-induced up-regulation of neuronal nitric oxide synthase (nNOS), carboxy-terminal PDZ ligand of nNOS (CAPON), and dexamethasone-induced ras protein 1 (Dexras1) and dendritic spine loss of dentate gyrus (DG) granule cells. Moreover, over-expression of CAPON by infusing LV-CAPON-L-GFP into the hippocampus induced nNOS-Dexras1 interaction and anxiety-like behaviors, and inhibition of NF-κB by PDTC reduced the LV-CAPON-L-GFP-induced increases in nNOS-Dexras1 complex and anxiogenic-like effects in mice. These findings indicate that hippocampal NF-κB mediates anxiogenic behaviors, probably via regulating the association of nNOS-CAPON-Dexras1, and uncover a novel approach to the treatment of anxiety disorders.
Subject(s)
Anxiety/etiology , Anxiety/pathology , Hippocampus/cytology , NF-kappa B/metabolism , Nitric Oxide Synthase Type I/metabolism , PDZ Domains/physiology , Stress, Psychological/complications , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Animals, Newborn , Antioxidants/pharmacology , Behavior, Animal/drug effects , Corticosterone/metabolism , Corticosterone/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Microtubule-Associated Proteins/metabolism , Pyrrolidines/pharmacology , Signal Transduction/physiology , Stress, Psychological/pathology , Thiocarbamates/pharmacology , Transcription Factor RelA/genetics , Transcription Factor RelA/metabolism , ras Proteins/metabolismABSTRACT
Jasmine virus H (JaVH) is a novel virus associated with symptoms of yellow mosaic on jasmine. The JaVH genome is 3,867 nt in length with five open reading frames (ORFs) encoding a 27-kDa protein (ORF 1), an 87-kDa replicase protein (ORF 2), two centrally located movement proteins (ORF 3 and 4), and a 37-kDa capsid protein (ORF 5). Based on genomic and phylogenetic analysis, JaVH is predicted to be a member of the genus Pelarspovirus in the family Tombusviridae.
Subject(s)
Genome, Viral , Jasminum/virology , Phylogeny , RNA, Viral/genetics , Tombusviridae/genetics , Base Sequence , Capsid Proteins/genetics , High-Throughput Nucleotide Sequencing , Open Reading Frames , RNA-Dependent RNA Polymerase/genetics , Tombusviridae/classification , Tombusviridae/isolation & purificationABSTRACT
Mechanisms underlying the female preponderance in affective disorders are poorly understood. Here we show that hippocampal nitric oxide (NO) plays a role in the sex difference of depression-like behaviors in rodents. Female mice had substantially lower NO production in the hippocampus and were significantly more likely to display negative affective behaviors than their male littermates. Eliminating the difference in the basal hippocampal NO level between male and female mice mended the sex gap of affective behaviors. Estradiol exerted a positive control on hippocampal NO production via estrogen receptor-ß-mediated neuronal NO synthase expression. Thus, low estrogen in the female hippocampus accounts for lower local NO than in the male hippocampus. Although estrogen has important significance in modulating affective behaviors, it is not estrogen but NO in the hippocampus that mediates the sex difference of affective behaviors directly, because hippocampal NO was necessary for the behavioral effects of estradiol, and NO was an independent factor in modulating behaviors. Stress promoted hippocampal NO production in males because of glucocorticoid release, thus leading to local NO excess. In contrast, stress suppressed NO production in females because of decreased estrogen, thereby resulting in hippocampal NO shortage. Whereas activating cAMP response element binding protein (CREB) rescued the depression-like effects of the intrahippocampal NO donor diethylenetriamine/nitric oxide adduct (DETA/NONOate), inactivating CREB abolished the antidepressant-like effects of the intrahippocampal NO donor DETA/NONOate. Our findings suggest a molecular mechanism underlying the sex difference of affective behaviors.
Subject(s)
Behavior, Animal/physiology , Hippocampus/physiology , Mood Disorders/physiopathology , Nitric Oxide/physiology , Sex Characteristics , Androgens/pharmacology , Androgens/physiology , Animals , CREB-Binding Protein/physiology , Chronic Disease , Corticosterone/pharmacology , Depressive Disorder/physiopathology , Estradiol/pharmacology , Estradiol/physiology , Estrogens/pharmacology , Estrogens/physiology , Female , Hippocampus/cytology , Male , Mice , Mice, Inbred Strains , Neurons/drug effects , Neurons/physiology , Organ Culture Techniques , Ovariectomy , Stress, Psychological/physiopathology , Testosterone/pharmacology , Testosterone/physiologyABSTRACT
Low-dose irradiation (LDI) induces osteoblast differentiation, however the underlying mechanisms are not fully understood. In this study, we explored the potential role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-Akt signaling in LDI-induced osteoblast differentiation. We confirmed that LDI promoted mouse calvarial osteoblast differentiation, which was detected by increased alkaline phosphatase (ALP) activity as well as mRNA expression of type I collagen (Col I) and runt-related transcription factor 2 (Runx2). In mouse osteoblasts, LDI (1Gy) induced phosphorylation of DNA-PKcs and Akt (mainly at Ser-473). The kinase inhibitors against DNA-PKcs (NU-7026 and NU-7441) or Akt (LY294002, perifosine and MK-2206), as well as partial depletion of DNA-PKcs or Akt1 by targeted-shRNA, dramatically inhibited LDI-induced Akt activation and mouse osteoblast differentiation. Further, siRNA-knockdown of SIN1, a key component of mTOR complex 2 (mTORC2), also inhibited LDI-induced Akt Ser-473 phosphorylation as well as ALP activity increase and Col I/Runx2 expression in mouse osteoblasts. Co-immunoprecipitation (Co-IP) assay results demonstrated that LDI-induced DNA-PKcs-SIN1 complexation, which was inhibited by NU-7441 or SIN1 siRNA-knockdown in mouse osteoblasts. In summary, our data suggest that DNA-PKcs-SIN1 complexation-mediated Akt activation (Ser-473 phosphorylation) is required for mouse osteoblast differentiation.
Subject(s)
Carrier Proteins/metabolism , Cell Differentiation/radiation effects , DNA-Activated Protein Kinase/metabolism , DNA-Binding Proteins/metabolism , Nuclear Proteins/metabolism , Osteoblasts/radiation effects , Proto-Oncogene Proteins c-akt/metabolism , Alkaline Phosphatase/metabolism , Animals , Base Sequence , Cells, Cultured , DNA Primers , Dose-Response Relationship, Radiation , Enzyme Activation , Mice , Osteoblasts/enzymology , Osteoblasts/metabolism , Real-Time Polymerase Chain ReactionABSTRACT
Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is attributed to age-related macular degeneration (AMD) pathogenesis. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, Annona glabra, has displayed significant cyto-protective activity. In the current study, we explored the pro-survival effect of FLZ in oxidative stressed-RPE cells and studied the underlying signaling mechanisms. Our results showed that FLZ attenuated hydrogen peroxide (H2O2)-induced viability decrease and apoptosis in the RPE cell line (ARPE-19 cells) and in primary mouse RPE cells. Western blotting results showed that FLZ activated AKT signaling in RPE cells. The AKT-specific inhibitor, MK-2206, the phosphoinositide 3-kinase (PI3K)/AKT pan inhibitor, wortmannin, and AKT1-shRNA (short hairpin RNA) depletion almost abolished FLZ-mediated pro-survival/anti-apoptosis activity. We discovered that epidermal growth factor receptor (EGFR) trans-activation mediated FLZ-induced AKT activation and the pro-survival effect in RPE cells, and the anti-apoptosis effect of FLZ against H2O2 was inhibited by the EGFR inhibitor, PD153035, or by EGFR shRNA-knockdown. In conclusion, FLZ protects RPE cells from oxidative stress through activation of EGFR-AKT signaling, and our results suggest that FLZ might have therapeutic values for AMD.
Subject(s)
Benzeneacetamides/pharmacology , ErbB Receptors/metabolism , Oxidative Stress/drug effects , Phenols/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Retinal Pigment Epithelium/drug effects , Animals , Apoptosis/drug effects , Cell Line , Cell Survival/drug effects , Cells, Cultured , Humans , Hydrogen Peroxide/metabolism , Mice , Mice, Inbred C57BL , Phosphatidylinositol 3-Kinases/metabolism , Reactive Oxygen Species/metabolism , Retinal Pigment Epithelium/cytology , Retinal Pigment Epithelium/metabolism , Signal Transduction/drug effectsABSTRACT
Chronic stress leads to social avoidance and anhedonia in susceptible individuals, a phenomenon that has been observed in both human and animal models. Nevertheless, the underlying molecular mechanisms underpinning stress susceptibility and resilience remain largely unclear. There is growing evidence that epigenetic histone deacetylase (HDAC) mediated histone acetylation is involved in the modulation of depressive-related behaviors. We hypothesized that histone deacetylase 5 (HDAC5), which is associated with stress-related behaviors and antidepressant response, may play a vital role in the susceptibility to chronic stress. In the current study, we detected the levels of HDAC5 and acetylation of histone 4 (H4) in the hippocampus subsequent to chronic social defeat stress (CSDS) in C57BL/6J mice. We found that CSDS induces a notable increase in HDAC5 expression, concomitant with a reduction in the acetylation of histone H4 at lysine 12 (H4K12) in the hippocampus of susceptible mice. Meanwhile, intrahippocampal infusion of HDAC5 shRNA or HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) both reversed the depression susceptibility in susceptible mice that subjected to CSDS. Furthermore, HDAC5 overexpression was sufficient to induce depression susceptibility following microdefeat stress, accompanied by a significant reduction in H4K12 level within the hippocampus of mice. Additionally, the Morris water maze (MWM) results indicated that neither CSDS nor HDAC5 exerted significant effects on spatial memory function in mice. Taken together, these investigations indicated that HDAC5-modulated histone acetylation is implicated in regulating the depression susceptibility, and may be serve as potential preventive targets for susceptible individuals.
Subject(s)
Hippocampus , Histone Deacetylases , Histones , Mice, Inbred C57BL , Social Defeat , Stress, Psychological , Animals , Stress, Psychological/metabolism , Hippocampus/metabolism , Acetylation , Histones/metabolism , Histone Deacetylases/metabolism , Male , Depression/metabolism , Histone Deacetylase Inhibitors/pharmacology , Mice , Vorinostat/pharmacology , Disease Susceptibility/metabolism , Disease Models, AnimalABSTRACT
BACKGROUND: With the continuous growth of the modern elderly population, the risk of fracture increases. Hip fracture is a common type of fracture in older people. Total hip arthroplasty (THA) has significant advantages in relieving chronic pain and promoting the recovery of hip joint function. AIM: To investigate the effect of ulinastatin combined with dexmedetomidine (Dex) on the incidences of postoperative cognitive dysfunction (POCD) and emergence agitation in elderly patients who underwent THA. METHODS: A total of 397 patients who underwent THA from February 2019 to August 2022. We conducted a three-year retrospective cohort study in Shaanxi Provincial People's Hospital. Comprehensive demographic data were obtained from the electronic medical record system. We collected preoperative, intraoperative, and postoperative data. One hundred twenty-nine patients who were administered Dex during the operation were included in the Dex group. One hundred fifty patients who were intravenously injected with ulinastatin 15 min before anesthesia induction were included in the ulinastatin group. One hundred eighteen patients who were administered ulinastatin combined with Dex during the operation were included in the Dex + ulinastatin group. The patients' perioperative conditions, hemodynamic indexes, postoperative Mini-Mental State Examination (MMSE) scores, Ramsay score, incidence of POCD, and serum inflammatory cytokines were evaluated. RESULTS: There was a significant difference in the 24 h visual analogue scale score among the three groups, and the score in the Dex + ulinastatin group was the lowest (P < 0.05). Compared with the Dex and ulinastatin group, the MMSE scores of the Dex + ulinastatin group were significantly increased at 1 and 7 d after the operation (all P < 0.05). Compared with those in the Dex and ulinastatin groups, incidence of POCD, levels of serum inflammatory cytokines in the Dex + ulinastatin group were significantly decreased at 1 and 7 d after the operation (all P < 0.05). The observer's assessment of the alertness/sedation score and Ramsay score of the Dex + ulinastatin group were significantly different from those of the Dex and ulinastatin groups on the first day after the operation (all P < 0.05). CONCLUSION: Ulinastatin combined with Dex can prevent the occurrence of POCD and emergence agitation in elderly patients undergoing THA.
ABSTRACT
The hippocampus is rich in both glucocorticoid receptor (GR) and neuronal nitric oxide synthase (nNOS). But the relationship between the two molecules under physiological states remains unrevealed. Here, we report that nNOS knockout mice display increased GR expression in the hippocampus. Both systemic administration of 7-Nitroindazole (7-NI), a selective nNOS activity inhibitor, and selective infusion of 7-NI into the hippocampus resulted in an increase in GR expression in the hippocampus. Moreover, KCl exposure, which can induce overexpression of nNOS, resulted in a decrease in GR protein level in cultured hippocampal neurons. Moreover, blockade of nNOS activity in the hippocampus leads to decreased corticosterone (CORT, glucocorticoids in rodents) concentration in the plasma and reduced corticotrophin-releasing factor expression in the hypothalamus. The results indicate that nNOS is an endogenous inhibitor of GR in the hippocampus and that nNOS in the hippocampus may participate in the modulation of Hypothalamic-Pituitary-Adrenal axis activity via GR.
Subject(s)
Hippocampus/enzymology , Nitric Oxide Synthase Type I/antagonists & inhibitors , Nitric Oxide Synthase Type I/physiology , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/biosynthesis , Animals , Enzyme Inhibitors/pharmacology , Hippocampus/drug effects , Indazoles/pharmacology , Male , Mice , Mice, 129 Strain , Mice, KnockoutABSTRACT
OBJECTIVE: To compare the quality of red ginseng in different transplanting systems, and thus provide the basis for ginseng cultivation and processing. METHOD: Based on the Chinese Pharmacopoeia and literature relating to red ginseng, the ten ginsenosides, total ash, acid-insoluble ash, volatile oil, ether extract and total protein of red ginseng in different transplanting systems were studied or determined. RESULT AND CONCLUSION: The content of total ash and acid-insoluble ash in red ginseng was less than 5.0%, 0.3%, respectively. The content of three ginsenosides (Rg1, Re, Rb1) was in accordance with the requirements of Chinese Pharmacopoeia version 2010, and the content of ten ginsenosides was significant different.
Subject(s)
Panax/chemistry , China , Chromatography, High Pressure Liquid , Drugs, Chinese Herbal/analysis , Panax/growth & development , Quality ControlABSTRACT
In the central nervous system, nitric oxide (NO), a free gas with multitudinous bioactivities, is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase (nNOS). In the past 20 years, the studies in our group and other laboratories have suggested a significant involvement of nNOS in a variety of neurological and neuropsychiatric disorders. In particular, the interactions between the PDZ domain of nNOS and its adaptor proteins, including post-synaptic density 95, the carboxy-terminal PDZ ligand of nNOS, and the serotonin transporter, significantly influence the subcellular localization and functions of nNOS in the brain. The nNOS-mediated protein-protein interactions provide new attractive targets and guide the discovery of therapeutic drugs for neurological and neuropsychiatric disorders. Here, we summarize the work on the roles of nNOS and its association with multiple adaptor proteins on neurological and neuropsychiatric disorders.
Subject(s)
Adaptor Proteins, Signal Transducing , Nervous System Diseases , Humans , Nitric Oxide Synthase Type I/metabolism , Brain/metabolismABSTRACT
The family Neopseustidae is reported from Yunnan Province, Southwest China, for the first time, with a new species, N. gaoligongensis Huang & Chen, sp. n., described from Mt. Gaoligong, West Yunnan, based on molecular and morphological evidence. The new species was found to belong to the N. bicornuta species-group and is closely related to N. fanjingshana Yang, 1988, but can be distinguished from it by the differences in morphology and a 3.2% COI distance. Adults and genitalia of the new species and N. fanjingshana are illustrated, and the molecular phylogeny based on COI barcoding of the genus Neopseustis is also updated.