nNOS-mediated protein-protein interactions: promising targets for treating neurological and neuropsychiatric disorders

Neurological and neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people.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 brain.Inhibiting nNOS benefits a variety of neurological and neuropsychiatric disorders,including stroke,depression and anxiety disorders,posttraumatic stress disorder,Parkinson’s disease,Alzheimer’s disease,chronic pain,and drug addiction.Due to critical roles of nNOS in learning and memory and synaptic plasticity,direct inhibition of nNOS may cause severe side effects.Importantly,interactions of several proteins,including post-synaptic density 95(PSD-95),carboxyterminal PDZ ligand of nNOS(CAPON)and serotonin transporter(SERT),with the PSD/Disc-large/ZO-1 homologous(PDZ)domain of nNOS have been demonstrated to influence the subcellular distribution and activity of the enzyme in the brain.Therefore,it will be a preferable means to interfere with nNOS-mediated proteinprotein interactions(PPIs),which do not lead to undesirable effects.Herein,we summarize the current literatures on nNOS-mediated PPIs involved in neurological and neuropsychiatric disorders,and the discovery of drugs targeting the PPIs,which is expected to provide potential targets for developing novel drugs and new strategy for the treatment of neurological and neuropsychiatric disorders.     

苍白球功能变化与帕金森症

As an important nucleus of basal ganglia, globus pallidus was concerned to involve in the neural mechanism of Parkinss disease (PD). Previous studies of PD patients and animal model indicate that neurotransmitters and receptors are changed in globus pallidus neurons, the balance between inhibition and excitation is broken in the output nuclei of basal ganglia, and globus pallidus neurons display bursting and oscillatory discharge, the synchronous tendency of neighboring neurons enhances. These neurophysiological changes are associated with PD symptoms, such as bradykinesia, rigidity and tremor, which reflects that globus pallidus plays an important role in the process of PD. In the present paper, the recent advances in pathophysiology in globus pallidus, its clinical application in treatment of Parkinsons disease, and the study direction in the future are reviewed.     

Chronic Obstructive Pulmonary Disease： Evidence for an Autoimmune Component

Chronic obstructive pulmonary disease （COPD） is characterized by an irreversible limitation on pulmonary airflow associated with chronic inflammation and mucous hypersecretion （chronic bronchitis） and/or the pathological destruction of alveolar airspaces leading to emphysema. COPD, predominantly as a result of tobacco smoke exposure, represents the fourth leading cause of mortality worldwide and its prevalence is increasing. Despite this, much of the basic mechanisms which contribute to disease progression remain to be elucidated and current therapeutic approaches are, for the most part, based upon alleviating patient symptoms （bronchodilators） as opposed to treating the underlying pathological mechanisms triggered in response to cigarette smoke exposure. The classic disease paradigm suggests that an imbalance of pulmonary matrix proteases versus anti-proteases underlies the tissue destruction and inflammation associated with COPD. However, there is a growing appreciation of the complex and multifaceted nature of the pathological mechanisms associated with disease progression. Recently, there has been mounting evidence indicating that COPD patients exhibit many of the characteristics of a classical autoimmune response. We will discuss current evidence in support of this paradigm and outline how future therapeutic approaches may be tailored to address this.     

Applying Surface Fitting in the Medical Thermal Tomography Technology

Based on the thermal tomography technology, this thesis tries to calculate quantity and distribution of heat source in vivo from body surface temperature. A superposition temperature image of a number of point heat sources is surface fitted to get the Q of heat sources (information of cancer cells) quantitatively. The result can reflect the disease area information because cancer cell’s Q value is much higher than that of normal cell. This application is a new try in the diagnosis of breast cancer, which has an important value on the early detection and diagnosis of disease source.     

Key role of microRNAs in mitochondrial fusion protein 1-mediated pulmonary vascular remodeling

<正>AIM:To investigate the pathological process of abnormal pulmonary arterial smooth muscle cell(PASMC)proliferation in the hypoxic pulmonary arterial hypertension(PAH)and the underlying molecular mechanism.METHODS:The methods of animal models,cell biology and molecular biology were used to detect the mitochondrial fusion protein 1(Mfn1)in hypo-xia-induced proliferation of     

Vascular Damages in Rats Immunized by α1-Adrenoceptor Peptides

Autoantibodies against the α1-adrenoceptor which had agonist activity as norepinephrine might play roles in the progression of hypertension,but whether the autoantibodies could induce vascular remodeling as norepinephrine is not clear.in this paper,the models with antibodies against the α1-adrenoceptor were made by immunizing Wistar rats with the synthesized the second extracellular loop of α1-adrenoceptor peptides.The homo-age male Wistar rats received BSA in the same immunizing manner and male spontaneous hypertensive rats(SHR)were used as control.All the rats were raised for one year.The blood pressure and morphological changes of arteries were measured.in the end,despite the systolic blood pressure of immunized rats had no difference with normal control,the media thickness of aortas and ratio of media to Iumen in the third-order arteries of mesenteric vasculature were increased in immunized rats.The observation with electron microscope showed that the mitochondria of vascular smooth muscle cells(VSMCs)had notable hyperplasia,and the interstitial collagen fibril was increased too.The effects of purified antibodies against α1-adrenoceptor on the proliferation of cultured VSMCs,and the expressions of c-jun,c-fos and α-adrenoceptor were detected.The results showed that the antibodies could promote the proliferation of cultured VSMCs,and enhance the expression of c-jun both in vitro and in vivo.So we concluded that antibodies against the α-adrenoceptor could contribute to vascular damages in rats by stimulating the growth of VSMCs which might be caused by the increased c-jun expression,and might play particular roles in the pathological changes of hypertension.     

Effects of serum containing wuzang wenyang huayu decoction on phosphorylated-tau protein expression in alzheimer’s disease cell model北大核心

BACKGROUND: Various previous studies have shown that Wuzang Wenyang Huayu Decoction has a good therapeutic effect on Alzheimer’s disease, but its pharmacological mechanism has not been fully elucidated. OBJECTIVE: To investigate the effect of Wuzang Wenyang Huayu Decoction drug-containing serum on the expression of peroxisome proliferator-activated receptor γ and phosphorylated-tau protein in Alzheimer’s disease cell model. METHODS: Beta amyloid protein was used to induce primary hippocampal neurons to establish the currently recognized Alzheimer’s disease cell model. Wuzang Wenyang Huayu Decoction drug-containing serum and donepezil hydrochloride drug-containing serum were given for intervention for 72 hours. The dendritic length and branch number of primary neurons cells were detected by immunofluorescence assay. The expression levels of peroxisome proliferator-activated receptor γ and phosphorylated-tau protein were detected by western blot assay. RESULTS AND CONCLUSION: Compared with the control group, the length and branch number of dendritic cells in the model group were significantly decreased (P < 0.05), peroxisome proliferator-activated receptor γ expression decreased, and phosphorylated-tau protein increased (P < 0. 05 or P < 0. 01). Compared with the model group, the dendritic length and branch number of neurons in Wuzang Wenyang Huayu group and donepezil hydrochloride group increased, the expression of PPARγ increased, and the expression of phosphorylated-tau protein significantly decreased (P < 0. 05 or P < 0. 01). Results confirmed that Wuzang Wenyang Huayu Decoction has neuroprotective effect on Alzheimer’s disease cells induced by beta amyloid protein, and its mechanism may be related to upregulation of peroxisome proliferator-activated receptor γ protein and inhibition of phosphorylated-tau protein. © 2022, Publishing House of Chinese Journal of Tissue Engineering Research. All rights reserved.     

Vascular damages in rats immunized by alpha1-adrenoceptor peptides

Autoantibodies against the α1-adrenoceptor which had agonist activity as norepinephrine might play roles in the progression of hypertension, but whether the autoantibodies could induce vascular remodeling as norepinephrine is not clear. In this paper, the models with antibodies against the α1-adrenoceptor were made by immunizing Wistar rats with the synthesized the second extracellular loop of α1-adrenoceptor peptides. The homo-age male Wistar rats received BSA in the same immunizing manner and male spontaneous hypertensive rats （SHR） were used as control. All the rats were raised for one year. The blood pressure and morphological changes of arteries were measured. In the end, despite the systolic blood pressure of immunized rats had no difference with normal control, the media thickness of aortas and ratio of media to lumen in the third-order arteries of mesenteric vasculature were increased in immunized rats. The observation with electron microscope showed that the mitochondria of vascular smooth muscle cells （VSMCs） had notable hyperplasia, and the interstitial collagen fibril was increased too. The effects of purified antibodies against α1-adrenoceptor on the proliferation of cultured VSMCs, and the expressions of c-jun, c-fos and α1-adrenoceptor were detected. The results showed that the antibodies could promote the proliferation of cultured VSMCs, and enhance the expression of c-jun both in vitro and in vivo. So we concluded that antibodies against the α1-adrenoceptor could contribute to vascular damages in rats by stimulating the growth of VSMCs which might be caused by the increased c-jun expression, and might play particular roles in the pathological changes of hypertension.     

外泌体中Micro-RNA可作为疾病的生物标志物？

BACKGROUND: Exosome, a kind of cystic vesicle with bilayer structure, is widely distributed in the body fluids. Exosomes are involved in various cellular communications, and its contents including proteins, short chain peptides, DNA, RNA, phospholipids, and miRNA are resistant to degradation. OBJECTIVE: To clarify the characters of exosomes, and to investigate the possibility of exosomal miRNAs as biomarkers for different diseases to provide a new strategy for clinical diagnosis. METHODS:A computer-based search of CNKI and PubMed databases was performed by the first author for articles related to exosomal miRNAs. The keywords were “exosome, microvesicles, extracellular vesicles, miRNA, biomarker, early diagnosis, progrosis” in Chinese and English, respectively. Totally 50 eligible articles were included in result analysis. RESULTS AND CONCLUSION: After reviewing researches of exosomes in different diseases, we can confirm that exosomes broadly participant in physiological and pathological process of various system diseases. The abnormal expression of exosomal micro-RNAs has been identified in many studies, indicating the exosomal micro-RNAs have a great potential to be biomarkers for disease diagnosis. Further studies should focus on extracting the contents of exosomes, the pathogenesis of exosomes is involved in and screening the appropriate exosomal miRNAs for early diagnosis. 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Gender-based differences in cardiac diseases

It has been observed that the incidence of heart failure and Brugada syndrome are higher in men,while women are more likely to have QT interval prolongation and develop torsades de pointes (TdP).Over the past decade,new studies have improved our understanding of the mechanisms of abnormal repolarization and the relationship between gender differences in cardiac repolarization and presentation of clinical syndromes.Nevertheless,the causes of gender-based differences in cardiac disease are still not completely clear.This review paper briefly summarized what is currently known about gender differences in heart failure,Brugada syndrome and long QT syndrome from molecular mechanisms to clinical presentations.     

The role of neutrophils in the development of liver diseases

Liver disease encompasses a wide variety of liver conditions, including liver failure, liver cirrhosis and a spectrum of acute and chronic hepatitis, such as alcoholic, fatty, drug, viral and chronic hepatitis. Liver injury is a primary causative factor in liver disease; generally, these factors include direct liver damage and immune-mediated liver injury. Neutrophils （also known as neutrophilic granulocytes or polymorphonuclear leukocytes （PMNs）） are the most abundant circulating white blood cell type in humans, and PMNs are a major innate immune cell subset. Inappropriate activation and homing of neutrophils to the microvasculature contributes to the pathological manifestations of many types of liver disease. This review summarizes novel concepts of neutrophil-mediated liver iniurv that are based on current clinical and animal model studies.     

Extracellular matrix synthesis in vascular disease:hypertension,and atherosclerosis

Extracellular matrix(ECM) within the vascular network provides both a structural and regulatory role.The ECM is a dynamic composite of multiple proteins that form structures connecting cells within the network.Blood vessels are distended by blood pressure and,therefore,require ECM components with elasticity yet with enough tensile strength to resist rupture.The ECM is involved in conducting mechanical signals to cells.Most importantly,ECM regulates cellular function through chemical signaling by controlling activation and bioavailability of the growth factors.Cells respond to ECM by remodeling their microenvironment which becomes dysregulated in vascular diseases such hypertension,restenosis and atherosclerosis.This review examines the cellular and ECM components of vessels,with specific emphasis on the regulation of collagen type I and implications in vascular disease.     

补肾益智方对D-半乳糖联合β-淀粉样蛋白25-35致老年痴呆模型 大鼠的作用及机制

BACKGROUND: Traditional Chinese medicine compound has the characteristics of multiple targets, which can regulate the central nervous system through a plurality of links, and can effectively improve the cognitive function of patients. Bushen Yizhi Decoction has been proven to improve the symptoms of patients with Alzheimer’s disease, thereby improving the quality of life. OBJECTIVE: To explore the effects of Bushen Yizhi Decoction on learning and memory abilities in seniledementia rats induced by D-galactose combined with amyloid-beta 25-35 and the underlying mechanism. METHODS:Healthy adult Sprague-Dawley rats were equivalently randomized into groups of control, model, positive drug (0.3 g/kg donepezil), high-dose drug (20 g/kg Bushen Yizhi Decoction) and low-dose drug (5 g/kg Bushen Yizhi Decoction). Model rats with Alzheimer's disease were established by subcutaneous injection of D-galactose and bilateral hippocampuses injected with amyloid-beta 25-35. After 8-week treatment with intragastric administration of Bushen Yizhi Decoction, the spatial learning and memory capacity were examined by the Morris water maze. High frequency stimulation was given on CA3 Schaffer collateral-commissural pathway, and long-term potentiation in hippocampal CA1 region was recorded to detect the change of synaptic plasticity in rat’s hippocampal neurons, and the levels of superoxide dismutase, malondiadehyde, monoamine oxidase B, choline acetyltransferase, acetylcholin esterase, tumor necrosis factor-α and interleukin-1 were detected. RESULTS AND CONCLUSION: (1) Morris water maze tests showed that the groups of Bushen Yizhi Decoction could remarkably improve the spatial learning and memory capacity of rats. Compared with the control group, the long-term potentiation in hippocampal CA1 region was significantly suppressed in model rats (P < 0.05). (2) There was no significant difference in the phase-shift amplitude between the model and the low-dose drug groups; however, the phase-shift amplitude in the high-dose drug group was significantly higher than that in the model and low-dose drug groups, high-dose drug relieved the suppression of long term potentiation, and the synaptic plasticity was significantly improved. (3) Bushen Yizhi Decoction could significantly decrease the levels of tumor necrosis factor-α, interleukin-1 and malondiadehyde as well as the activity of acetylcholin esterase, and significantly increase the activity of superoxide dismutase and choline acetyltransferase (P < 0.05). (4) These results suggest that the nootropic effect of Bushen Yizhi Decoction on the rat model of Alzheimer’s disease may be related with the inhibition of inflammation, adjustment of cholinergic nerve transmitter activity and antioxidation.  中国组织工程研究杂志出版内容重点：肾移植;肝移植;移植;心脏移植;组织移植;皮肤移植;皮瓣移植;血管移植;器官移植;组织工程     

Chemerin,a novel player in inflammatory bowel disease

Inflammatory bowel disease （IBD） manifests during Crohn＇s disease and ulcerative colitis as well as in a group of inflammatory disorders of the gastrointestinal tract.1 The etiology of IBD is thought to be a combination of genetics and environmental factors, including the microbiome and immune system of the individual.     

Clinical usefulness of ankle brachial index and brachial-ankle pulse wave velocity in patients with ischemic stroke

Ankle brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) are widely used noninvasive modalities to evaluate atherosclerosis. Recently, evidence has increased supporting the use of ABI and baPWV as markers of cerebrovascular disease. This study sought to examine the relationship between ABI and baPWV with ischemic stroke. This study also aimed to determine which pathogenic mechanism, large artery disease (LAD) or small vessel disease (SVD), is related to ABI or baPWV. Retrospectively, 121 patients with ischemic stroke and 38 subjects with no obvious ischemic stroke history were recruited. First, ABI and baPWV were compared between the groups. Then, within the stroke group, the relevance of ABI and baPWV with regard to SVD and LAD, which were classified by brain magnetic resonance image (MRI) and magnetic resonance angiography (MRA) or computed tomography angiography (CTA) findings, was assessed. The baPWV was higher in the stroke group than non-stroke group (1,944.18土416.6 cm/s vs. 1,749.76土669.6 cm/s, P< 0.01). Regarding LAD, we found that mean ABI value was lower in the group with extacranial large artety stenosis (P < 0.01), and there was an inverse linear correlation between ABI and the grade of extracranial large artery stenosis (P<0.01). For SVD, there was a significant correlation between SVD and baPWV (2,057.6土456.57 cm/s in the SVD (+) group vs. 1,491 土271.62 cm/s in the SVD (-) group; P<0.01). However, the grade of abnormalities detected in SVD did not correlate linearly with baPWV. These findings show that baPWV is a reliable surrogate marker of ischemic stroke. Furthermore, baPWV and ABI can be used to indicate the presence of small vessel disease and large arterial disease, respectively.     

REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters

An urgent global quest for effective therapies to prevent and treat coronavirus disease 2019(COVID-19)is ongoing.We previously described REGN-COV2,a cocktail of two potent neutralizing antibodies(REGN10987 and REGN10933)that targets nonoverlapping epitopes on the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike protein.In this report,we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques,which may model mild disease,and golden hamsters,which may model more severe disease.We demonstrate that REGN-COV-2 can greatly reduce virus load in the lower and upper airways and decrease virus-induced pathological sequelae when administered prophylactically or therapeutically in rhesus macaques.     

Autoantibodies highly increased in patients with thyroid dysfunction

To evaluate the significance of antithyroid antibodie levels, five hundred and twenty-six patients with thyroid diseases and 292 health subjects from Yuci district, Shanxi province, China, were studied. Serum levels were determined for thyroid hormone receptor antibody （TRAb）, microsomal antibody （TMAb） and thyroglobulin antibody （TGAb）. Among patients, the percentages for nodular goiter and thyroid adenoma, Graves＇ disease, and Hashimoto＇s thyroiditis are 44.1%, 19.6% and 17.7%, respectively. The ratios of female to male were 2.0 to 15.6. Antibody-positive patients for TMAb, TGAb and TRAb were detectable as 94.6%, 76.3% and 20.4% for Hashimoto＇s thyroiditis, and 40.0%, 30.0% and 90.3% for Graves＇s disease. In conclusion, the high levels of the TRAb in Graves＇ disease, and those of the TGAbFFMAb in Hashimoto＇s thyroiditis and idiopathic hypothyroidism are meaningful for characterizing the epidemiological basis of the diseases and for using as prognostic indicators for the relapse in individual patients. Cellular ＆ Molecular Immunology.     

医学前沿

Auto-aggressive CXCR6 + CD8 T cells cause liver immune pathology in NASHMichael DudekNonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liverdisease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, but mechanisticunderstandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features ofhuman NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology.     

Future directions of clinical laboratory evaluation ol pregnancy

In recent years, our understanding of how the immune system interacts with the developing fetus and placenta has greatly expanded. There are many laboratories that provide tests for diagnosis of pregnancy outcome in women who have recurrent pregnancy loss （RPL） or pre-eclampsia. These tests are based on the premise that immune response to the fetus is equivalent to the adaptive immune response to a transplant. New understanding leads to the concept that the activated innate response is vital for pregnancy and this can result in more effective testing and treatment to prevent an abnormal pregnancy in the future. We describe here only three such areas for future testing： one area involves sperm and semen and factors necessary for successful fertilization; another area would determine conditions for production of growth factors necessary for implantation in the uterus; finally, the last area would be to determine conditions necessary for the vascularization of the placenta and growing fetus by activated natural killer （NK） cells （combinations of killer cell immunoglobulin-like receptor （KIR） family genes with HLA-C haplotypes） that lead to capability of secreting angiogenic growth factors. These areas are novel but understanding their role in pregnancy can lead to insight into how to maintain and treat pregnancies with complicating factors.