Mitochondrial dynamics in neurological diseases: a narrative review.

Background and Objective: The mitochondrion is a crucial organelle for aerobic respiration and energy metabolism. It undergoes dynamic changes, including changes in its shape, function, and distribution through fission, fusion, and movement. Under normal conditions, mitochondrial dynamics are in homeostasis. However, once the balance is upset, the nervous system, which has high metabolic demands, will most likely be affected. Recent studies have shown that the imbalance of mitochondrial dynamics is involved in the occurrence and development of various neurological diseases. However, whether the regulation of mitochondrial dynamics can be used to treat neurological diseases is still unclear. We aimed to comprehensively analyze mitochondrial dynamics regulation and its potential role in the treatment of neurological diseases. Methods: A comprehensive literature review was carried out to understand the mechanisms and applications of mitochondrial dynamics in neurological diseases based on the literature available in PubMed, Web of Science, and Google Scholar. Key Content and Findings: This review discusses the molecular mechanisms related to mitochondrial dynamics and expounds upon the role of mitochondrial dynamics in the occurrence and development of neurodegenerative diseases, epilepsy, cerebrovascular disease, and brain tumors. Several clinically tested drugs with fewer side effects have been shown to improve the mitochondrial dynamics and nervous system function in neurological diseases. Conclusions: Disorders of mitochondrial dynamics can cause various neurological diseases. Elucidation of mechanisms and applications involved in mitochondrial dynamics will inform the development of new therapeutic targets and strategies for neurological diseases. Dynamin-related protein 1 (Drp1), as a highly relevant molecular for mitochondrial dynamics, might be a potential target for treating neurological diseases in the future.

Transient Receptor Potential Channel Vanilloid 1 Contributes to Facial Mechanical Hypersensitivity in a Mouse Model of Atopic Asthma.

Sensitive skin, a common pathophysiological feature of allergic diseases, is defined as an unpleasant sensation in response to stimuli that normally should not provoke such sensations. However, the relationship between allergic inflammation and hypersensitive skin in the trigeminal system remains to be elucidated. To explore whether bronchial allergic inflammation affects facial skin and primary sensory neurons, we used an ovalbumin (OVA)-induced asthma mouse model. Significant mechanical hypersensitivity was observed in the facial skin of mice with pulmonary inflammation induced by OVA sensitization compared to mice treated with adjuvant or vehicle as controls. The skin of OVA-treated mice showed an increased number of nerve fibers, especially rich intraepithelial nerves, compared to controls. Transient receptor potential channel vanilloid 1 (TRPV1)-immunoreactive nerves were enriched in the skin of OVA-treated mice. Moreover, epithelial TRPV1 expression was higher in OVA-treated mice than in controls. Trigeminal ganglia of OVA-treated mice displayed larger numbers of activated microglia/macrophages and satellite glia. In addition, more TRPV1 immunoreactive neurons were found in the trigeminal ganglia of OVA-treated mice than in controls. Mechanical hypersensitivity was suppressed in OVA-treated Trpv1-deficient mice, while topical skin application of a TRPV1 antagonist before behavioral testing reduced the reaction induced by mechanical stimulation. Our findings reveal that mice with allergic inflammation of the bronchi had mechanical hypersensitivity in the facial skin that may have resulted from TRPV1-mediated neuronal plasticity and glial activation in the trigeminal ganglion.

Increased GLUT1 expression and localization to Golgi apparatus of acinar cells in the parotid gland of Goto-Kakizaki diabetic rats.

OBJECTIVE: Patients with diabetes are known to have high salivary glucose levels. But the mechanisms are still unclear. We hypothesized that the topological changes of glucose transporters affect the salivary glucose level. METHODS: We used adult Goto-Kakizaki (GK) rats, an animal model of advanced diabetes, and Wistar rats as a control, with or without glucose load. The sections of salivary glands from the animals were processed for standard histological, immunohistochemical, and immunofluorescent staining. RESULTS: Parotid acinar cells of GK rats appeared like mucous filled with low-eosin-stained granules and possessing a flat nucleus located basally, whereas those of Wistar rats appeared as a typical serous gland with eosin-rich cytoplasm and a spherical nucleus. Cytoplasmic granules of GK rat parotid acinar cells showed no reaction of polysaccharide staining. In acinar cell cytoplasm of GK rats, intense GLUT1 immunoreactivity was observed compared to Wistar rats. By double immunostaining for GLUT1 and Golgi apparatus-specific markers, it was determined that GLUT1 was localized to the Golgi apparatus. By glucose loading in starved GK rats, the distribution of GLUT1-immunoreactive signals was spread out clearly from the apical side of the nucleus to the basolateral side. CONCLUSIONS: In rat model of diabetes, highly localized GLUT1 at Golgi apparatus in acinar cells seems to increase taking up cytoplasmic glucose to form exocytotic vesicles. This phenomenon may transform parotid glands from serous to mucous-like and result in saccharide-rich saliva.

Real-world safety of ulinastatin: a post-marketing surveillance of 11,252 patients in China.

BACKGROUND: The safety assessment of ulinastatin can guide clinical practice. The present study aimed to investigate the real-world safety of ulinastatin in China. METHODS: This multicenter study retrospectively analyzed the post-marketing surveillance data of consecutive patients treated with ulinastatin between August 2014 and June 2017 in the general wards and the intensive care units (ICU) of nine hospitals in China. Adverse drug reactions/adverse drug events (ADRs/ADEs) were collected and evaluated in a post-marketing database. RESULTS: A total of 11,252 consecutive patients were included in the study: 7009 ICU patients and 4243 general ward patients. Eleven patients with ADRs/ADEs were observed, including nine ICU patients and two general ward patients. The clinical manifestations were liver dysfunction (n = 5 ICU cases, n = 1 general case), thrombocytopenia (n = 2 ICU cases, n = 1 general case), leukopenia (n = 1 ICU case), and rash (n = 1 ICU case). During the study period, the drug ADR/ADE rate of ulinastatin injection was 0.98‰ (11/11,252 × 1000‰). Among the 11,252 valid patients, only 327 received ulinastatin in accordance with the drug specifications. After excluding unreasonable drug use, the calculated ADR rate was 3.06‰ (1/327 × 1000‰) (95% confidence interval: 0.0‰-17.1‰). In ICU and general ward patients, the use of other drugs combined with ulinastatin was associated with the occurrence of ADRs/ADEs (100% with ADRs/ADEs vs. 0% in controls, P < 0.001). CONCLUSIONS: The incidence of ADRs/ADEs of ulinastatin is < 5‰. The ADRs/ADEs involved limited organs, mainly the skin, gastrointestinal tract, and blood. In most cases, the ADRs/ADEs gradually alleviated or recovered after drug withdrawal. The inappropriate/off-label use of ulinastatin should be the focus of surveillance.

Isorhamnetin promotes functional recovery in rats with spinal cord injury by abating oxidative stress and modulating M2 macrophages/microglia polarization.

Spinal cord injury (SCI), mostly caused by sports injuries, falls, or traffic accidents, is a major cause of disability. The aim of current work was to investigate the therapeutic effect of isorhamnetin (ISO) on functional recovery in rats with SCI. The male adult rats were exposed to a clip-compression SCI and treated with ISO. ISO treatment improved locomotor function and reduced the loss of motor neurons in SCI rats. Treatment with ISO markedly relieved SCI-induced hypersensitivities to mechanical and thermal stimulation in rats. ISO treatment activated nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway and abated oxidative stress in injured spinal cords. ISO treatment partly suppressed microglial and glial activation and reduced expression of inflammatory cytokines including TNF-α, monocyte chemotactic protein-1 (MCP-1), and IL-1ß in injured spinal cords. More importantly, ISO treatment promoted M2 macrophage activation in the injured region. lipopolysaccharide (LPS) or IL-4 was employed to stimulate macrophages/microglia into M1 or M2 phenotype in cultured BV2 cells in vitro. ISO treatment enhanced the expression of characteristic microglial anti-inflammatory polarization markers in BV2 cells. In conclusions, ISO treatment promotes functional recovery in rats with SCI by abating oxidative stress and modulating M1/M2 macrophage polarization.

Psychological impact of 2019 novel coronavirus (2019-nCoV) outbreak in health workers in China.

The first case of 2019-nCoV pneumonia infection occurred in Wuhan, Hubei Province, South China Seafood Market in December 2019. As a group with a high probability of infection, health workers are faced with a certain degree of psychological challenges in the process of facing the epidemic. This study attempts to evaluate the impact of 2019-nCoV outbreak on the psychological state of Chinese health workers and to explore the influencing factors. During the period from 31 January 2020 to 4 February 2020, the 'Questionnaire Star' electronic questionnaire system was used to collect data. The 2019-nCoV impact questionnaire and The Impact of Event Scale (IES) were used to check the psychological status of health workers in China. A total of 442 valid data were collected in this study. Seventy-four (16.7%) male and 368 (83.3%) female individuals participated in this study. The average score of high arousal dimension was 5.15 (s.d. = 4.71), and the median score was 4.0 (IQR 2.0, 7.0). The average score of IES was 15.26 (s.d. = 11.23), and the median score was 13.5 (IQR 7.0, 21.0). Multiple regression analysis showed that there were critical statistical differences in high arousal scores among different gender groups (male 3.0 vs. female 5.0, P = 0.075). Whether being quarantined had significant statistical differences of IES scores (being quarantined 16.0 vs. not being quarantined 13.0, P = 0.021). The overall impact of the 2019-nCoV outbreak on health workers is at a mild level. Chinese health workers have good psychological coping ability in the face of public health emergencies.

Enhanced junctional epithelial permeability in TRPV4-deficient mice.

BACKGROUND AND OBJECTIVE: As the interface between the oral cavity and the teeth, the junctional epithelial barrier is critical for gingival defense. The junctional epithelium is subject to mechanical stresses from biting force or external insults such as bacterial attacks, but little is known about the effects of mechanical stimuli on epithelial functions. Transient receptor potential vanilloid 4 (TRPV4) functions as a mechanosensitive nonselective cation channel. In the present study, based on marked expression of TRPV4 in the mouse junctional epithelium, we aimed to clarify the putative links between TRPV4 and junctional complexes in the junctional epithelium. METHODS AND RESULTS: Histological observations revealed that the junctional epithelium in TRPV4-deficient (TRPV4-/- ) mice had wider intercellular spaces than that in wild-type (TRPV4+/+ ) mice. Exogenous tracer penetration in the junctional epithelium was greater in TRPV4-/- mice than in TRPV4+/+ mice, and immunoreactivity for adherens junction proteins was suppressed in TRPV4-/- mice compared with TRPV4+/+ mice. Analysis of a mouse periodontitis model showed greater bone volume loss in TRPV4-/- mice compared with TRPV4+/+ mice, indicating that an epithelial barrier deficiency in TRPV4-/- mice may be associated with periodontal complications. CONCLUSION: The present findings identify a crucial role for TRPV4 in the formation of adherens junctions in the junctional epithelium, which could regulate its permeability. TRPV4 may be a candidate pharmacological target to combat periodontal diseases.

Bilobalide protects H9c2 cell from oxygen-glucose-deprivation-caused damage through upregulation of miR-27a.

Background: Myocardial ischemia is a troublesome disease. Bilobalide possesses multiple biological functions. We researched the consequents of bilobalide in OGD-irritated H9c2 cells. Methods: OGD-stimulated H9c2 cells were treated by bilobalide, and/or transfected with miR-27a inhibitor or negative control. Use CCK-8 and flow cytometry to test cell activity and apoptosis, respectively. Luciferase activity experiment was to test targeting link between miR-27a and Tmub1. Levels of cell-cycle and apoptosis relative proteins and phosphorylation of PI3K/AKT and Wnt/ß-catenin related proteins were detected through western blot. Results: OGD stimulation reduced cell activity and negatively regulated the expression of CDK4, CDK6 and CyclinD1. Cell apoptosis was increased and its related proteins were affected by OGD. Bilobalide administration reversed all the results above caused by OGD. OGD negatively regulated miR-27a while bilobalide upregulated miR-27a. miR-27a's target gene was Tmub1. The protection consequents of bilobalide were suppressed when cells were transfected with a miR-27a inhibitor that cell activity was reduced and apoptosis was raised. Attenuation in the phosphorylation level of PI3K, AKT and ß-catenin by OGD was reversed by bilobalide, whereas there were opposite results after transfected with miR-27a inhibitor. Conclusion: Bilobalide relieved OGD-caused H9c2 cell damage, raising cell activity and attenuating apoptosis via upregulating miR-27a and activating of PI3K/AKT and Wnt/ß-catenin signal pathway. Highlights Bilobalide alleviates OGD-induced H9c2 cell injury. Bilobalide upregulates miR-27a expression in OGD-stimulated H9c2 cells. Bilobalide alleviates cell injury by upregulation of miR-27a. Bilobalide actuates PI3K/AKT and Wnt/ß-catenin pathways.

Impaired Junctions and Invaded Macrophages in Oral Epithelia With Oral Pain.

Recurrent or chronic oral pain is a great burden for patients. Recently, the links between epithelial barrier loss and disease were extended to include initiation and propagation. To explore the effects of pathohistological changes in oral epithelia on pain, we utilized labial mucosa samples in diagnostic labial gland biopsies from patients with suspected Sjögren's syndrome (SS), because they frequently experience pain and discomfort. In most labial mucosa samples from patients diagnosed with SS, disseminated epithelial cellular edema was prevalent as ballooning degeneration. The disrupted epithelia contained larger numbers of infiltrating macrophages in patients with oral pain than in patients without pain. Immunohistochemistry revealed that edematous areas were distinct from normal areas, with disarranged cell-cell adhesion molecules (filamentous actin, E-cadherin, ß-catenin). Furthermore, edematous areas were devoid of immunostaining for transient receptor potential channel vanilloid 4 (TRPV4), a key molecule in adherens junctions. In an investigation on whether impaired TRPV4 affect cell-cell adhesion, calcium stimulation induced intimate cell-cell contacts among oral epithelial cells from wild-type mice, while intercellular spaces were apparent in cells from TRPV4-knockout mice. The present findings highlight the relationship between macrophages and epithelia in oral pain processing, and identify TRPV4-mediated cell-cell contacts as a possible target for pain treatment.

Relationship between left ventricular diastolic dyssynchrony and systolic dyssynchrony in hypertrophic cardiomyopathy by single-cardiac real-time three-dimensional ultrasonography.

The relationship between left ventricular diastolic and systolic dyssynchrony in hypertrophic cardiomyopathy (HCM) was investigated by single-cardiac real-time three-dimensional ultrasonography. A total of 52 patients with HCM were selected in Jining No. 1 People's Hospital from July 2016 to June 2017. Additionally, a total of 52 healthy people were selected to serve as the control group. All participants received real-time two- and three-dimensional ultrasonography to evaluate left ventricular morphology, function and systolic and diastolic function. The relevant parameters included left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), end-systolic/diastolic sphericity index (ESSI/EDSI), systolic dyssynchrony index (SDI), diastolic dyssynchrony index (DDI), dispersion end systole (DISPES), diastolic dyssynchrony index-late (DDI-late) and dispersion end diastole (DISPED-late). The LVEF of observation group was significantly lower than that of the control group, while LVEDV, LVESV, E/A and E/Ea were significantly higher than those in control group (P<0.05); EDSI, DDI-late and DISPED-late were significantly higher in observation than in control group (P<0.05); ESSI, SDI and DISPES in observation were significantly higher than those in control group (P<0.05); The 16-segment time-volume curve of observation group was disordered without synchronization, while the curve of control group was regular and smooth with synchronization; Pearson's correlation analysis showed that SDI and DDI were positively correlated (P<0.05). In conclusion, three-dimensional ultrasonography can be used to effectively evaluate left ventricular diastolic and systolic dyssynchrony in HCM. The severity of diastolic is positively correlated with systolic dyssynchrony.

The oral mucosal membrane and transient receptor potential channels.

The oral cavity is the first line of defense, sensation, and secretion of the alimentary canal. Oral perception contributes to the enjoyment of food and beverages and to avoiding consumption of poisonous or harmful substances. Oral sensation is served by somatosensory nervous systems distributed to the oral membrane. Recent studies reported that oral epithelial cells may transduce temperature and touch through membranous sensors, which comprise ion channels with multimodal properties, and nerves. Here, we describe the possible role of oral epithelial cells in oral perception.

rs10719 Polymorphism Located within DROSHA 3'-Untranslated Region is Responsible for Development of Primary Hypertension by Disrupting Binding with microRNA-27b.

BACKGROUND MiR-27b is reportedly involved with many diseases (e.g., gastric cancer) by acting on different signaling pathways. In this study, we aimed at understanding the relationship between miR-27b and hypertension and its underlying molecular mechanism. MATERIAL AND METHODS Peripheral blood was collected from patients with hypertension, and statistical analysis was performed to study the association between rs10719 and risk of hypertension. Tissue samples were collected from patients with lung cancer, and the expression of miR-27b and DROSHA was determined using Western blot analysis and real-time PCR. RESULTS We first searched the miRNA database online, and identified DROSHA as a virtual target of miR-27b with the "seed sequence" located within the 3'-UTR of the target gene, and then validated DROSHA to be the direct gene via luciferase reporter assay system. We also established the negative regulatory relationship between miR-27b and DROSHA via studying the relative luciferase activity. We also conducted real-time PCR to study the mRNA and protein expression level of miR-27b among different groups. Furthermore, we conducted real-time PCR and densitometry analysis to study the mRNA and protein expression level of DROSHA among different groups of cells treated with scramble control, miR-27b mimics, DROSHA siRNA, and miR-27b inhibitors to verify the negative regulatory relationship between MiR-27b and DROSHA. CONCLUSIONS The presence of rs10719 disrupted the interaction between miR-27b and DROSHA, which might be the underlying mechanism of the observation that rs10719 is significantly associated with risk of primary hypertension.

Ticagrelor overcomes high platelet reactivity in patients with acute myocardial infarction or coronary artery in-stent restenosis: a randomized controlled trial.

High on-treatment platelet reactivity (HTPR) is accompanied by an increased risk of adverse outcomes. Direct comparison of the antiplatelet effects between ticagrelor and high-dose clopidogrel has not yet been reported in acute myocardial infarction (AMI) or coronary artery in-stent restenosis (ISR) patients with HTPR. Consecutive patients with AMI or coronary artery ISR treated with standard-dose clopidogrel (75 mg/day) were screened with the VerifyNow assay, defining HTPR as P2Y12 reaction units (PRUs)>208. Of the 102 screened patients, 48 (47.06%) patients with HTPR were randomly assigned to either ticagrelor (180 mg/90 mg twice daily) or high-dose clopidogrel (150 mg/day) for 24 hours. Baseline characteristics and mean PRUs were similar in both groups. After 24 hours, ticagrelor was associated with a significantly lower platelet reactivity than high-dose clopidogrel (44.38±40.26 vs. 212.58±52.34 PRU, P<0.05). No patient receiving ticagrelor exhibited HTPR, whereas 15 (62.50%) patients after treatment with high-dose clopidogrel remained HTPR (P<0.05). During the follow-up (mean, 138.42±53.59 days), no patient exhibited a major bleeding event in either treatment group. In conclusion, in patients with AMI or coronary artery ISR exhibiting HTPR after standard clopidogrel treatment, ticagrelor is significantly more effective compared with high-dose clopidogrel in overcoming HTPR.

A novel epitope from CD22 regulates Th1 and Th17 cell function in systemic lupus erythematosus.

The published antibodies (Abs) against CD22 on B cells including Epratuzumab could inhibit B cell activation mainly through binding to C2-set Ig domain of CD22, but they are rarely reported to modulate the pathogenic CD4(+) T cell function in systemic lupus erythematosus (SLE). Recently, it was proved that the extracellular amino-terminal V-set Ig domain of CD22 might mediate the interaction of B and T cells, but for now the exact effect of this domain on CD4(+) T cell biology have not been identified. Thus, in this study, we screened out a peptide termed B2285 from this V-set Ig domain, developed the novel specific anti-B2285 Abs in rabbits, and investigated their effects in MRL/lpr mice with spontaneous SLE. The results showed that anti-B2285 Abs could ameliorate the disease severity obviously in spontaneous SLE mice with the decreased differentiations of Th1 and Th17 cells and no changes of Th2 and Treg cells. In co-cultured B cells and CD4(+) T cells, this specific anti-CD22 Abs was observed to inhibit the anti-dsDNA Abs production, CD4(+) T cells proliferation, the protein levels of T-bet and RORγt, and the mRNA levels of TNF-α, IFN-γ, IL-6 and IL-17 in CD4(+) T cells. Moreover, the expression of CD45RO on CD4(+) T cells could be also apparently diminished by this novel Abs. The data suggested that anti-B2285 Abs could slow SLE progression significantly by regulating Th1 and Th17 cells function via B-T cell interaction and the cytokine network regulation. The treatment against V-set Ig domain of CD22 would be a valuable therapeutic method for SLE and other autoimmune diseases.

Correlation between HLA-DRB1, HLA-DQB1 polymorphism and autoantibodies against angiotensin AT(1) receptors in Chinese patients with essential hypertension.

BACKGROUND: The autoantibodies (AAs) against angiotensin AT(1) receptors (AT(1) -AAs) have been discovered in patients with preeclampsia, malignant hypertension, and essential hypertension (EH); however, the mechanism of AA production remains to be investigated. HYPOTHESIS: Polymorphisms of HLA-DRB1 or HLA-DQB1 are related to production of AAs in autoimmune diseases. We hypothesis that the polymorphisms of the HLA molecules are also associated with production of AT(1) -AAs in patients with EH. METHODS: We enrolled 394 patients with EH and 224 normotensive subjects in this study. Autoantibodies in sera of donors were detected by enzyme-linked immunosorbent assay. The subjects' clinical data were collected, including gender, age, body mass index, blood pressure, smoking status, and diabetes. The patients and the normotensive subjects were classified respectively into AA-positive and AA-negative groups. Typing of DNA for HLA-DRB1 and HLA-DQB1 alleles was done by polymerase chain reaction amplification with sequence-specific primers. RESULTS: Thirteen HLA-DRB1 and 7 HLA-DQB1 alleles were found in this population. The frequencies of AT(1) -AAs were related to blood pressure level. The frequency of AT(1) -AAs in the EH group was higher than that in the normotensive group (P = 0.0001). The levels of AAs in different groups of EH show a significant difference (P = 0.027). In addition, HLA-DRB1(*) 04 and HLA-DRB1(*) 14 (odds ratio [OR]: 3.06, 95% confidence interval [CI]: 1.56-5.97, P = 0.001; and OR: 2.53, 95% CI: 1.080-5.91, P = 0.033, respectively) were related to AT(1) -AA production in normotensive subjects after adjusting for covariants. The HLA-DRB1(*) 04 allele might be related to AT(1) -AA production in hypertensive subjects, and the P value was of baseline statistical significance after adjusting for blood pressure and other covariants (OR: 1.63, 95% CI: 0.95-2.78, P = 0.070). CONCLUSIONS: These results suggest a difference in the immunogenetic background between the positive and negative AAs with hypertension or normotension. The HLA-DRB1(*) 04 allele increases the risk for AT(1) -AA production.

Th17 cells contribute to viral replication in coxsackievirus B3-induced acute viral myocarditis.

Acute viral myocarditis (AVMC) is characterized by virus-triggered myocardial inflammation, and Coxsackievirus B3 (CVB3) is the primary pathogen. We previously proved that Th17 cells, besides having proinflammatory effects, were involved in AVMC by enhancing humoral response. However, the relationship between Th17 cells and CVB3 replication remains unknown. In this experiment, we infected BALB/c mice with CVB3 for establishing AVMC models and then found that, with the increase of viral replication, the expressions of splenic Th17 cells, serum IL-17, and cardiac IL-17 mRNA were elevated significantly, accompanied by the progressive cardiac injuries of AVMC. Furthermore, on day 5, the peak time for viral replication, correlation was positive between cardiac IL-17 mRNA and CVB3 RNA (correlation index = 0.835; p < 0.01). Although the expressions of Th1 and CD8(+) T cells, which could secrete the antiviral cytokine IFN-γ and damage the heart, were also elevated, along with Th17 cells, in AVMC, the neutralization of IL-17 further upregulated the percentages of splenic Th1 and CD8(+) T cells and the levels of cardiac IFN-γ mRNA. The cardiac pathological changes were obviously improved after neutralization, with reduced viral replication followed by decreases in the cardiac inflammatory cytokines IL-17, TNF-α, and IL-1ß. These data suggest that Th17 cells contribute to CVB3 replication in AVMC, and that IL-17 might be an important target for regulating the balance of antiviral immunities.

Th17 cells facilitate the humoral immune response in patients with acute viral myocarditis.

BACKGROUND: Recently, the Th17 cell, a newly determined CD4+Th subset, was reported to participate in the inflammation of myocarditis combined with Th1 cells, and this study aimed to explore whether it was involved in the Th2 cell-mediated humoral immunity in viral myocarditis. METHODS: A total of 34 patients, including 16 acute viral myocarditis (AVMC) and 18 dilated cardiomyopathy (DCM) having a history of AVMC, were enrolled for this study besides 18 healthy volunteers. RESULTS: The frequencies of Th17 and Th1 cells, especially Th17 cells in AVMC patients, while those of Th1 and Th2 cells, especially Th2 cells in DCM group, were all increased significantly compared with those in healthy volunteers (P < 0.01), with no changes of Th2 cells in AVMC and Th17 cells in DCM groups. The similar results were also observed in Th cell cytokines (IL-17, INF-gamma, and IL-4) and key transcript factors (RORgammat, T-bet, and GATA-3). Meanwhile, antiheart antibodies (AHA) of IgG type were found in 15 (93.8%) patients with AVMC and ten (55.6%) cases with DCM, accompanied by the higher expression of IL-17R on B cells and the frequencies of B cells than those in healthy controls (P < 0.01 in AVMC and P < 0.05 in DCM, respectively) who had no AHA. Furthermore, both of the B cell activities in AVMC and DCM groups were elevated and positively correlated to serum IL-17 (R = 0.66, P < 0.01) and IL-4 (R = 0.47, P < 0.05) respectively, with no correlation to INF-gamma. CONCLUSIONS: It was Th17 cells but not Th2 cells that helped the B cells to produce AHA in AVMC and not until at the late phase of viral myocarditis could Th2 cells play the important role in mediating humoral response.

Neutralization of IL-17 inhibits the production of anti-ANT autoantibodies in CVB3-induced acute viral myocarditis.

Anti-adenine nucleotide translocator (ANT) autoantibodies are related to the development of Coxsackievirus B3 (CVB3)-triggered acute viral myocarditis (AVMC). Recently, studies suggested that IL-17 especially produced by a novel CD4(+) Th-cell subset Th17 cells contributed to the production of pathogenic autoantibodies in some autoimmune diseases. However, the pathogenic role of IL-17 in AVMC remains largely unknown. In this study, we investigated whether IL-17 was associated with the disease progression and the production of anti-ANT autoantibodies in AVMC mouse model. The results showed that IL-17 monoclonal antibody (mAb)-treated AVMC mice had decreased HW/BW, reduced serum CK-MB activity and improved pathological score of heart sections along with the reduction of circulating IL-17 level and serum anti-ANT autoantibodies. The correlation index of serum IL-17 concentration and anti-ANT-autoantibody level was 0.874, p<0.01. In addition, the experimental results in vitro further proved that IL-17mAb could inhibit the proliferation of CD19(+) B lymphocytes and the secretion of anti-ANT autoantibodies. Our data suggested that IL-17 was related to the disease progression in AVMC mouse model by regulating the production of autoantibodies and blocking IL-17 might represent a promising novel therapeutic approach.

[Association between ADRA1A gene polymorphism and autoantibodies against the alpha1-adrenergic receptor in hypertensive patients.].

OBJECTIVE: To observe the association between ADRA1A gene polymorphism and autoantibodies against the alpha1-adrenergic receptor in hypertensive patients. METHODS: A total of 396 patients with essential hypertension admitted to our hospital were selected and autoantibodies in sera were detected by ELISA, and patients were divided into the autoantibody positive and negative group. Genomic DNA was extracted from erythrocytes obtained from EDTA-treated blood by the Blood DNA extraction kit. Gene polymorphisms were detected by ligase detection reaction (LDR), including rs574584, rs1048101, rs3739216 and rs3802241. The frequency of genotypes and haplotype were analyzed. RESULTS: The frequencies of detected genotypes between the autoantibody against the alpha1-adrenergic receptor positive group and negative group were similar (P > 0.05) while significant difference was in the frequencies of haplotypes (all P < 0.05). The frequencies of genotypes with rs1048101 (genotype C/C, C/T, P = 0.017) and rs3802241 (genotype A/A, A/G, P = 0.004) were significant different in autoantibody positive group compared to negative group in patients with stage 2. CONCLUSION: ADRA1A gene polymorphism might correlate with the alpha1-adrenergic receptor autoantibody production in hypertensive patients.