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.

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.

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.

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.

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.

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.

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.