In multiple sclerosis plaques, oligodendroglial connexin (Cx) 47 constituting main gap junction channels with astroglial Cx43 is persistently lost. As mice with Cx47 single knockout exhibit no demyelination, the roles of Cx47 remain undefined. We aimed to clarify the effects of oligodendroglia-specific Cx47 inducible conditional knockout (icKO) on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein peptide (MOG35-55) in PLP/CreERT;Cx47fl/fl mice at 14 d after tamoxifen injection. Cx47 icKO mice demonstrated exacerbation of acute and chronic relapsing EAE with more pronounced demyelination than Cx47 flox (fl)/fl littermates. CD3+ T cells more abundantly infiltrated the spinal cord in Cx47 icKO than in Cx47 fl/fl mice throughout the acute to chronic phases. CXCR3-CCR6+CD4+ and IL17+IFNγ-CD4+ helper T (Th) 17 cells isolated from spinal cord and brain tissues were significantly increased in Cx47 icKO mice compared with Cx47 fl/fl mice, while MOG35-55-specific proliferation and proinflammatory cytokine production of splenocytes were unaltered. Microarray analysis of isolated microglia revealed stronger microglial activation toward proinflammatory and injury-response phenotypes with increased expressions of chemokines that can attract Th17 cells, including Ccl2, Ccl3, Ccl4, Ccl7, and Ccl8, in Cx47 icKO mice compared with Cx47 fl/fl mice. In Cx47 icKO mice, NOS2+ and MHC class II+ microglia were more enriched immunohistochemically, and A1-specific astroglial gene expressions and astroglia immunostained for C3, a representative A1 astrocyte marker, were significantly increased at the acute phase, compared with Cx47 fl/fl mice. These findings suggest that oligodendroglia-specific Cx47 ablation induces severe inflammation upon autoimmune demyelination, underscoring a critical role for Cx47 in regulating neuroinflammation. Significance In multiple sclerosis plaques, oligodendroglial connexin (Cx) 47 constituting main gap junction channels with astroglia is persistently lost. The roles of Cx47 remain undefined. Here, we show that oligodendroglia-specific conditional ablation of Cx47 exacerbated acute and chronic relapsing experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein peptide (MOG_35-55) immunization, with florid infiltration of CD3⁺ T cells, especially helper T (Th) 17 cells, and pronounced demyelination without influencing MOG-specific T cell induction. Microarray and immunohistochemistry analyses revealed stronger activation of proinflammatory and injury-response microglia with increased expressions of chemokines that can attract Th17 cells, and A1 astroglia at the acute phase. These findings suggest that oligodendroglia-specific Cx47 loss can augment inflammation upon autoimmune demyelination, underscoring a role for Cx47 in neuroinflammation.

Neuronal signaling together with synapse activity in the central nervous system requires a precisely regulated microenvironment. Recently, the blood-brain barrier is considered as a “neuro-glia-vascular unit,” a structural and functional compound composed of capillary endothelial cells, glial cells, pericytes, and neurons, which plays a pivotal role in maintaining the balance of the microenvironment in and out of the brain. Tight junctions and adherens junctions, which function as barriers of the blood-brain barrier, are two well-known kinds in the endothelial cell junctions. In this review, we focus on the less-concerned contribution of gap junction proteins, connexins in blood-brain barrier integrity under physio-/pathology conditions. In the neuro-glia-vascular unit, connexins are expressed in the capillary endothelial cells and prominent in astrocyte endfeet around and associated with maturation and function of the blood-brain barrier through a unique signaling pathway and an interaction with tight junction proteins. Connexin hemichannels and connexin gap junction channels contribute to the physiological or pathological progress of the blood-brain barrier; in addition, the interaction with other cell-cell-adhesive proteins is also associated with the maintenance of the blood-brain barrier. Lastly, we explore the connexins and connexin channels involved in the blood-brain barrier in neurological diseases and any programme for drug discovery or delivery to target or avoid the blood-brain barrier.

Guidelines divide patients with heart failure (HF) into 3 distinct groups based on left ventricular ejection fraction (LVEF) We used the Minnesota Living with Heart Failure Questionnaire (MLHFQ) to quantify the health-related quality of life in patients with HF. Patients were stratified into three cohorts: preserved LVEF (>50%), mid-range LVEF (40–49%) and reduced LVEF (<40%). The MLHFQ scores were evaluated using one-way ANOVA, and differences were observed among the groups. The association of New York Heart Association (NYHA) class with the physical scores was analyzed by Spearman’s correlation analysis. The predictive utility of the total MLHFQ scores was assessed with Kaplan-Meier curves for death and HF-related hospitalization. The Cox proportional hazards model was used to identify the risk factors for prognosis. Internal reliability was assessed with Cronbach’s α. There were significant differences in the total MLHFQ scores and the MLHFQ subscale scores among the three groups (p<0.05). MLHFQ domains demonstrated high internal consistency among the three groups (Cronbach’s α = 0.92, 0.96 and 0.93). The MLHFQ physical subscale scores were significantly associated with NYHA class in HFrEF (r = 0.59, p<0.001) and HFmrEF patients (r = 0.537, p<0.001). The survival analysis indicated that there was a significant difference among the three groups regarding high MLHFQ scores (p = 0.038). In the groups with low MLHFQ scores, the HFmrEF group exhibited significantly increased rates of death and HF-related hospitalization compared with the HFpEF group (p = 0.035). The features and clinical outcomes varied among heart failure patients with different EF values. The MLHFQ appears to be a valid and reliable measurement of health status and offers excellent prognostic ability.

Id proteins, inhibitors of DNA binding, are transcription regulators containing a highly conserved helix-loop-helix domain. During multiple stages of normal cardiogenesis, Id proteins play major roles in early development and participate in the differentiation and proliferation of cardiac progenitor cells and mature cardiomyocytes. The fact that a depletion of Ids can cause a variety of defects in cardiac structure and conduction function is further evidence of their involvement in heart development. Multiple signalling pathways and growth factors are involved in the regulation of Ids in a cell- and tissue- specific manner to affect heart development. Recent studies have demonstrated that Ids are related to multiple aspects of cardiovascular diseases, including congenital structural, coronary heart disease, and arrhythmia. Although a growing body of research has elucidated the important role of Ids, no comprehensive review has previously compiled these scattered findings. Here, we introduce and summarize the roles of Id proteins in heart development, with the hope that this overview of key findings might shed light on the molecular basis of consequential cardiovascular diseases. Furthermore, we described the future prospective researches needed to enable advancement in the maintainance of the proliferative capacity of cardiomyocytes. Additionally, research focusing on increasing embryonic stem cell culture adaptability will help to improve the future therapeutic application of cardiac regeneration.