Translational research : the journal of laboratory and clinical medicine
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The concept of gap junctions and their role in intercellular communication has been known for around 50 years. Considerable progress has been made in understanding the fundamental biology of connexins in mediating gap junction intercellular communication (GJIC) and their role in various cellular processes including pathological conditions. However, this understanding has not led to development of advanced therapeutics utilizing GJIC. ⋯ AsODN, antisense oligodeoxynucleotides; BMPs, bone morphogenetic proteins; BMSCs, bone marrow stem cells; BG, bioglass; Cx, Connexin; CxRE, connexin-responsive elements; CoCr NPs, cobalt-chromium nanoparticles; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; cAMP, cyclic adenosine monophosphate; ERK1/2, extracellular signal-regulated kinase 1/2; EMT, epithelial-mesenchymal transition; EPA, eicosapentaenoic acids; FGFR1, fibroblast growth factor receptor 1; FRAP, fluorescence recovery after photobleaching; 5-FU, 5-fluorouracil; GJ, gap junction; GJIC, gap junctional intercellular communication; HGPRTase, hypoxanthine phosphoribosyltransferase; HSV-TK, herpes virus thymidine kinase; HSA, human serum albumin; HA, hyaluronic acid; HDAC, histone deacetylase; IRI, ischemia reperfusion injury; IL-6, interleukin-6; IL-8, interleukin-8; IONPs, iron-oxide nanoparticles; JNK, c-Jun N-terminal kinase; LAMP, local activation of molecular fluorescent probe; MSCs, mesenchymal stem cells; MMP, matrix metalloproteinase; MI, myocardial infarction; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; NO, nitric oxide; PKC, protein kinase C; QDs, quantum dots; ROI, region of interest; RGO, reduced graphene oxide; siRNA, small interfering RNA; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis factor-α; UCN, upconversion nanoparticles; VEGF, vascular endothelial growth factor. In this review, we discuss briefly the role of connexins and gap junctions in various physiological and pathological processes, with special emphasis on cancer. We further discuss the application of nanotechnology and tissue engineering in developing treatments for various connexin based disorders.
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Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by vascular dysplasia. Mutations of the endoglin (ENG) gene that encodes a co-receptor of the transforming growth factor β1 signaling pathway cause type I HHT. ENG is primarily expressed in endothelial cells (ECs), but its interaction with other key angiogenic pathways to control angiogenesis has not been well addressed. ⋯ Functional analysis revealed that ENG knockdown inhibited cell migratory but enhanced anti-apoptotic activity induced by VEGF. In contrast, bFGF, angiopoietin-1 and -2 induced HUVEC migration and anti-apoptotic activities were not affected by ENG knockdown. In conclusion, ENG deficiency alters the VEGF/VEGFR2 pathway, which may play a role in HHT pathogenesis.
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The molecular understanding of the pathophysiological changes elicited by diabetes in platelets may help in further elucidating the involvement of this pseudo-cell in the increased risk of developing cardiovascular disease and thrombosis in diabetic subjects. We aimed to investigate the differential characteristics of platelets from diabetic patients and nondiabetic controls to unveil the molecular mechanisms behind the increased platelet reactivity in diabetes. We compared platelets from diabetic and control subjects by 2 dimensional-electrophoresis followed by mass spectrometry. ⋯ Changes in the chaperones HSPA8 and Hsp90, and in CSK2α protein contents correlated with changes in platelet aggregation and blood coagulation activity. In conclusion, the complex HSPA8/Hsp90/CSK2α is involved in diabetes-related platelet hyperreactivity. The role of the HSPA8/Hsp90/CSK2α complex may become a molecular target for the development of future preventive and therapeutic strategies for platelet dysfunction associated with diabetes and its complications.
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Rituximab is an important second line therapy in difficult nephrotic syndrome (NS), especially given toxicity of long-term glucocorticoid or calcineurin inhibitor (CNI) use. However, clinical response to rituximab is heterogenous. We hypothesized that this was underpinned by immunological differences amongst patients with NS. ⋯ In particular, IL-13 showed a significant decrease in sustained remission group [-0.56 (-0.64, -0.35)pg/ml, P=0.007)], but not in the early relapse group. In conclusion, early relapse following rituximab is associated with baseline reductions in Treg and T-cell hyporesponsiveness, which suggest chronic T-cell activation and may be useful predictive biomarkers. Sustained remission, on the other hand, is associated with downregulation of Th2 cytokines following rituximab.
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Clinical utility of cisplatin based neoadjuvant chemotherapy (NAC) prior to radical cystectomy is limited because of lack of tools that can guide for a better patient selection. We aim to explore if a combination of biomarkers is superior to a single marker. Pretreatment tumor specimens and clinical data from two randomized trials including 250 patients with T2-T4 urothelial bladder cancer, were used. ⋯ The combination of CCTα with survivin or BCL-2 yielded similar results. In a group of patients with muscle invasive bladder cancer a combination of two biomarkers might improve the possibility to identify patients most likely to benefit from the use of NAC. Further studies designed to have sufficient power to detect an interaction effect are needed.