T cell responses in immune-mediated IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is a complex autoimmune disease with various underlying causes and significant clinical heterogeneity. There are large individual differences in its development, and the etiology and pathogenesis are still poorly understood. While it is known that immunobiological factors play a significant role in the pathophysiology of IgAN, the specific nature of these factors has yet to be fully elucidated. Numerous investigations have verified that cluster of differentiation 4+ (CD4+) and CD8+ T lymphocytes are involved in the immunopathogenesis of IgAN. Furthermore, certain data also point to γδT cells' involvement in the pathophysiology of IgAN. By thoroughly examining the mechanisms of action of these T cells in the context of IgAN, this review sheds light on the immunopathogenesis of the disease and its associated factors. The review is intended to provide reference value for the future research in this field and promising treatment clues for clinical patients.

Deciphering roles of protein post-translational modifications in IgA nephropathy progression and potential therapy.

Immunoglobulin A nephropathy (IgAN), one type of glomerulonephritis, displays the accumulation of glycosylated IgA in the mesangium. Studies have demonstrated that both genetics and epigenetics play a pivotal role in the occurrence and progression of IgAN. Post-translational modification (PTM) has been revealed to critically participate in IgAN development and progression because PTM dysregulation results in impaired degradation of proteins that regulate IgAN pathogenesis. A growing number of studies identify that PTMs, including sialylation, o-glycosylation, galactosylation, phosphorylation, ubiquitination and deubiquitination, modulate the initiation and progression of IgAN. Hence, in this review, we discuss the functions and mechanisms of PTMs in regulation of IgAN. Moreover, we outline numerous compounds that govern PTMs and attenuate IgAN progression. Targeting PTMs might be a useful strategy to ameliorate IgAN.

Thermal Rectification in Modularly Designed Bulk Metamaterials.

Thermal rectification is a phenomenon of great practical importance where heat transfer is preferential in one direction. Programmable control of heat transfer in 3D space is key to enable thermal rectification at the macroscale but is rarely realized in natural materials or in current existing devices that are constructed at the nano and microscales with high system complexity. Here, modularly designed bulk metamaterials that can break the symmetry of heat transfer from one direction to the other are created, leading to thermal rectification in convergent or divergent states by tuning the metamaterial microstructural design. These thermal metamaterials are microstructured composites made using one material composition, however, they offer sufficient microstructural design freedom to allow tunable local thermal properties for unusual macroscopic heat transfer. The strategy and performance achieved are promising for next-generation thermal management.

Microstructured BN Composites with Internally Designed High Thermal Conductivity Paths for 3D Electronic Packaging.

Miniaturized and high-power-density 3D electronic devices pose new challenges on thermal management. Indeed, prompt heat dissipation in electrically insulating packaging is currently limited by the thermal conductivity achieved by thermal interface materials (TIMs) and by their capability to direct the heat toward heat sinks. Here, high thermal conductivity boron nitride (BN)-based composites that are able to conduct heat intentionally toward specific areas by locally orienting magnetically functionalized BN microplatelets are created using magnetically assisted slip casting. The obtained thermal conductivity along the direction of alignment is unusually high, up to 12.1 W m-1 K-1 , thanks to the high concentration of 62.6 vol% of BN in the composite, the low concentration in polymeric binder, and the high degree of alignment. The BN composites have a low density of 1.3 g cm-3 , a high stiffness of 442.3 MPa, and are electrically insulating. Uniquely, the approach is demonstrated with proof-of-concept composites having locally graded orientations of BN microplatelets to direct the heat away from two vertically stacked heat sources. Rationally designing the microstructure of TIMs to direct heat strategically provides a promising solution for efficient thermal management in 3D integrated electronics.

Friction and Wear Characteristics of 18Ni(300) Maraging Steel under High-Speed Dry Sliding Conditions.

18Ni(300) maraging steel, which has exceptional strength and toughness, is used in the field of aviation and aerospace. In this paper, using a high-speed tribo-tester, tribological behaviors of 18Ni(300) maraging steel were investigated under high-speed dry sliding conditions. Morphology of the worn surfaces and the debris was analyzed by scanning electron microscope, and the oxides of worn surfaces caused by friction heat were detected by X-ray diffraction. The experiment results reveal that the friction coefficient of frictional pairs declines with increasing load and speed. With the speed and load increasing, oxides of the worn surfaces of 18Ni(300) maraging steel change from FeO to Fe3O4 and the wear mechanism converts from adhesive wear into severe oxidative or extrusion wear.

Smoothened Regulates Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via Activation of Rho GTPase Signaling.

Fibroblast-like synoviocytes (FLSs) acquire aggressive phenotypes characterized with enhanced migration abilities and inherent invasive qualities in rheumatoid arthritis (RA). Smoothened (Smo) is a key component of sonic hedgehog (Shh) signaling and contributes to tumor cell invasion and metastasis. The objective of this study is to investigate the role of Smo in the modulation of cell migration and explore the underlying molecular mechanism(s). FLSs were isolated from RA synovium. Shh levels were regulated by a Smo agonist (purmorphamine), Smo antagonist (KAAD-cyclopamine), or small interfering RNA targeting the Smo gene (Smo-siRNA) in RA-FLSs. Expression of Smo was detected by real-time PCR and western blot analysis. Cell migration was examined by Transwell assay and activation of Rho GTPases was measured by pull-down assays. Incubation with purmorphamine resulted in a significant increase of cell migration and activation of Rho GTPase signaling compared to controls (P < 0.05). However, treatment with KAAD-cyclopamine or transfection with Smo-siRNA suppressed migration of RA-FLSs and showed an inhibitory effect of Rho GTPase signaling. Together, these results suggest that Smo plays an important role in RA-FLSs migration through activation of Rho GTPase signaling and may contribute to progression of RA, thus, targeting Shh signal may have a therapeutic potential in patients with RA.

Inhibition of smoothened decreases proliferation of synoviocytes in rheumatoid arthritis.

Fibroblast-like synoviocytes (FLSs) contribute to synovial hyperplasia in rheumatoid arthritis (RA). Smoothened (Smo) is a key component of sonic hedgehog (Shh) signaling and contributes to tumor cell proliferation. The objective of this study was to investigate the role of Smo in RA synoviocyte proliferation. FLSs were isolated from RA synovium. Shh signaling was studied using a Smo antagonist (GDC-0449) and small interfering RNA (siRNA) targeting the Smo gene in FLSs. Cell proliferation was quantified by using kit-8 assay and cell cycle distribution and apoptosis were evaluated by flow cytometry. Cell cycle-related genes and proteins were detected by real-time PCR and western blot. FLSs treated with GDC-0449 or Smo-siRNA showed significantly decreased proliferation compared to controls (P < 0.05). Incubation with GDC-0449 or transfection with Smo-siRNA resulted in a significant increase of G1 phase cells compared to controls (P < 0.05). Cell cycle arrest was validated by the significant increase in cyclin D1 and E1 mRNA expression, decrease in cyclin-dependent kinase p21 mRNA expression in Smo-siRNA transfected cells (P < 0.05). Protein expression of cyclin D1 was also downregulated after Smo gene knockdown (P < 0.05). The results suggest that Shh signaling plays an important role in RA-FLSs proliferation in a Smo-dependent manner and may contribute to synovial hyperplasia. Targeting Shh signaling may help control joint damage in patients with RA.

Sonic hedgehog signalling pathway regulates apoptosis through Smo protein in human umbilical vein endothelial cells.

OBJECTIVE: The aim of this study was to investigate the expression of smoothened protein (Smo), a sonic hedgehog (Shh) signalling component, in synovium of RA and its role in the survival and apoptosis of endothelial cells. METHODS: The expression of Smo pxrotein in RA synovial tissue was examined by immunohistochemistry. Real-time PCR and western blotting techniques were employed to measure the expression of Shh signalling components in EA.hy926 endothelial cells exposed to TNF-α in the presence or absence of cyclopamine (a Smo-specific antagonist). Lastly, the effect of cyclopamine and Smo small interfering RNA on apoptosis induced by TNF-α and actinomycin D (ActD) was determined. RESULTS: We found that Smo was highly expressed in synovial tissues of RA, especially in endothelial cells, compared with the trauma group. TNF-α significantly increased the expression of Shh signalling components in EA.hy926 endothelial cells, while cyclopamine decreased the expression of Shh signalling components. EA.hy926 endothelial cells treated with various concentrations of cyclopamine (2-8 µmol/l) showed a significant decrease in cell viability and cell survival rate, and an increase in the rate of cell apoptosis compared with endothelial cells treated with TNF-α and ActD (P < 0.05). EA.hy926 endothelial cells transfected with Smo-siRNA also showed a lower cell survival rate and higher apoptotic rate, compared with cells in the control group (P < 0.05). CONCLUSION: The Shh signalling pathway plays a role in regulating endothelial cell apoptosis in a Smo-dependent manner.

Sonic hedgehog signaling drives proliferation of synoviocytes in rheumatoid arthritis: a possible novel therapeutic target.

Sonic hedgehog (Shh) signaling controls many aspects of human development, regulates cell growth and differentiation in adult tissues, and is activated in a number of malignancies. Rheumatoid arthritis (RA) is characterized by chronic synovitis and pannus formation associated with activation of fibroblast-like synoviocytes (FLS). We investigated whether Shh signaling plays a role in the proliferation of FLS in RA. Expression of Shh signaling related components (Shh, Ptch1, Smo, and Gli1) in RA synovial tissues was examined by immunohistochemistry (IHC) and in FLS by IHC, immunofluorescence (IF), quantitative RT-PCR, and western blotting. Expression of Shh, Smo, and Gli1 in RA synovial tissue was higher than that in control tissue (P < 0.05). Cyclopamine (a specific inhibitor of Shh signaling) decreased mRNA expression of Shh, Ptch1, Smo, and Gli1 in cultured RA FLS, Shh, and Smo protein expression, and significantly decreased FLS proliferation. Flow cytometry analysis suggested that cyclopamine treatment resulted in cell cycle arrest of FLS in G1 phase. Our data show that Shh signaling is activated in synovium of RA patients in vivo and in cultured FLS form RA patients in vitro, suggesting a role in the proliferation of FLS in RA. It may therefore be a novel therapeutic target in RA.

Infliximab reduces CD147, MMP-3, and MMP-9 expression in peripheral blood monocytes in patients with active rheumatoid arthritis.

Recent studies have reported elevated expression levels in active rheumatoid arthritis patients of the cluster of differentiation (CD) 147 on CD14(+) peripheral blood monocytes and as a result, CD147 may be a target for the development of a novel rheumatoid arthritis therapy. This report describes the inhibitory effects of infliximab on CD147 and metalloproteinases (MMP)-3 and MMP-9 overexpression in peripheral blood monocytes obtained from patients with active rheumatoid arthritis. Thirty patients with active rheumatoid arthritis that were refractory to methotrexate therapy were randomized at a 4:1 ratio into groups A and B, respectively. Group A received three to four infusions of infliximab (3mg/kg) and group B participants received four infusions of placebo. Both groups were also treated with a stable background dose of methotrexate. The CD147 expression levels on CD14(+) peripheral blood monocytes of rheumatoid arthritis patients was detected by flow cytometry. The expression of CD147, MMP-3, and, MMP-9 mRNA in peripheral blood mononuclear cells was assayed by real-time quantitative PCR, and the expression of MMP-3 and MMP-9 in serum was measured by a multiplexed microsphere-based flow assay. Results showed that the expression of CD147 and MMP-9 mRNA in group A decreased compared to group B. Expression of CD147 on CD14(+) monocytes was reduced (P<0.05), and serum MMP-3 and -9 levels in group A were decreased by week 18. These data suggested that infliximab could inhibit CD147 expression on CD14(+) monocytes as well as reduce the levels of MMP-3 and MMP-9 in peripheral blood monocytes.

[Cytodiagnosis and cytomorphologic analysis of hematolymphoid malignancy in serous effusion: a study of 23 cases].

OBJECTIVE: To evaluate the value of cytomorphologic and immunocytochemical approaches in the diagnosis of hematologic neoplasms in serous effusion. METHODS: The cytospin and Thinprep smears of effusion specimens were prepared from 23 cases of lymphoid malignancies with histological confirmation and 30 cases of benign effusions used as control. Morphological assessment of the cellular components was conducted, including the ratio of mesothelium to lymphocyte, karyomorphism of lymphoid cell and the presence of apoptosis and mitosis. Immunocytochemical study was performed in all the cases, with flow cytometry in one case. RESULTS: Among the 23 tumor cases, 14 represented disease relapse, and in the remaining nine cases, the serous effusion was the primary manifestation. The proportion of mesothelium was low in the tumor group, being less than 10% in 20 cases (87.0%, 20/23). It was more than 10% in most of benign cases (20/30, 66.7%). Lymphoid cells were prominent (> 80% cells) in 69.6% of the tumor cases, and the cellular component in some control cases (63.3%, 19/30) showed fewer lymphocytes. Nipple-like projection of lymphocytic nuclei could be detected in almost all the tumor cases (91.3%, 21/23), but was occasionally found in the control group (26.7%, 8/30). Apoptosis and mitosis were obvious in lymphomatous effusion, but observed in only 6.7% of the control cases. Significant difference of the previously mentioned cytomorphologic features existed between the tumor and control groups (P < 0.01). The results of immunocytochemical staining in cell block were identical to the corresponding immunohistochemistry, and one case of mantle cell lymphoma was confirmed by flow cytometry. The cytologic findings seen in all the 23 studied cases were in agreement with the corresponding histologic diagnosis. CONCLUSIONS: Some cytomorphologic features, including decreased number of mesothelium, increased number of lymphoid cells, nuclear nipple-like projection, and the presence of apoptosis and mitosis, are very useful for diagnosing lymphoid malignancy in serous effusion. Immunocytochemistry is an important approach to the cytodiagnosis and classification of lymphoma.