Identification of Tensin-3 as a MALT1 substrate that controls B cell adhesion and lymphoma dissemination.

The protease MALT1 promotes lymphocyte activation and lymphomagenesis by cleaving a limited set of cellular substrates, most of which control gene expression. Here, we identified the integrin-binding scaffold protein Tensin-3 as a MALT1 substrate in activated human B cells. Activated B cells lacking Tensin-3 showed decreased integrin-dependent adhesion but exhibited comparable NF-κB1 and Jun N-terminal kinase transcriptional responses. Cells expressing a noncleavable form of Tensin-3, on the other hand, showed increased adhesion. To test the role of Tensin-3 cleavage in vivo, mice expressing a noncleavable version of Tensin-3 were generated, which showed a partial reduction in the T cell-dependent B cell response. Interestingly, human diffuse large B cell lymphomas and mantle cell lymphomas with constitutive MALT1 activity showed strong constitutive Tensin-3 cleavage and a decrease in uncleaved Tensin-3 levels. Moreover, silencing of Tensin-3 expression in MALT1-driven lymphoma promoted dissemination of xenografted lymphoma cells to the bone marrow and spleen. Thus, MALT1-dependent Tensin-3 cleavage reveals a unique aspect of the function of MALT1, which negatively regulates integrin-dependent B cell adhesion and facilitates metastatic spread of B cell lymphomas.

Chemical composition, antioxidant and hepatoprotective activities of methanol extracts from leaves of Terminalia bellirica and Terminalia sericea (Combretaceae).

BACKGROUND: Plants belonging to the genus Terminalia such as Terminalia bellirica and Terminalia sericea are used traditionally to treat several diseases and health disorders. Up to this date, the roots of Terminalia sericea and the fruits of Terminalia bellirica are the mostly studied plant parts. The phytochemical composition and the biological activities of the leaves of both species are not well identified so far. METHODS: The secondary metabolites of Terminalia bellirica and Terminalia sericea leaves were identified using HPLC-PDA-MS/MS. The antioxidant activities of the leaves extracts were determined by DPPH and FRAP assays. The hepatoprotective potential was evaluated in rats with D-galactosamine induced liver damage. The effect of the extracts on the expression of the anti-apoptotic marker Bcl-2 was measured in an immunohistochemical study. The most abundant compounds identified in the studied extracts were docked into Bcl-2: Bim (BH3) interaction surface using molecular operating environment software. RESULTS: A total of 85 secondary metabolites were identified in the leaf extracts of both species. Ellagitannins such as corilagin, chebulagic acid, galloylpunicalagin, and digalloyl-hexahydroxydiphenoyl-hexoside were found to be the major components in Terminalia bellirica whereas flavonoid glycosides including quercetin rutinoside and quercetin galloyl-glucoside were highly abundant in Terminalia sericea. The studied extracts exhibited pronounced antioxidant activities, moderate anti-apoptotic and hepatoprotective potential. In silico docking experiments revealed that the compounds abundant in the extracts were able to bind to Bcl-2: Bim (BH3) interaction surface with an appreciable binding free energy. DISCUSSION: The antioxidant and hepatoprotective activities exhibited by the studied extracts might be attributed to the high content of the polyphenols. The anti-apoptotic activity could be due to the interference with the apoptotic pathway mediated by Bcl-2: Bim interaction. These findings support the medicinal relevance of Terminalia bellirica and Terminalia sericea and provide a rational base for their utilization in folk medicine.

Polyphenolic Extract of Euphorbia supina Attenuates Manganese-Induced Neurotoxicity by Enhancing Antioxidant Activity through Regulation of ER Stress and ER Stress-Mediated Apoptosis.

Manganese (Mn) is an important trace element present in human body, which acts as an enzyme co-factor or activator in various metabolic reactions. While essential in trace amounts, excess levels of Mn in human brain can produce neurotoxicity, including idiopathic Parkinson's disease (PD)-like extrapyramidal manganism symptoms. This study aimed to investigate the protective role of polyphenolic extract of Euphorbia supina (PPEES) on Mn-induced neurotoxicity and the underlying mechanism in human neuroblastoma SKNMC cells and Sprague-Dawley (SD) male rat brain. PPEES possessed significant amount of total phenolic and flavonoid contents. PPEES also showed significant antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and reducing power capacity (RPC) assays. Our results showed that Mn treatment significantly reduced cell viability and increased lactate dehydrogenase (LDH) level, which was attenuated by PPEES pretreatment at 100 and 200 µg/mL. Additionally, PPEES pretreatment markedly attenuated Mn-induced antioxidant status alteration by resolving the ROS, MDA and GSH levels and SOD and CAT activities. PPEES pretreatment also significantly attenuated Mn-induced mitochondrial membrane potential (ΔΨm) and apoptosis. Meanwhile, PPEES pretreatment significantly reversed the Mn-induced alteration in the GRP78, GADD34, XBP-1, CHOP, Bcl-2, Bax and caspase-3 activities. Furthermore, administration of PPEES (100 and 200 mg/kg) to Mn exposed rats showed improvement of histopathological alteration in comparison to Mn-treated rats. Moreover, administration of PPEES to Mn exposed rats showed significant reduction of 8-OHdG and Bax immunoreactivity. The results suggest that PPEES treatment reduces Mn-induced oxidative stress and neuronal cell loss in SKNMC cells and in the rat brain. Therefore, PPEES may be considered as potential treat-ment in Mn-intoxicated patients.