Project description:To explore BML-260 how to increase thermogenesis, we treated brown adipocytes with BML-260 and DMSO for 1 day or 3 days after seven days' differenciation. Meanwhile, we also set ISO (isoproterenol)-treated brown adipocytes as positive control. We found that BML-260 treatment led to very significant upregulation of genes involved in oxidative phosphorylation, fatty acid beta-oxidation, and mitochondrial function.When compared to cells treated with ISO, although both showed significant upregulation of UCP1, BML-260-treated cells showed a rather distinct gene profile when compared to ISO-treated cells. This work provides evidences that BML-260 can also exert a JSP-1-independent effect in activating UCP1 and thermogenesis in adipocytes, and be potentially applied to treat obesity.
Project description:To explore BML-260 how to increase thermogenesis, we examined the effect of BML-260 by direct in situ injection into the subcutaneous white adipose depot. Three days after a single injection, mice were dissected and subcutaneous adipose tissues were obtained for RNA extraction. we noticed that BML-260 treatment resulted in a very significant upregulation of genes involved in thermogenesis. And gene signatures of muscle cell differentiation, muscle structure development, regulation of muscle system process were among the most enriched GO terms. Our work provides evidences that BML-260 can also exert a JSP-1-independent effect in activating UCP1 and thermogenesis in adipocytes, and be potentially applied to treat obesity.
Project description:We investigated the molecular mechanism by which BML-210 enhanced the response of breast tumor cells to cytotoxic CD8+ T cells. For this purpose, we performed RNA sequencing and analyzed the genome-wide gene expression profiles to systematically identify transcriptom reprogramming in the BML-210-treated cells.
Project description:Skeletal muscle wasting results from numerous conditions, such as sarcopenia, glucocorticoid therapy or intensive care. It prevents independent living in the elderly, predisposes to secondary diseases, and ultimately reduces lifespan. There is no approved drug therapy and the major causative mechanisms are not fully understood. Dual specificity phosphatase 22 (DUSP22) is a pleiotropic signaling molecule that plays important roles in immunity and cancer. However, the role of DUSP22 in skeletal muscle wasting is unknown. In this study, DUSP22 was found to be upregulated in sarcopenia patients and models of skeletal muscle wasting. DUSP22 knockdown or pharmacological inhibition with BML-260 prevented multiple forms of muscle wasting. Mechanistically, targeting DUSP22 suppressed FOXO3a, a master regulator of skeletal muscle wasting, via downregulation of the stress-activated kinase JNK, which occurred independently of aberrant Akt activation. DUSP22 targeting was also effective in human skeletal muscle cells undergoing atrophy. In conclusion, phosphatase DUSP22 is a novel target for preventing skeletal muscle wasting and BML-260 is a therapeutically effective small molecule inhibitor. The DUSP22-JNK-FOXO3a axis could be exploited to treat sarcopenia or related aging disorders.
Project description:Bone marrow lesions (BML) are well described in osteoarthritis (OA) using magnetic resonance imaging (MRI) and associate with pain however, little is known about their role in disease process and pattern of gene expression within the lesions. This study evaluated the gene expression profile of OA BML (n=14) in comparison to normal bone (n=10) by microarray profiling. MR imaging and the MOAKS scoring was used to locate lesions and the scaled axial images were used to sample BMLs. The bone tissue controls were harvested from participants undergoing surgery following trauma.
Project description:We performed a high-throughput, multiplexed quantitative proteomics analysis to determine protein abundance changes produced by BML-111 treatment in EAM and Ctrl mice. EAM was induced in 7 weeks-old BALB/c female mice by immunization at days 0 and 7 with a subcutaneous injection of 350 μg of murine cardiac myosin (MyHCα) in a 1:1 emulsion with complete Freund’s Adjuvant (SIGMA). MyHCα was isolated from hearts of Balb/c mice; control mice were injected with a 1:1 emulsion of physiological saline solution with complete Freund’s Adjuvant. Mice were treated daily for two weeks from day 7 by intraperitoneal injection with two complementary treatments: 1mg/Kg BML-111(Enzo Life Science) or its vehicle (2.5% ethanol). The proteomics analysis was performed in heart tissue protein extracts (four animals per group: Ctrl+Veh, EAM+Veh, Ctrl+BML and EAM+BML.
