ABSTRAKTujuan penelitian ini adalah mengetahui efek intervensi minuman tempe terhadap tekanan darah pada penderita hipertensi dan sekaligus hiperkolesterolemia. Desain yang digunakan dalam penelitian ini adalah Randomized Controlled Trial (RCT) dengan total 30 subjek pria dan wanita yang dibagi dalam tiga kelompok, yaitu kelompok yang diberi Minuman Tempe A (MTA) yang diformulasikan dari keledai lokal yang dikecambahkan, Minuman Tempe B (MTB) yang diformulasikan dari kedelai impor, dan kelompok kontrol. Kriteria inklusi yaitu dewasa berusia 25-55 tahun, belum mengalami menopause atau tidak sedang hamil, kadar kolesterol total ≥200 mg/dl, tekanan darah 121-139 mmHg, tekanan darah diastolik 81-89 mmHg serta bersedia berpartisipasi dalam penelitian dan menandatangani informed consent. Minuman tempe diberikan tiga gelas sehari selama empat minggu berturut-turut dan paling sedikit mengandung 25 g protein/hari. Kelompok kontrol tidak diberi minuman tempe. Darah untuk analisis kadar kolesterol total dikumpulkan melalui darah vena setelah puasa sebelum dan setelah intervensi. Tekanan darah dikumpulkan setiap minggu selama intervensi. Hasil penelitian menunjukkan bahwa terdapat perbedaan signifikan pada efek MTA dan MTB dibandingkan dengan subjek kelompok kontrol pada tekanan darah sistolik. Tidak terdapat perbedaan signifikan pada efek MTA dan MTB pada tekanan darah diastolik dibandingkan dengan kelompok kontrol, namun kecenderungan mengalami penurunan.Kata kunci: hipertensi, minuman tempe, tekanan darah * Korespondensi: Telp: +628161374074, Surel: mastawan@yahoo.com
We investigated the role of CD4+CD25+FoxP3+ regulatory T cells on diabetes resistance in aged NOD mice that do not develop diabetes in pathogen-free housing. At 60 weeks age, <80% NOD mice developed diabetes. Adoptive transfer of lymphocytes from diabetic mice to aged nodiabetic NOD mice did not significantly increase the onset of diabetes. When 1x107 lymphocytes from age NOD mice were co-transferred with 5x106 lymphocytes from diabetes NOD mice into NOD.scid mice, all mice developed diabetes at 6 weeks. When 2x107 lymphocytes from aged NOD mice were co-transferred, none developed diabetes at 6 weeks and only 50% NOD.scid mice developed diabetes at 12 weeks. When 1x106 CD4+CD25- T cells was cotransferred with 5x106 lymphocytes from diabetic NOD mice, diabetes was developed in all NOD.scid mice. When 1x106 CD4+CD25+ T cells were used, only 17% mice developed diabetes at 12 weeks. The percentages of CD4+CD25+Foxp3+ T cells in the pancreatic lymph nodes, spleen and peripheral blood were 20.1±5.3%, 14.6±4.1% and 9.8±3.5% in aged NOD mice; 5.8±1.5%, 8.6±0.7% and 6.4±1.7% in control diabetic NOD mice. When a low dose of cyclosphamiade was given, diabetes was developed in 75% young NOD mice and in 18% aged NOD mice. However, when the high dose was given, 58% aged NOD mice had diabetes and CD4+CD25+Foxp3+ T cells in pancreatic lymph nodes were 7.0±1.7%. Our data demonstrated that immunoregulation through CD4+CD25+Foxp3+ T cells mediated the resistance of diabetes in aged NOD mice.
G-protein coupled receptor 40 (GPR40) and G-protein coupled receptor (GPR120) are expressed on intestinal L cells, monocytes and/or macrophages. We investigated the effect of GW9508 (GW), a GPR40 and GPR120 dual agonist, on modulating autoimmunity in NOD mice. New-onset diabetic NOD mice were treated with GW for up to 8 weeks. Nonfasting blood glucose was monitored. After the treatment, CD4+CD25+FoxP3+ T (Treg) cells in thymus, spleen and pancreatic lymph nodes were measured. To detect IL-17+CD4+ T (Th17) cells, lymphocytes from these mice were cultured for 5 days. To determine in vitro effect of GW on Th17 cells, lymphocytes from NOD mice were cultured with or without GW. Cytokines and chemokines in supernatants were determined. Diabetes was reversed in 13% of vehicle (DMSO) treated mice, in 54% of mice treated with GW at 10mg/kg/day and in 69% of mice treated with GW at 20 mg/kg/day (P<0.01). The insulitis score was significantly lower in GW-treated mice (P<0.05). Although the percentage of Treg cells was not significant different, the percentage of Th17 cells and the ratio of Th17 cells to Treg cells in GW-treated mice were significantly lower (P<0.01). Th17 cells in GW-treated lymphocytes in culture were significantly reduced (P<0.05). IL-17, IFN-γ, IP-10, RANTES, and MIP-1α in supernatants of GW-treated lymphocytes were also significantly reduced (P<0.05). Our data indicate that targeting GPR40 /GPR120 is a new therapeutic approach for treating type 1 diabetes.
Background: Pancreatic ductal adenocarcinoma (PDAC) is an extremely fatal disease due to lack of efficient therapy and resistance to current standard therapy, gemcitabine (GEM). Numerous studies implicate the intimate reciprocal interactions due to paracrine Hedgehog (Hh) signaling between epithelia and underlying stroma that leads to desmoplasia and causes chemoresistance in PDAC. We report for the first time that a non-steroidal drug, ormeloxifene (ORM) has anticancer properties and depletes tumor-associated stromal tissue by inhibiting the Hh cellular signaling pathway in PDAC. This provoked us to investigate the combinatorial effects of ORM with GEM and we observed that ORM disrupts the stroma of pancreatic tumors, alters vascular network and thereby facilitates delivery and sensitivity of GEM. Methods: Using cell line models, Western blotting and QPCR were used to investigate the treatment effects of ORM, GEM and their combination on Hh signaling pathway and the related proteins involved in PDAC. To determine the effect of ORM on anti-tumorigenic sensitivity of GEM, we developed PDAC xenograft mice models using PanCa cells, BXPC3. Tumor tissue sections were stained for SHH (sonic hedgehog), cygb/STAP (stellate cell selective markers), α-SMA (PSC activation), FSP-1 (Fibroblast surface protein-1), collagen-1 by immunoflorescence, F4/80 (macrophage), CD31 (vasularization) through immunohistochemistry and microRNAs through in situ hybridization. ELIZA was performed for SDF1/CXCL12 and SHH secretion. Results: ORM inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. ORM alone and in combination with GEM inhibits the Hh signaling pathway by downregulating both the protein and mRNA levels of SHH and its related important downstream targets: GLI1, PTCH1/2, NFκB, p-AKT and Cyclin D1. ORM potentiates the anti-tumorigenic effect of GEM by 75% in PDAC xenograft mice. Investigations of treated xenograft tumor tissues show that ORM depletes tumor-associated stromal tissue by inhibiting the Hh cellular signaling pathway and both mouse/human collagen-1, a hallmark of desmoplastic reaction. These xenograft tumors treated with ORM in combination with GEM also show the inhibition of oncogenic miR-21 and restoration of tumor suppressor, miR-132. The combination therapy inhibits stromal cell populations infiltrating into the tumor tissue and produces increased intratumoral vascular density and concentration of GEM, leading to transient stabilization of tumor growth. Tumor cells, co-cultivated with TGFβ stimulated human pancreatic stromal cells, displayed increased invasive capabilities which were inhibited on treatment with ORM alone or in combination with GEM. Conclusion: We propose that ORM has a high therapeutic index and represents a great promise for a combination therapy with GEM against stroma and neoplastic cells as a treatment of choice Citation Format: Sheema Khan, Mara Ebeling, A. Ansarullah, Neeraj Chauhan, Rishi Kumar Gara, Meena Jaggi, Haotian Zhao, Subhash C. Chauhan. A novel approach to enhance delivery and sensitivity of gemcitabine in pancreatic cancer by suppression of desmoplasia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3603. doi:10.1158/1538-7445.AM2014-3603
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