Anti-apoptotic Effects of Bone Marrow on Human Islets: A Preliminary Report.

Apoptosis is one of the major factors contributing to the failure of human islet transplantation. Contributors to islet apoptosis exist in both the pre-transplantation and post transplantation stages. Factors include the islet isolation process, deterioration in vitro prior to transplantation, and immune rejection post transplantation. Previous studies have demonstrated that co-cultured bone marrow cells with human islets not only significantly enhanced the longevity of human islets but also maintained function. We hypothesized that the protective effects of bone marrow cells on human islets are through mechanisms related to preventing apoptosis. This study observed the levels of inflammatory factors such as interleukin-1ß (IL-1ß), the release of extracellular ATP in vitro, and expression levels of P2X7 ATP receptor (P2X7R), all of which lead to the occurrence of apoptosis in human islets. When human islets were co-cultured with human bone marrow, there was a reduction in the rate of apoptosis correlated with the reduction in inflammatory factors, extra cellular ATP accumulation, and ATP receptor P2X7R expression versus human islets cultured alone. These results suggest that co-culturing bone marrow cells with human islets inhibits inflammation and reduces apoptosis, thus protecting islets from self-deterioration.

Human Bone Marrow Subpopulations Sustain Human Islet Function and Viability In vitro.

AIMS: Allogeneic bone marrow (BM) has been shown to support human islet survival and function in long-term culture by initiating human islet vascularization and ß-cell regeneration. Various BM subpopulations may play different roles in human islet functions and survival. In this paper we investigated the effects of BM and its subpopulations, endothelial progenitor cells (E) and mesenchymal (M) cells on human islet's ß-cell function and regeneration. STUDY DESIGN: Isolation and identification of subpopulations from human bone marrow and culture with allogeneic human islet to investigate effects of different cell population on human islet function and regeneration. PLACE AND DURATION OF STUDY: Department of Medicine, Center for Stem Cell & Diabetes Research, RWMC, Providence, RI, USA, between 2010 - 2014. METHODOLOGY: Human islets were distributed from Integrated Islet Distribution Program (IIDP) and human bone marrow (BM) was harvested by Bone marrow transplantation center at Roger Williams Hospital. BM subpopulation was identified cell surface markers through Fluorescence-activated cell sorting, applied in flow cytometry (FACS), islet function was evaluated by human ELISA kit and ß cell regeneration was evaluated by three methods of Cre-Loxp cell tracing, ß cell sorting and RT-PCR for gene expression. RESULTS: Four different BM and seven different islet donates contributed human tissues. We observed islet ß-cell having self regeneration capability in short term culture (3∼5 days) using a Cre-Loxp cell tracing. BM and its subtype E, M have similar benefits on ß cell function during co-culture with human islet comparison to islet only. However, only whole BM enables to sustain the capability of islet ß-cell self regeneration resulting in increasing ß cell population while single E and M individual do not significantly affect on that. Mechanism approach to explore ß-cell self regeneration by evaluating transcription factor expressions, we found that BM significantly increases the activations of ß-cell regeneration relative transcription factors, the LIM homeodomain protein (Isl1), homologue to zebrafish somite MAF1 (MAFa), the NK-homeodomain factor 6.1 (NKX6.1), the paired box family factors 6 (PAX6), insulin promoter factor 1 (IPF1) and kinesin family member 4A (KIF4a). CONCLUSION: These results suggest that BM and its derived M and E cells enable to support human islet ß-cell function. However, only BM can sustain the capability of ß-cell self regeneration through initiating ß-cell transcriptional factors but not individual E and M cells suggesting pure E and M cells less supportive for islet long-term survival in vitro.

Role of calcium/ magnesium infusion in oxaliplatin-based chemotherapy for colorectal cancer patients.

The combination of oxaliplatin plus fluorouracil/leucovorin is known as the FOLFOX regimen, and it has become a standard regimen for colorectal cancer (CRC), both as adjuvant therapy and as treatment for metastatic disease. Unfortunately, platinum-based chemotherapies also produce neurotoxicity as a side effect. Neurotoxicity is the most common dose-limiting toxicity of oxaliplatin, and it is one of the major causes for patients to stop receiving chemotherapy. It can manifest as either of two distinct syndromes: a transient, acute syndrome that can appear during or shortly after the infusion (approximately 1%-2% of patients), and a dose-limiting, cumulative sensory neuropathy. Calcium/magnesium (Ca/Mg) infusions have been used to decrease the incidence of oxaliplatin-induced neuropathy. The actual utility of Ca/Mg infusions in this setting has been an interesting and controversial topic. They may reduce the severity of neurotoxicity, but some investigators have questioned whether they also will alter the efficacy of these chemotherapy regimens. In this paper, we review the clinical data concerning the usefulness of Ca/Mg infusions in reducing the incidence of oxaliplatin-induced neuropathy as well as their effect on responsiveness to chemotherapy.

Increased ATP content/production in the hypothalamus may be a signal for energy-sensing of satiety: studies of the anorectic mechanism of a plant steroidal glycoside.

A steroidal glycoside with anorectic activity in animals, termed P57AS3 (P57), was isolated from Hoodia gordonii and found to have homologies to the steroidal core of cardiac glycosides. Intracerebroventricular (i.c.v.) injections of the purified P57AS3 demonstrated that the compound has a likely central (CNS) mechanism of action. There is no evidence of P57AS3 binding to or altering activity of known receptors or proteins, including Na/K-ATPase, the putative target of cardiac glycosides. The studies demonstrated that the compound increases the content of ATP by 50-150% in hypothalamic neurons. In addition, third ventricle (i.c.v.) administration of P57, which reduces subsequent 24-h food intake by 40-60%, also increases ATP content in hypothalamic slice punches removed at 24 h following the i.c.v. injections. In related studies, in pair fed rats fed a low calorie diet for 4 days, the content of ATP in the hypothalami of control i.c.v. injected animals fell by 30-50%, which was blocked by i.c.v. injections of P57AS3. With growing evidence of metabolic or nutrient-sensing by the hypothalamus, ATP may be a common currency of energy sensing, which in turn may trigger the appropriate neural, endocrine and appetitive responses as similar to other fundamental hypothalamic homeostatic centers for temperature and osmolarity.