Histone acetylation regulates intracellular pH.

Differences in global levels of histone acetylation occur in normal and cancer cells, although the reason why cells regulate these levels has been unclear. Here we demonstrate a role for histone acetylation in regulating intracellular pH (pH(i)). As pH(i) decreases, histones are globally deacetylated by histone deacetylases (HDACs), and the released acetate anions are coexported with protons out of the cell by monocarboxylate transporters (MCTs), preventing further reductions in pH(i). Conversely, global histone acetylation increases as pH(i) rises, such as when resting cells are induced to proliferate. Inhibition of HDACs or MCTs decreases acetate export and lowers pH(i), particularly compromising pH(i) maintenance in acidic environments. Global deacetylation at low pH is reflected at a genomic level by decreased abundance and extensive redistribution of acetylation throughout the genome. Thus, acetylation of chromatin functions as a rheostat to regulate pH(i) with important implications for mechanism of action and therapeutic use of HDAC inhibitors.

Bone Marrow Therapies for Chronic Heart Disease.

Chronic heart failure is a leading cause of death. The demand for new therapies and the potential regenerative capacity of bone marrow-derived cells has led to numerous clinical trials. We critically discuss current knowledge of the biology and clinical application of bone marrow cells. It appears unlikely that bone marrow cells can develop into functional cardiomyocyte after infusion but may have favorable paracrine effects. Most, but not all, clinical trials report a modest short- but not long-term benefit of infusing bone marrow-derived cells. Effect size appears to correlate with stringency of study-design: the most stringent trials report the smallest effect-sizes. We conclude there may be short- but not substantial long-term benefit of infusing bone marrow-derived cells into persons with chronic heart failure and any benefit observed is unlikely to result from trans-differentiation of bone marrow-derived cells into functioning cardiomyocytes.

Concise review: bone marrow autotransplants for liver disease?

There are increasing reports of using bone marrow-derived stem cells to treat advanced liver disease. We consider several critical issues that underlie this approach. For example, are there multipotent stem cell populations in human adult bone marrow? Can they develop into liver cells or supporting cell types? What are stromal stem/progenitor cells, and can they promote tissue repair without replacing hepatocytes? Does reversal of end-stage liver disease require new hepatocytes, a new liver microenvironment, both, neither or something else? Although many of these questions are unanswered, we consider the conceptual and experimental bases underlying these issues and critically analyze results of clinical trials of stem cell therapy of end-stage liver disease.

New interpretation for diagnostic yield of ileoscopy: A prospective study and a brief review.

BACKGROUND: Lower digestive endoscopy is mostly limited to the cecum without any attempt to penetrate the ileum. One of the probable reasons is the expectation of a low diagnostic yield. This study aimed to examine the feasibility of ileoscopy during colonoscopy and its diagnostic yield. METHODS: We prospectively studied 128 consecutive patients, who were referred to Poursina Hakim Research Institute for lower GI disorders evaluation over a four months period, from March to July 2003. We tried to do total colonoscopy and ileal intubation with special attention to the timing and success rate of colonoscopy in each landmark. RESULTS: Out of 128 subjects, successful examination of cecum was done in 120 (93.6%). Out of 120 patients whose cecum was reached and studied, we intended to perform ileal intubation in 99 patients. Successful terminal ileal (TI) intubation was accomplished in 93(93.9 %) of the examinations. Abnormal findings were seen in 4 cases. Normal ileal findings were also helpful in ruling out TI pathology in 78 other patients with abdominal pain, weight loss, lower GI bleeding or colonic inflammation, which made ileoscopy clinically valuable in 82 of 95 normal ileal examinations (86.3%) in this study. CONCLUSIONS: Ileoscopy is safe, fast and feasible, so we recommend it in all symptomatic cases since normal findings are also valuable in patients' clinical management. Considering normal findings, the routine ileoscopy had surprisingly higher diagnostic yield compared to the results of previous studies.

MCT1 Modulates Cancer Cell Pyruvate Export and Growth of Tumors that Co-express MCT1 and MCT4.

Monocarboxylate transporter 1 (MCT1) inhibition is thought to block tumor growth through disruption of lactate transport and glycolysis. Here, we show MCT1 inhibition impairs proliferation of glycolytic breast cancer cells co-expressing MCT1 and MCT4 via disruption of pyruvate rather than lactate export. MCT1 expression is elevated in glycolytic breast tumors, and high MCT1 expression predicts poor prognosis in breast and lung cancer patients. Acute MCT1 inhibition reduces pyruvate export but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that co-express MCT1 and MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest MCT1 expression is elevated in glycolytic cancers to promote pyruvate export that when inhibited, enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors, further supporting their use as anti-cancer therapeutics.

Highly efficient differentiation of functional hepatocytes from human induced pluripotent stem cells.

Human induced pluripotent stem cells (hiPSCs) hold great potential for use in regenerative medicine, novel drug development, and disease progression/developmental studies. Here, we report highly efficient differentiation of hiPSCs toward a relatively homogeneous population of functional hepatocytes. hiPSC-derived hepatocytes (hiHs) not only showed a high expression of hepatocyte-specific proteins and liver-specific functions, but they also developed a functional biotransformation system including phase I and II metabolizing enzymes and phase III transporters. Nuclear receptors, which are critical for regulating the expression of metabolizing enzymes, were also expressed in hiHs. hiHs also responded to different compounds/inducers of cytochrome P450 as mature hepatocytes do. To follow up on this observation, we analyzed the drug metabolizing capacity of hiHs in real time using a novel ultra performance liquid chromatography-tandem mass spectrometry. We found that, like freshly isolated primary human hepatocytes, the seven major metabolic pathways of the drug bufuralol were found in hiHs. In addition, transplanted hiHs engrafted, integrated, and proliferated in livers of an immune-deficient mouse model, and secreted human albumin, indicating that hiHs also function in vivo. In conclusion, we have generated a method for the efficient generation of hepatocytes from induced pluripotent stem cells in vitro and in vivo, and it appears that the cells function similarly to primary human hepatocytes, including developing a complete metabolic function. These results represent a significant step toward using patient/disease-specific hepatocytes for cell-based therapeutics as well as for pharmacology and toxicology studies.

New approaches in the differentiation of human embryonic stem cells and induced pluripotent stem cells toward hepatocytes.

Orthotropic liver transplantation is the only established treatment for end-stage liver diseases. Utilization of hepatocyte transplantation and bio-artificial liver devices as alternative therapeutic approaches requires an unlimited source of hepatocytes. Stem cells, especially embryonic stem cells, possessing the ability to produce functional hepatocytes for clinical applications and drug development, may provide the answer to this problem. New discoveries in the mechanisms of liver development and the emergence of induced pluripotent stem cells in 2006 have provided novel insights into hepatocyte differentiation and the use of stem cells for therapeutic applications. This review is aimed towards providing scientists and physicians with the latest advancements in this rapidly progressing field.