Hepatocellular Carcinoma in Chad: A Retrospective Study of 219 Cases

Background: Although hepatocellular carcinoma was historically considered an important scourge in Middle Africa, there is no publication describing this disease in Chad. Methods: We conducted a retrospective analysis of 219 patients with hepatocellular carcinoma (HCC) attending care at the University Reference Hospital of Ndjamena between 2007 and 2016. Results: This series of HCC was characterized by a male predominance (M:F = 2.4) with a mean tumor onset at the end of the fifth decade of life (49.9 ± 14.7 years). Tumors appear on a cirrhotic liver in 70% of cases and were already multifocal at diagnosis in two thirds of the patients. Alpha-fetoprotein was above the physiological threshold (10 ng/mL) in 73.4% of cases measured and above the so-called diagnostic level (400 ng/mL) in 53.4% of patients. The principal risk factor was chronic infection with hepatitis B virus, detected in 52.6% of cases. Patients seropositive for hepatitis C virus were infrequent (8.6%) and heavy alcohol intake was even less prevalent (5.9%). Remarkably, a very large subset of patients did not present any infectious or lifestyle risk factor (43.4%). Mean AFP values or fibrosis assessment scores are usually lower in these patients than in HBV-infected ones. Conclusions: The etiological spectrum of HCC is far from being fully established in Chad. Further epidemiological research is warranted to identify risk factors involved in a large proportion of cases. Exposure to aflatoxin B1 and dysmetabolic conditions affecting the liver have to be investigated as priority.

Risk Factors of Liver Cirrhosis in Chad: Large Proportion of Cases without Clear Etiology

Background: In comparison to other forms of chronic liver diseases, cirrhosis is generally poorly studied in sub Saharan Africa. In Chad, more particularly, no data are available despite the burden of liver diseases considered as the first cause of hospitalizations in the country. Methods: We conducted a retrospective analysis of 268 patients with liver cirrhosis attending care at the University Reference Hospital between 2007 and 2016. Results: This series of liver cirrhoses was characterized by a weak mal predominance (M:F = 1.7). The age of onset occurs significantly earlier in women than in men (40.6 ± 12.0 vs. 44.4 ± 13.4, p = 0.0171). The principal risk factor was persistent infection with hepatitis B virus (49% of cases) followed distantly by infection with hepatitis C virus (13%) and excessive alcohol consumption (10%). Men were more frequently carrying HBV surface antigen than women (65.6% vs 35.9% p = 0.0019). HBV-associated liver cirrhosis was overall more severe than diseases from other causes. A large proportion of cirrhosis (30%), observed primarily in women (48.1% vs 24.1%, p = 0.0036), was considered are cryptogenic. Conclusions: The etiological spectrum of liver cirrhosis remains to be properly defined in Chad. This lack of knowledge prevents the implementation of an efficient policy of prevention. A significant effort should be secured to characterize hitherto neglected infectious, lifestyle or genetic risk factors responsible of this form of terminal disease and improve subsequently liver health of local populations.

FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma

AIM:To evaluate the efficacy and tolerance of FOLFIRI plus bevacizumab treatment outcome as second-line treatment for metastatic intrahepatic cholangiocarcinoma.METHODS:Thirteen consecutive patients with metastatic intrahepatic cholangiocarcinoma who were refractory tofirst-line therapy consisting of gemcitabine plus oxaliplatinbased first-line chemotherapy given intravenously via intra-arterial infusion were treated with FOLFIRI[irinotecan(180 mg/m2 i.v.over 90 min)concurrently with folinic acid(400 mg/m2 i.v.over 120 min)followed by fluorouracil(400 mg/m2 i.v.bolus)then fluorouracil 2400 mg/m2 intravenous infusion over 46 h]and bevacizumab(5mg/kg)every 2 wk.Tumor response was evaluated by computed tomography scan every 4 cycles.RESULTS:The best tumor responses using response evaluation criteria in solid tumor criteria were:complete response for 1 patient,partial response for 4 patients,and stable disease for 6 patients after 6 mo of follow-up.The response rate was 38.4%(95%CI:12.5-89)and the disease control rate was 84.5%(95%CI:42-100).Seven deaths occurred at the time of analysis,progression free survival was 8 mo(95%CI:7-16),and median overall survival was 20 mo(95%CI:8-48).No grade 4toxic events were observed.Four grade 3 hematological toxicities and one grade 3 digestive toxicity occurred.An adaptive reduction in chemotherapy dosage was required in 2 patients due to hematological toxicity,and a delay in chemotherapy cycles was required for 3 patients.CONCLUSION:FOLFIRI plus bevacizumab combination treatment showed promising efficacy and safety as second-line treatment for metastatic intrahepatic cholangiocarcinoma after failure of the first-line treatment of gemcitabine plus oxaliplatin chemotherapy.

Insulin-mimetic compound hexaquis(benzylammonium) decavanadate is antilipolytic in human fat cells

AIM To assess in rodent and human adipocytes the antilipolytic capacity of hexaquis(benzylammonium) decavanadate(B6V10), previously shown to exert antidiabetic effects in rodent models, such as lowering free fatty acids(FFA) and glucose circulating levels.METHODS Adipose tissue(AT) samples were obtained after informed consent from overweight women undergoing plastic surgery. Comparison of the effects of B6V10 and reference antilipolytic agents(insulin,benzylamine,vanadate) on the lipolytic activity was performed on adipocytes freshly isolated from rat, mouse and human AT. Glycerol release was measured using colorimetric assay as an index of lipolytic activity. The influence of B6V10 and reference agents on glucose transport into human fat cells was determined using the radiolabelled 2-deoxyglucose uptake assay.RESULTS In all the species studied, B6V10 exhibited a dosedependent inhibition of adipocyte lipolysis when triglyceride breakdown was moderately enhanced by β-adrenergic receptor stimulation. B6V10 exerted on human adipocyte a maximal lipolysis inhibition of glycerol release that was stronger than that elicited by insulin. However, B6V10 did not inhibit basal and maximally stimulated lipolysis. When incubated at dose ≥ 10 μmol/L, B6V10 stimulated by twofold the glucose uptake in human fat cells, but-similarly to benzylamine-without reaching the maximal effect of insulin, while it reproduced one-half of the insulin-stimulation of lipogenesis in mouse fat cells. CONCLUSION B6V10 exerts insulin-like actions in adipocytes, including lipolysis inhibition and glucose transport activation. B6V10 may be useful in limiting lipotoxicity related to obesity and insulin resistance.

Structure Sorting of Multiple Macromolecular States in Heterogeneous Cryo-EM Samples by 3D Multivariate Statistical Analysis

Heterogeneity of biological samples is usually considered a major obstacle for three-dimensional (3D) structure determination of macromolecular complexes. Heterogeneity may occur at the level of composition or conformational variability of complexes and affects most 3D structure determination methods that rely on signal averaging. Here, an approach is described that allows sorting structural states based on a 3D statistical approach, the 3D sampling and classification (3D-SC) of 3D structures derived from single particles imaged by cryo electron microscopy (cryo-EM). The method is based on jackknifing & bootstrapping of 3D sub-ensembles and 3D multivariate statistical analysis followed by 3D classification. The robustness of the statistical sorting procedure is corroborated using model data from an RNA polymerase structure and experimental data from a ribosome complex. It allows resolving multiple states within heterogeneous complexes that thus become amendable for a structural analysis despite of their highly flexible nature. The method has important implications for high-resolution structural studies and allows describing structure ensembles to provide insights into the dynamics of multi-component macromolecular assemblies.

Polydopamine Particles Effect on Melanoma Cells Proliferation and Melanin Secretion

Melanin is a biopolymer implicated in the protection of cellular membranes and DNA produced by melanocytes. This pigment has a dual role and should be considered as a photo-protector and as a photosensitizer due to its interaction with UV. The design of multifunctional and biologically responsive coatings is of major interest in modern biomaterials science. The aim of this study is not only to characterize the deposition of multilayered polyelectrolytes films made from polydopamine particles and polyamines like poly-(L-lysine hydrobromide) (PLL), but also to evaluate melanoma cells activity in terms of proliferation and their capacity to stimulate melanin secretion. One could expect that the presence of a melanin like material in the film may have a positive or a negative feedback on the melanin biosynthesis and consequently on melanoma development. Some comparisons are also done with pure polydopamine grains in suspension in the cell culture medium, to investigate if the immobilization of the polydopamine grains has an influence on their bioactivity.

Effect of alcohol consumption on liver stiffness measured by transient elastography

AIM:To determine the evolution of transient elastography(TE) in patients with alcoholic liver disease according to alcohol cessation or continuation.METHODS:We retrospectively selected in our local database all patients who had two TE between June 2005 and November 2010 with chronic alcohol excessive consumption and excluded those with associated cause of liver disease.TE was performed at least one week apart by senior operator.TE examinations with less than ten successful measures or with an interquartile range above 30% were excluded.We retrospectively reviewed file of all patients to include only patient followed up by trained addictologist and for which definite information on alcohol consumption was available.Concomitant biological parameters [aspartate amino transferase(AST),alanine amino transferase and gamma-glutamyl transpeptidase(GGT)] within 4 wk of initial and final TE were recorded.Putative fibrosis score according to initial and final TE were determined with available cut-off for alcoholic liver disease and hepatitis C.Initial and final putative fibrosis score were compared according to alcohol consumption during follow-up.RESULTS:During the study period 572 patients had TE examination for alcoholic liver disease and 79 of them had at least two examinations.Thirty-seven patients met our criteria with a median follow-up of 32.5 wk.At the end of the study,13(35%) were abstinent,and 24(65%) relapsers.Eight patients had liver biopsy during follow-up.TE decreased significantly during follow-up in 85% of abstinent patients [median(range):-4.9(-6.1,-1.9)],leading to a modification of the putative fibrosis stage in 28%-71% of patient according to different cut-off value.In relapsers TE increased in 45% and decreased in 54% of patient.There was no statistical difference between initial and final TE in relapsers.In the overall population,using 22.6 kPa as cut-off for cirrhosis,4 patients had cirrhosis at initial TE and 3 patients had cirrhosis at final TE.Using 19.5 kPa as cut-off for cirrhosis,7 patients had cirrhosis at initial TE and 5 patients had cirrhosis at final TE.Using 12.5 kPa as cut-off for cirrhosis,16 patients had cirrhosis at initial TE and 15 patients had cirrhosis at final TE.Evolution of biological data was in accordance with the relapse or abstinent status:abstinence ratio(duration of abstinence/duration follow-up) was correlated with AST ratio(r =-0.465,P = 0.007) and GGT ratio(r =-0.662,P<0.0001).GGT was correlated with initial(r = 0.488,P = 0.002) and final TE(r = 0.49,P<0.005).Final TE was correlated with AST(r = 0.362,P<0.05).Correlation between TE ratio and AST ratio(r = 0.44,P = 0.01) revealed that TE varied proportionally to AST for all patients irrespective of their alcohol status.The same relationship was observed between TE ratio and GGT ratio(r = 0.65,P<0.0001).Evolution of TE was significantly correlated with the ratio of time of abstinence to observation time(r =-0.387,P = 0.016) and the evolution of liver enzymes.CONCLUSION:TE significantly decreased with abstinence.Results of TE in alcoholic liver disease cannot be interpreted without taking into account alcohol consumption and liver enzymes.

Dimensions of hepatocellular carcinoma phenotypic diversity

Hepatocellular carcinoma(HCC) is the 3^(rd) leading cause of cancer-related death worldwide. More than 80% of HCCs arise within chronic liver disease resulting from viral hepatitis, alcohol, hemochromatosis, obesity and metabolic syndrome or genotoxins. Projections based on Western lifestyle and its metabolic consequences anticipate a further increase in incidence, despite recent breakthroughs in the management of viral hepatitis. HCCs display high heterogeneity of molecular phenotypes, which challenges clinical management. However, emerging molecular classifications of HCCs have not yet formed a unified corpus translatable to the clinical practice. Thus, patient management is currently based upon tumor number, size, vascular invasion, performance status and functional liver reserve. Nonetheless, an impressive body of molecular evidence emerged within the last 20 years and is becoming increasingly available to medical practitioners and researchers in the form of repositories. Therefore, the aim this work is to review molecular data underlying HCC classifications and to organize this corpus into the major dimensions explaining HCC phenotypic diversity. Major efforts have been recently made worldwide toward a unifying "clinically-friendly" molecular landscape. As a result, a consensus emerges on three major dimensions explaining the HCC heterogeneity. In the first dimension, tumor cell proliferation and differentiation enabled allocation of HCCs to two major classes presenting profoundly different clinical aggressiveness. In the second dimension, HCC microenvironment and tumor immunity underlie recent therapeutic breakthroughs prolonging patients' survival. In the third dimension,metabolic reprogramming, with the recent emergence of subclass-specific metabolic profiles, may lead to adaptive and combined therapeutic approaches. Therefore, here we review recent molecular evidence, their impact on tumor histopathological features and clinical behavior and highlight the remaining challenges to translate our cognitive corpus into patient diagnosis and allocation to therapeutic options.

Probiotic yeasts: Anti-inflammatory potential of various non-pathogenic strains in experimental colitis in mice

AIM: To evaluate the in vitro immunomodulation capacity of various non-pathogenic yeast strains and to investigate the ability of some of these food grade yeasts to prevent experimental colitis in mice.METHODS: In vitro immunomodulation was assessed by measuring cytokines [interleukin (IL)-12p70,IL-10,tumor necrosis factor and interferon γ] released by human peripheral blood mononuclear cells after 24 h stimulation with 6 live yeast strains (Saccharomyces ssp.) and with bacterial reference strains.A murine model of acute 2-4-6-trinitrobenzene sulfonic acid (TNBS)-colitis was next used to evaluate the distinct prophylactic protective capacities of three yeast strains compared with the performance of prednisolone treatment.RESULTS: The six yeast strains all showed similar non-discriminating anti-inflammatory potential when tested on immunocompetent cells in vitro .However,although they exhibited similar colonization patterns in vivo ,some yeast strains showed significant anti-inflammatory activities in the TNBS-induced colitis model,whereas others had weaker or no preventive effect at all,as evidenced by colitis markers (body-weight loss,macroscopic and histological scores,myeloperoxidase activities and blood inflammatory markers).CONCLUSION: A careful selection of strains is required among the biodiversity of yeasts for specific clinical studies,including applications in inflammatory bowel disease and other therapeutic uses.

Retinoid receptor-related orphan receptor alpha： a key gene setting brain circuits

The retinoid receptor-related orphan receptor alpha（RORα） is thought to act as a constitutive activator of transcription by binding to the ROR response element（RORE） of target genes. Several mouse models in which RORα is defective have revealed the decisive roles of RORα on the development, maturation and neuroprotection of various cerebral regions including the cerebellar and somatosensory systems. We have recently shown that RORα is needed for accurate thalamic sensory system organization and somatosensory cortex development. The phenotype of various RORα deficient mice models（staggerer mutant or mouse lacking RORα in specific somatosensory regions） is, in part, reminiscent of what has been described in mice lacking thyroid hormone triiodothyronine（T3）. As in in vitro studies or in other models, our studies strongly suggest that the T3/RORα-pathway, among others, is in part responsible for the staggerer phenotype. We have indeed identified some genes that were both regulated by T3 and RORα and that are known to be implicated in the cerebellar or somatosensory system development. Moreover, several groups have shown that RORα is at the crossroad of many biological processes and pathologies, including psychiatric and degenerative disorders. In particular, defective RORα-signalling has been demonstrated in humans to be associated with the emergence of autistic-like disorders. We believe that determining the appropriate amount of RORα activity could be crucial in detecting and preventing the emergence of specific brain diseases.

Hepatitis C virus-mediated angiogenesis:Molecular mechanisms and therapeutic strategies

Angiogenesis is an essential process for organ growth and repair. Thus, an imbalance in this process can lead to several diseases including malignancy. Angiogenesis is a critical step in vascular remodeling, tissue damage and wound healing besides being required for invasive tumor growth and metastasis. Because angiogenesis sets an important point in the control of tumor progression, its inhibition is considered a valuable therapeutic approach for tumor treatment. Chronic liver disease including hepatitis C virus(HCV) infection is one of the main cause for the development of hepatic angiogenesis and thereby plays a critical role in the modulation of hepatic angiogenesis that finally leads to hepatocellular carcinoma progression and invasion. Thus, understanding of the molecular mechanisms of HCV-mediated hepatic angiogenesis will help design a therapeutic protocol for the intervention of HCV-mediated angiogenesis and subsequently its outcome. In this review, we will focus on the molecular mechanisms of HCV-mediated hepatic angiogenesis and the related signaling pathways that can be target for current and under development therapeutic approaches.

Magnesium sulfate and fetal neuroprotection: overview of clinical evidence

Antenatal administration of magnesium sulfate is an important part of the neuroprotective strategy for preterm infants. Strong evidence from five randomized controlled trials and five meta-analyses has demonstrated that magnesium sulfate, when administered before preterm delivery, significantly reduces the risk of cerebral palsy at two years. Through secondary analyses of randomized controlled trials and other original clinical studies, this state-of-the-art review highlights the absence of serious adverse effects in both pregnant women and neonates, as well as the impact of maternal body mass index and preeclamptic status on the maternal and neonatal magnesium levels, which could influence the magnitude of the neuroprotective effect. Although antenatal magnesium sulfate is a cost-effective strategy, some practice surveys have demonstrated that the use of magnesium sulfate is not sufficient and that its use is heterogeneous, differing among different maternity wards. Since 2010, an increasing number of obstetrical societies have recommended its use to improve the neurological outcomes of preterm infants, especially the International Federation of Gynecology and Obstetrics and World Health Organization in 2015, and France in 2017. Considering the neuroprotective impact of magnesium sulfate when administered before delivery, postnatal administration should be considered, and its effects should be assessed using randomized controlled trials.

丙肝病毒相关的 hepatocellular 癌: 卓见进分子的机制和治疗学的策略

Hepatitis C virus(HCV) infects more than 170 million people worldwide,and thereby becomes a series global health challenge.Chronic infection with HCV is considered one of the major causes of end-stage liver disease including cirrhosis and hepatocellular carcinoma.Although the multiple functions of the HCV proteins and their impacts on the modulation of the intracellular signaling transduction processes,the drive of carcinogenesis during the infection with HCV,is thought to result from the interactions of viral proteins with host cell proteins.Thus,the induction of mutator phenotype,in liver,by the expression of HCV proteins provides a key mechanism for the development of HCV-associated hepatocellular carcinoma(HCC).HCC is considered one of the most common malignancies worldwide with increasing incidence during the past decades.In many countries,the trend of HCC is attributed to several liver diseases including HCV infection.However,the development of HCC is very complicated and results mainly from the imbalance between tumor suppressor genes and oncogenes,as well as from the alteration of cellular factors leading to a genomic instability.Besides the poor prognosis of HCC patients,this type of tumor is quite resistance to the available therapies.Thus,understanding the molecular mechanisms,which are implicated in the development of HCC during the course of HCV infection,may help to design a general therapeutic protocol for the treatment and/or the prevention of this malignancy.This review summarizes the current knowledge of the molecular mechanisms,which are involved in the development of HCV-associated HCC and the possible therapeutic strategies.

Prognostic value of chemotherapy-induced hematological toxicity in metastatic colorectal cancer patients

AIM: To establish whether chemotherapy-induced neutropenia is predictive of better outcome in patients with metastatic colorectal cancer(mCRC). METHODS: Survival and patient characteristics from consecutive mCRC patients treated in the Centre Georges Francois Leclerc, Dijon, France between January 2001 and December 2011 were analyzed. Patient and tumor characteristics, hematological toxicity(neutropenia, anemia, and thrombocytopenia), and type of chemotherapy received were recorded. RESULTS: We retrospectively analyzed data from 399 consecutive patients with mCRC who received at least one line of chemotherapy. Median follow up was 6.3 years. Eighty-eight percent of the patients received more than two lines of chemotherapy. By univariate analysis, whatever their grade, neutropenia and thrombocytopenia occurring during the first two lines of chemotherapy were significantly associated with better overall survival(HR = 0.55, 95%CI: 0.43-0.70, P < 0.0001 and HR = 0.70, 95%CI: 0.56-0.88, P = 0.025 respectively). In contrast, anemia during chemotherapy was significantly associated with poorer overall survival(HR = 1.9, 95%CI: 1.22-2.97, P = 0.005). Multivariate analysis revealed that both neutropenia and thrombocytopenia were significantly associated with better overall survival: HR = 0.43, 95%CI: 0.29-0.64, P < 0.0001 and HR = 0.69, 95%CI: 0.49-0.98, P = 0.036, respectively. CONCLUSION: These data suggest that occurrence of neutropenia or thrombocytopenia during first- or second-line chemotherapy for mCRC is associated with better survival.

Non-Linear Phase Tomography Based on Fréchet Derivative

Phase imaging coupled to micro-tomography acquisition has emerged as a powerful tool to investigate specimens in a non-destructive manner. While the intensity data can be acquired and recorded, the phase information of the signal has to be “retrieved” from the data modulus only. Phase retrieval is an ill-posed non-linear problem and regularization techniques including a priori knowledge are necessary to obtain stable solutions. Several linear phase recovery methods have been proposed and it is expected that some limitations resulting from the linearization of the direct problem will be overcome by taking into account the non-linearity of the phase problem. To achieve this goal, we propose and evaluate a non-linear algorithm for in-line phase micro-tomography based on an iterative Landweber method with an analytic calculation of the Fréchet derivative of the phase-intensity relationship and of its adjoint. The algorithm was applied in the projection space using as initialization the linear mixed solution. The efficacy of the regularization scheme was evaluated on simulated objects with a slowly and a strongly varying phase. Experimental data were also acquired at ESRF using a propagation-based X-ray imaging technique for the given pixel size 0.68 μm. Two regularization scheme were considered: first the initialization was obtained without any prior on the ratio of the real and imaginary parts of the complex refractive index and secondly a constant a priori value was assumed on ?. The tomographic central slices of the refractive index decrement were compared and numerical evaluation was performed. The non-linear method globally decreases the reconstruction errors compared to the linear algorithm and is achieving better reconstruction results if no prior is introduced in the initialization solution. For in-line phase micro-tomography, this non-linear approach is a new and interesting method in biomedical studies where the exact value of the a priori ratio is not known.

Defensins couple dysbiosis to primary immunodeficiency in Crohn's disease

Antimicrobial peptides,including defensins,are essential effectors in host defence and in the maintenance of immune homeostasis.Clinical studies have linked the defective expression of both α-and β-defensin to the reduced killing of certain microorganisms by the intestinal mucosa of patients suffering from ileal and colonic Crohn's disease(CD),respectively.Only recently have the events leading to defective expression of defensins in CD been further elucidated,and are discussed herein.These events may account for CD-associated alterations in the microbiome and may subsequently precipitate the development of granulomatous inflammatory lesions in genetically-predisposed patients.We also address how these discoveries may pave the way for the development of a molecular medicine aimed at restoring gut barrier function in CD.

Killing of p53-deficient hepatoma cells by parvovirus H-1 and chemotherapeutics requires promyelocytic leukemia protein

AIM: To evaluate the synergistic targeting and killing of human hepatocellular carcinoma (HCC) cells lacking p53 by the oncolytic autonomous parvovirus (PV) H-1 and chemotherapeutic agents and its dependence on functional promyelocytic leukemia protein (PML). METHODS: The role of p53 and PML in regulating cy-totoxicity and gene transfer mediated by wild-type (wt) PV H-1 were explored in two pairs of isogenic human hepatoma cell lines with different p53 status. Further-more,H-1 PV infection was combined with cytostatic drug treatment. RESULTS: While the HCC cells with different p53 status studied were all susceptible to H-1 PV-induced apoptosis,the cytotoxicity of H-1 PV was morepronounced in p53-negative than in p53-positive cells. Apoptosis rates in p53-negative cell lines treated by genotoxic drugs were further enhanced by a treatment with H-1 PV. In flow cytometric analyses,H-1 PV infection resulted in a reduction of the mitochondrial transmembrane potential. In addition,H-1 PV cells showed a significant increase in PML expression. Knocking down PML expression resulted in a striking reduction of the level of H-1 PV infected tumor cell death. CONCLUSION: H-1 PV is a suitable agent to circumvent the resistance of p53-negative HCC cells to genotoxic agents,and it enhances the apoptotic process which is dependent on functional PML. Thus,H-1 PV and its oncolytic vector derivatives may be considered as therapeutic options for HCC,particularly for p53-negative tumors.

Ecto-F_1-ATPase: A moonlighting protein complex and an unexpected apoA-I receptor

Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F1-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F1-ATPase. Particularly, the role of the F1-ATPase pathway(s) in HDL-cholesterol uptake and apoA-Imediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.

Short-term effects of obestatin on hexose uptake and triacylglycerol breakdown in human subcutaneous adipocytes

AIM To study complete dose-dependent effects of obestatin on lipolytic and glucose transport activities in human adipocyte preparations highly responsive to insulin.METHODS Adipocytes were prepared by liberase digestion from subcutaneous abdominal adipose tissue obtained from overweight subjects undergoing plastic surgery. The index of lipolytic activity was the glycerol released in the incubation medium, while glucose transport was assessed by [~3H]-2-deoxyglucose uptake assay.RESULTS When tested from 0.1 nmol/L to 1 μmol/L, obestatin did not stimulate glycerol release; it did not inhibit the lipolytic effect of isoprenaline and did not alter the insulin antilipolytic effect. Obestatin hardly activated glucose transport at 1 μmol/L only. Moreover, the obestatin stimulation effect was clearly lower than the threefold increase induced by insulin 100 nmol/L.CONCLUSION Low doses of obestatin cannot directly influence lipolysis and glucose uptake in human fat cells.