|
1
|
Cocchi V, Jávega B, Gasperini S, O’Connor JE, Lenzi M, Hrelia P. 6-(Methylsulfonyl) Hexyl Isothiocyanate: A Chemopreventive Agent Inducing Autophagy in Leukemia Cell Lines. Biomolecules 2022; 12:1485. [PMID: 36291694 PMCID: PMC9599183 DOI: 10.3390/biom12101485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/11/2022] [Indexed: 01/18/2023] Open
Abstract
Autophagy is a fundamental catabolic process of cellular survival. The role of autophagy in cancer is highly complex: in the early stages of neoplastic transformation, it can act as a tumor suppressor avoiding the accumulation of proteins, damaged organelles, and reactive oxygen species (ROS), while during the advanced stages of cancer, autophagy is exploited by cancer cells to survive under starvation. 6-(Methylsulfonyl) hexyl isothiocyanate (6-MITC) is the most interesting compound in the Wasabia Japonica rizhome. Recently, we proved its ability to induce cytotoxic, cytostatic, and cell differentiation effects on leukemic cell lines and its antimutagenic activity on TK6 cells. In the current study, to further define its chemopreventive profile, Jurkat and HL-60 cells were treated with 6-MITC for 24 h. The modulation of the autophagic process and the involvement of ROS levels as a possible trigger mechanisms were analyzed by flow cytometry. We found that 6-MITC induced autophagy in Jurkat and HL-60 cells at the highest concentration tested and increased ROS intracellular levels in a dose-dependent manner. Our results implement available data to support 6-MITC as an attractive potential chemopreventive agent.
Collapse
Affiliation(s)
- Veronica Cocchi
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, 40127 Bologna, Italy
| | - Beatriz Jávega
- Laboratory of Cytomics, Joint Research Unit CIPF-UVEG, Department of Biochemistry and Molecular Biology, University of Valencia, 46010 Valencia, Spain
| | - Sofia Gasperini
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, 40127 Bologna, Italy
| | - José-Enrique O’Connor
- Laboratory of Cytomics, Joint Research Unit CIPF-UVEG, Department of Biochemistry and Molecular Biology, University of Valencia, 46010 Valencia, Spain
| | - Monia Lenzi
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, 40127 Bologna, Italy
| | - Patrizia Hrelia
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, 40127 Bologna, Italy
| |
Collapse
|
|
2
|
Mohan J, Ghazi T, Chuturgoon AA. A Critical Review of the Biochemical Mechanisms and Epigenetic Modifications in HIV- and Antiretroviral-Induced Metabolic Syndrome. Int J Mol Sci 2021; 22:ijms222112020. [PMID: 34769448 PMCID: PMC8584285 DOI: 10.3390/ijms222112020] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic syndrome (MetS) is a non-communicable disease characterised by a cluster of metabolic irregularities. Alarmingly, the prevalence of MetS in people living with Human Immunodeficiency Virus (HIV) and antiretroviral (ARV) usage is increasing rapidly. This study aimed to look at biochemical mechanisms and epigenetic modifications associated with HIV, ARVs, and MetS. More specifically, emphasis was placed on mitochondrial dysfunction, insulin resistance, inflammation, lipodystrophy, and dyslipidaemia. We found that mitochondrial dysfunction was the most common mechanism that induced metabolic complications. Our findings suggest that protease inhibitors (PIs) are more commonly implicated in MetS-related effects than other classes of ARVs. Furthermore, we highlight epigenetic studies linking HIV and ARV usage to MetS and stress the need for more studies, as the current literature remains limited despite the advancement in and popularity of epigenetics.
Collapse
|
|
3
|
Monnin A, Vizeneux A, Nagot N, Eymard-Duvernay S, Meda N, Singata-Madliki M, Ndeezi G, Tumwine JK, Kankasa C, Goga A, Tylleskär T, Van de Perre P, Molès JP. Longitudinal Follow-Up of Blood Telomere Length in HIV-Exposed Uninfected Children Having Received One Year of Lopinavir/Ritonavir or Lamivudine as Prophylaxis. CHILDREN (BASEL, SWITZERLAND) 2021; 8:796. [PMID: 34572228 PMCID: PMC8468502 DOI: 10.3390/children8090796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 11/16/2022]
Abstract
Telomere shortening can be enhanced upon human immunodeficiency virus (HIV) infection and by antiretroviral (ARV) exposures. The aim of this study was to evaluate the acute and long-term effect on telomere shortening of two ARV prophylaxes, lopinavir/ritonavir (LPV/r) and lamivudine (3TC), administered to children who are HIV-exposed uninfected (CHEU) to prevent HIV acquisition through breastfeeding during the first year of life, and to investigate the relationship between telomere shortening and health outcomes at six years of age. We included 198 CHEU and measured telomere length at seven days of life, at week-50 and at six years (year-6) using quantitative polymerase chain reaction. At week-50, telomere shortening was observed among 44.3% of CHEU, irrespective of the prophylactic treatment. Furthermore, this telomere shortening was neither associated with poor growth indicators nor neuropsychological outcomes at year-6, except for motor abilities (MABC test n = 127, β = -3.61, 95%CI: -7.08, -0.14; p = 0.04). Safety data on telomere shortening for infant HIV prophylaxis are scarce. Its association with reduced motor abilities deserves further attention among CHEU but also HIV-infected children receiving ARV treatment.
Collapse
Affiliation(s)
- Audrey Monnin
- Pathogenèse et Contrôle des Infections Chroniques, INSERM U1058, Université Montpellier, Etablissement Français du Sang, University of Antilles, 34093 Montpellier, France; (A.M.); (A.V.); (N.N.); (S.E.-D.); (P.V.d.P.)
| | - Amélie Vizeneux
- Pathogenèse et Contrôle des Infections Chroniques, INSERM U1058, Université Montpellier, Etablissement Français du Sang, University of Antilles, 34093 Montpellier, France; (A.M.); (A.V.); (N.N.); (S.E.-D.); (P.V.d.P.)
| | - Nicolas Nagot
- Pathogenèse et Contrôle des Infections Chroniques, INSERM U1058, Université Montpellier, Etablissement Français du Sang, University of Antilles, 34093 Montpellier, France; (A.M.); (A.V.); (N.N.); (S.E.-D.); (P.V.d.P.)
| | - Sabrina Eymard-Duvernay
- Pathogenèse et Contrôle des Infections Chroniques, INSERM U1058, Université Montpellier, Etablissement Français du Sang, University of Antilles, 34093 Montpellier, France; (A.M.); (A.V.); (N.N.); (S.E.-D.); (P.V.d.P.)
| | - Nicolas Meda
- Centre Muraz, Bobo-Dioulasso 01 P.O. Box 390, Burkina Faso;
| | - Mandisa Singata-Madliki
- Effective Care Research Unit, Cecilia Makiwane Hospital, University of Fort Hare, East London 5207, South Africa;
| | - Grace Ndeezi
- Department of Paediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University, Kampala P.O. Box 317, Uganda; (G.N.); (J.K.T.)
| | - James Kashugyera Tumwine
- Department of Paediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University, Kampala P.O. Box 317, Uganda; (G.N.); (J.K.T.)
- School of Medicine, Kabale University, Kabale P.O. Box 317, Uganda
| | - Chipepo Kankasa
- Department of Paediatric and Child Health, University Teaching Hospital, University of Zambia School of Medicine, Lusaka P.O. Box 50110, Zambia;
| | - Ameena Goga
- HIV Prevention Research Unit, South African Medical Research Council, Private Bag x385, Pretoria 0001, South Africa;
| | - Thorkild Tylleskär
- Centre for International Health, Faculty of Medicine, University of Bergen, 5009 Bergen, Norway;
| | - Philippe Van de Perre
- Pathogenèse et Contrôle des Infections Chroniques, INSERM U1058, Université Montpellier, Etablissement Français du Sang, University of Antilles, 34093 Montpellier, France; (A.M.); (A.V.); (N.N.); (S.E.-D.); (P.V.d.P.)
| | - Jean-Pierre Molès
- Pathogenèse et Contrôle des Infections Chroniques, INSERM U1058, Université Montpellier, Etablissement Français du Sang, University of Antilles, 34093 Montpellier, France; (A.M.); (A.V.); (N.N.); (S.E.-D.); (P.V.d.P.)
| |
Collapse
|
|
4
|
Mitochondrial stress response in drug-induced liver injury. Mol Biol Rep 2021; 48:6949-6958. [PMID: 34432218 DOI: 10.1007/s11033-021-06674-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 08/19/2021] [Indexed: 12/11/2022]
Abstract
Drug-induced liver injury (DILI) caused by the ingestion of medications, herbs, chemicals or dietary supplements, is a clinically widespread health problem. The underlying mechanism of DILI is the formation of reactive metabolites, which trigger mitochondrial oxidative stress and the opening of mitochondrial permeability transition (MPT) pores through direct toxicity or immune response, leading to cell inflammation, apoptosis, and necrosis. Traditionally, mitochondria play an indispensable role in maintaining the physiological and biochemical functions of cells by producing ATP and mediating intracellular signal transduction; drugs can typically stimulate the mitochondria and, in the case of sustained stress, can eventually cause impairment of mitochondrial function and metabolic activity. Meanwhile, the mitochondrial stress response, as an adaptive protective mechanism, occurs when mitochondrial homeostasis is threatened. In this review, we summarize the relevant frontier researches of the protective effects of mitochondrial stress response in DILI as well as the potential related mechanisms, thus providing some thoughts for the clinical treatment of DILI.
Collapse
|
|
5
|
Cheney L, Barbaro JM, Berman JW. Antiretroviral Drugs Impact Autophagy with Toxic Outcomes. Cells 2021; 10:909. [PMID: 33920955 PMCID: PMC8071244 DOI: 10.3390/cells10040909] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/13/2021] [Accepted: 04/14/2021] [Indexed: 01/18/2023] Open
Abstract
Antiretroviral drugs have dramatically improved the morbidity and mortality of people living with HIV (PLWH). While current antiretroviral therapy (ART) regimens are generally well-tolerated, risks for side effects and toxicity remain as PLWH must take life-long medications. Antiretroviral drugs impact autophagy, an intracellular proteolytic process that eliminates debris and foreign material, provides nutrients for metabolism, and performs quality control to maintain cell homeostasis. Toxicity and adverse events associated with antiretrovirals may be due, in part, to their impacts on autophagy. A more complete understanding of the effects on autophagy is essential for developing antiretroviral drugs with decreased off target effects, meaning those unrelated to viral suppression, to minimize toxicity for PLWH. This review summarizes the findings and highlights the gaps in our knowledge of the impacts of antiretroviral drugs on autophagy.
Collapse
Affiliation(s)
- Laura Cheney
- Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
| | - John M. Barbaro
- Department of Pathology, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA; (J.M.B.); (J.W.B.)
| | - Joan W. Berman
- Department of Pathology, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA; (J.M.B.); (J.W.B.)
- Department of Microbiology and Immunology, Montefiore Medical Center and Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
| |
Collapse
|
|
6
|
Akita S, Suzuki K, Yoshimoto H, Ohtsuru A, Hirano A, Yamashita S. Cellular Mechanism Underlying Highly-Active or Antiretroviral Therapy-Induced Lipodystrophy: Atazanavir, a Protease Inhibitor, Compromises Adipogenic Conversion of Adipose-Derived Stem/Progenitor Cells through Accelerating ER Stress-Mediated Cell Death in Differentiating Adipocytes. Int J Mol Sci 2021; 22:ijms22042114. [PMID: 33672735 PMCID: PMC7924614 DOI: 10.3390/ijms22042114] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 12/27/2022] Open
Abstract
Lipodystrophy is a common complication in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART). Previous studies demonstrated that endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) is involved in lipodystrophy; however, the detailed mechanism has not been fully described in human adipogenic cell lineage. We utilized adipose tissue-derived stem cells (ADSCs) obtained from human subcutaneous adipose tissue, and atazanavir (ATV), a protease inhibitor (PI), was administered to ADSCs and ADSCs undergoing adipogenic conversion. Marked repression of adipogenic differentiation was observed when ATV was administered during 10 days of ADSC culture in adipogenic differentiation medium. Although ATV had no effect on ADSCs, it significantly induced apoptosis in differentiating adipocytes. ATV treatment also caused the punctate appearance of CCAAT-enhancer-binding (C/EBP) protein homologous protein (CHOP), and altered expression of CHOP and GRP78/Bip, which are the representation of ER stress, only in differentiating adipocytes. Administration of UPR inhibitors restored adipogenic differentiation, indicating that ER stress-mediated UPR was induced in differentiating adipocytes in the presence of ATV. We also observed autophagy, which was potentiated in differentiating adipocytes by ATV treatment. Thus, adipogenic cell atrophy leads to ATV-induced lipodystrophy, which is mediated by ER stress-mediated UPR and accelerated autophagy, both of which would cause adipogenic apoptosis. As our study demonstrated for the first time that ADSCs are unsusceptible to ATV and its deleterious effects are limited to the differentiating adipocytes, responsible target(s) for ATV-induced lipodystrophy may be protease(s) processing adipogenesis-specific protein(s).
Collapse
Affiliation(s)
- Sadanori Akita
- Department of Plastic Surgery, Wound Repair and Regeneration, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan;
- Department of Plastic and Reconstructive Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan; (A.H.); (H.Y.)
| | - Keiji Suzuki
- Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan;
- Correspondence: Correspondence: ; Tel.: +81-95-819-7116
| | - Hiroshi Yoshimoto
- Department of Plastic and Reconstructive Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan; (A.H.); (H.Y.)
| | - Akira Ohtsuru
- Takashi Nagai Memorial International Hibakusha Medical Center, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Nagasaki, Nagasaki852-8523, Japan;
| | - Akiyoshi Hirano
- Department of Plastic and Reconstructive Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan; (A.H.); (H.Y.)
| | - Shunichi Yamashita
- Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan;
- Takashi Nagai Memorial International Hibakusha Medical Center, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Nagasaki, Nagasaki852-8523, Japan;
- Fukushima Medical University School of Medicine, 1 Hikariga-oka, Fukushima 960-1295, Japan
- Center for Advanced Radiation Emergency Medicine at the National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
| |
Collapse
|
|
7
|
Schank M, Zhao J, Moorman JP, Yao ZQ. The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging. Cells 2021; 10:cells10010174. [PMID: 33467074 PMCID: PMC7830696 DOI: 10.3390/cells10010174] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 02/07/2023] Open
Abstract
According to the WHO, 38 million individuals were living with human immunodeficiency virus (HIV), 25.4 million of which were using antiretroviral therapy (ART) at the end of 2019. Despite ART-mediated suppression of viral replication, ART is not a cure and is associated with viral persistence, residual inflammation, and metabolic disturbances. Indeed, due to the presence of viral reservoirs, lifelong ART therapy is required to control viremia and prevent disease progression into acquired immune deficiency syndrome (AIDS). Successful ART treatment allows people living with HIV (PLHIV) to achieve a similar life expectancy to uninfected individuals. However, recent studies have illustrated the presence of increased comorbidities, such as accelerated, premature immune aging, in ART-controlled PLHIV compared to uninfected individuals. Studies suggest that both HIV-infection and ART-treatment lead to mitochondrial dysfunction, ultimately resulting in cellular exhaustion, senescence, and apoptosis. Since mitochondria are essential cellular organelles for energy homeostasis and cellular metabolism, their compromise leads to decreased oxidative phosphorylation (OXPHOS), ATP synthesis, gluconeogenesis, and beta-oxidation, abnormal cell homeostasis, increased oxidative stress, depolarization of the mitochondrial membrane potential, and upregulation of mitochondrial DNA mutations and cellular apoptosis. The progressive mitochondrial damage induced by HIV-infection and ART-treatment likely contributes to accelerated aging, senescence, and cellular dysfunction in PLHIV. This review discusses the connections between mitochondrial compromise and cellular dysfunction associated with HIV- and ART-induced toxicities, providing new insights into how HIV and current ART directly impact mitochondrial functions and contribute to cellular senescence and aging in PLHIV. Identifying this nexus and potential mechanisms may be beneficial in developing improved therapeutics for treating PLHIV.
Collapse
Affiliation(s)
- Madison Schank
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (M.S.); (J.Z.); (J.P.M.)
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Juan Zhao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (M.S.); (J.Z.); (J.P.M.)
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Jonathan P. Moorman
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (M.S.); (J.Z.); (J.P.M.)
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
- Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN 37614, USA
| | - Zhi Q. Yao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (M.S.); (J.Z.); (J.P.M.)
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
- Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN 37614, USA
- Correspondence: ; Tel.: +423-439-8063; Fax: +423-439-7010
| |
Collapse
|
|
8
|
Pisciotta A, Bertani G, Bertoni L, Di Tinco R, De Biasi S, Vallarola A, Pignatti E, Tupler R, Salvarani C, de Pol A, Carnevale G. Modulation of Cell Death and Promotion of Chondrogenic Differentiation by Fas/FasL in Human Dental Pulp Stem Cells (hDPSCs). Front Cell Dev Biol 2020; 8:279. [PMID: 32500073 PMCID: PMC7242757 DOI: 10.3389/fcell.2020.00279] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 03/31/2020] [Indexed: 01/01/2023] Open
Abstract
Human dental pulp stem cells (hDPSCs) are characterized by high proliferation rate, the multi-differentiation ability and, notably, low immunogenicity and immunomodulatory properties exerted through different mechanisms including Fas/FasL pathway. Despite their multipotency, hDPSCs require particular conditions to achieve chondrogenic differentiation. This might be due to the perivascular localization and the expression of angiogenic marker under standard culture conditions. FasL stimulation was able to promote the early induction of chondrogenic commitment and to lead the differentiation at later times. Interestingly, the expression of angiogenic marker was reduced by FasL stimulation without activating the extrinsic apoptotic pathway in standard culture conditions. In conclusion, these findings highlight the peculiar embryological origin of hDPSCs and provide further insights on their biological properties. Therefore, Fas/FasL pathway not only is involved in determining the immunomodulatory properties, but also is implicated in supporting the chondrogenic commitment of hDPSCs.
Collapse
Affiliation(s)
- Alessandra Pisciotta
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Bertani
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Laura Bertoni
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Rosanna Di Tinco
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Sara De Biasi
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonio Vallarola
- Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy
| | - Elisa Pignatti
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Rossella Tupler
- Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy
| | - Carlo Salvarani
- Rheumatology Unit, Azienda Unitá Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Anto de Pol
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Gianluca Carnevale
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| |
Collapse
|
|
9
|
Ganta KK, Chaubey B. Mitochondrial dysfunctions in HIV infection and antiviral drug treatment. Expert Opin Drug Metab Toxicol 2019; 15:1043-1052. [PMID: 31715109 DOI: 10.1080/17425255.2019.1692814] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Introduction: With the introduction of highly active anti-retroviral therapy (HAART), treatment of HIV infection has improved radically, shifting the concept of HIV disease from a highly mortal epidemic to a chronic illness which needs systematic management. However, HAART does not target the integrated proviral DNA. Hence, prolonged use of antiviral drugs is needed for sustaining life. As a consequence, severe side effects emerge. Several parameters involve in causing these adverse effects. Mitochondrial dysfunctions were pointed as common factor among them. It is, therefore, necessary to critically examine mitochondrial dysfunction in order to understand the side effects.Areas covered: There are many events involved in causing drug-induced side-effects; in this review, we only highlight mitochondrial dysfunctions as one of the events. We present up-to-date findings on mitochondrial dysfunction caused by HIV infection and antiviral drug treatment. Both in vivo and in vitro studies on mitochondrial dysfunction like change in morphology, membrane depolarization, mitophagy, mitochondrial DNA depletion, and intrinsic apoptosis have been discussed.Expert opinion: Mitochondrial dysfunction is associated with severe complications that often lead to discontinuation or change in treatment regimen. Prior knowledge of side effects of antiviral drugs would help in better management and future research should focus to avoid mitochondrial targeting of antiviral drugs while maintaining their antiviral properties.
Collapse
Affiliation(s)
- Krishna Kumar Ganta
- Functional Genomics Lab, Centre for Advanced Study, Department of Botany, University of Calcutta, Kolkata, India
| | - Binay Chaubey
- Functional Genomics Lab, Centre for Advanced Study, Department of Botany, University of Calcutta, Kolkata, India
| |
Collapse
|
|
10
|
Lake JE, Moser C, Johnston L, Magyar C, Nelson SD, Erlandson KM, Brown TT, McComsey GA. CT Fat Density Accurately Reflects Histologic Fat Quality in Adults With HIV On and Off Antiretroviral Therapy. J Clin Endocrinol Metab 2019; 104:4857-4864. [PMID: 31329901 PMCID: PMC6733493 DOI: 10.1210/jc.2018-02785] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 04/05/2019] [Indexed: 12/21/2022]
Abstract
CONTEXT Microscopic measurement of adipocyte size is the gold standard for determining adipose tissue (AT) quality. AT density on CT may also reflect adipocyte quality (lower density = poorer quality). OBJECTIVE We used abdominal subcutaneous AT (SAT) specimens and CT scans to validate CT SAT density as a marker of SAT quality in adults living with HIV. SETTING AND DESIGN Secondary data analysis from completed trial of antiretroviral therapy (ART) initiation (ACTG A5224s). CT abdominal SAT density was measured in HU. SAT specimens were digitally scanned for calculation of mean adipocyte area. PARTICIPANTS Participants had SAT biopsy and CT data at baseline (n = 54) and HIV-1 RNA <50 copies per milliliter on ART and biopsy or CT data at week 96 (n = 30). OUTCOME MEASURES Spearman correlations and linear regression models adjusting for participant characteristics examined associations between SAT density and adipocyte area. RESULTS Baseline median age was 40 years, CD4+ T lymphocyte count 219 cells per cubic millimeter, and body mass index 26.0 kg/m2; 89% were male and 67% white. Median SAT area and density were 199 cm2 and -100 HU. Over 96 weeks, SAT area increased (+18%) and SAT density decreased (-3%). Mean SAT adipocyte area correlated with SAT density (P < 0.01) off and on ART after adjustment for SAT area, age, race, sex, CD4+ T lymphocyte count, and HIV-1 RNA. CONCLUSIONS CT SAT density correlates with biopsy-quantified SAT adipocyte size in adults with HIV on and off ART, suggesting that CT is a useful tool for noninvasive assessment of SAT quality.
Collapse
Affiliation(s)
- Jordan E Lake
- University of California, Los Angeles, California
- University of Texas Health Science Center at Houston, Houston, Texas
| | | | | | - Clara Magyar
- University of California, Los Angeles, California
| | | | | | | | - Grace A McComsey
- University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio
| |
Collapse
|
|
11
|
Tripathi A, Thangaraj A, Chivero ET, Periyasamy P, Callen S, Burkovetskaya ME, Guo ML, Buch S. Antiretroviral-Mediated Microglial Activation Involves Dysregulated Autophagy and Lysosomal Dysfunction. Cells 2019; 8:cells8101168. [PMID: 31569373 PMCID: PMC6829395 DOI: 10.3390/cells8101168] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 09/23/2019] [Accepted: 09/25/2019] [Indexed: 01/07/2023] Open
Abstract
In the era of combined antiretroviral therapy (cART), as infected individuals continue to have longer lifespans, there is also an increased prevalence of HIV-associated neurocognitive disorders (HAND). Inflammation is one of the underlying features of HAND, with the role of viral proteins and antiretroviral drugs implicated in this process. Microglia are extremely sensitive to a plethora of stimuli, including viral products and cART. The current study was undertaken to understand the molecular mechanism(s) underlying cART-mediated activation of microglia. Herein we chose a combination of three commonly used drugs, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and dolutegravir (DTG). We demonstrated that exposure of microglia to this cART cocktail induced lysosomal membrane permeabilization (LMP), which subsequently resulted in impaired lysosomal functioning involving elevated pH and decreased cathepsin D (CTSD) activity. cART exposure of microglia resulted in increased formation of autophagosomes as demonstrated by a time-dependent increase of autophagy markers, with a concomitant defect in the fusion of the lysosomes with the autophagosome. Taken together, our findings suggest a novel mechanism by which cART impairs lysosomal functioning, resulting in dysregulated autophagy and increased neuroinflammation. Interventions aimed at lysosome protection could likely be envisioned as promising therapeutic targets for abrogating cART-mediated microglia activation, which in turn, could thus be considered as adjunctive therapeutics for the treatment of HAND pathogenesis.
Collapse
Affiliation(s)
- Ashutosh Tripathi
- Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Annadurai Thangaraj
- Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Ernest T Chivero
- Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Palsamy Periyasamy
- Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Shannon Callen
- Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Maria E Burkovetskaya
- Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Ming-Lei Guo
- Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Shilpa Buch
- Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| |
Collapse
|
|
12
|
Bresciani E, Saletti C, Squillace N, Rizzi L, Molteni L, Meanti R, Omeljaniuk RJ, Biagini G, Gori A, Locatelli V, Torsello A. miRNA-218 Targets Lipin-1 and Glucose Transporter Type 4 Genes in 3T3-L1 Cells Treated With Lopinavir/Ritonavir. Front Pharmacol 2019; 10:461. [PMID: 31133852 PMCID: PMC6524698 DOI: 10.3389/fphar.2019.00461] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 04/11/2019] [Indexed: 12/23/2022] Open
Abstract
Background: Metabolic complications represent a common and serious problem associated with HIV infection and combined Antiretroviral Therapy (cART). Alterations in body fat distribution are associated with significantly increased risks of (i) metabolic derangements, (ii) cardiovascular pathologies, and (iii) insulin resistance. A case control study showed that in subcutaneous adipose tissue from HIV-infected patients on cART presenting lipodystrophy (LS), the levels of miRNA-218 were upregulated and those of lipin-1, a putative target gene of miRNA-218, were downregulated compared with HIV-negative subjects. Lipin-1 is one of the most important factors linked to development of LS. Lipin-1, by controlling PPARγ2, regulates the expression of specific genes, such as that of glucose transporter type 4 (GLUT-4), required for maturation and maintenance of adipocytes. Objectives: To determine whether lopinavir/ritonavir (LPV/RTV) can modulate lipogenesis in adipocytes affecting miRNA-218 and lipin-1 mRNA expression, and to investigate the functional link between miRNA-218 and GLUT-4 mRNA expression. Methods: Differentiated 3T3-L1 cells were treated with various combinations of LPV/RTV, followed by measurements of cell viability, lipid accumulation, lipin-1 and GLUT-4 mRNA and miRNA-218 levels. Transfection of anti-miR-218 or a miRNA-218 mimic were used to investigate the role of miRNA-218 in lipogenesis. Results: LPV/RTV treatment of 3T3-L1 cells did not affect the viability of differentiated 3T3-L1 cells, but caused (i) a significant decrease of lipid accumulation, (ii) an overexpression of miRNA-218, and (iii) a reduction of lipin-1 and GLUT-4 mRNA levels. The anti-miR-218 transfection of 3T3-L1 cells significantly ameliorated the adipogenic dysfunction and restored mRNA levels of lipin-1 and GLUT-4 consequent to LPV/RTV treatment. By contrast, 3T3-L1 cells transfected with a specific miRNA-218 mimic showed (i) an overexpression of miRNA-218, (ii) a reduced cellular lipid fraction, and (iii) decreased levels of mRNA for lipin-1 and GLUT-4. Conclusion: 3T3-L1 cells, treated with LPV/RTV, show altered lipid content due to increased miRNA-218 levels, which affects lipin-1 mRNA. Moreover, increased miRNA-218 levels were inversely correlated with changes in GLUT-4 expression, which suggests a role for miRNA-218 in mediating the insulin resistance consequent to cART.
Collapse
Affiliation(s)
- Elena Bresciani
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Cecilia Saletti
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Nicola Squillace
- Division of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital, Monza, Italy
| | - Laura Rizzi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Laura Molteni
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Ramona Meanti
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | | | - Giuseppe Biagini
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Andrea Gori
- Infectious Diseases Unit, Department of Internal Medicine, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Vittorio Locatelli
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Antonio Torsello
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| |
Collapse
|
|
13
|
Laurence J, Elhadad S, Ahamed J. HIV-associated cardiovascular disease: importance of platelet activation and cardiac fibrosis in the setting of specific antiretroviral therapies. Open Heart 2018; 5:e000823. [PMID: 30018781 PMCID: PMC6045710 DOI: 10.1136/openhrt-2018-000823] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Revised: 05/02/2018] [Accepted: 05/15/2018] [Indexed: 12/18/2022] Open
Abstract
HIV infection is a risk factor for cardiovascular disease (CVD). This risk is accentuated by certain combination antiretroviral therapies (cARTs), independent of their effects on lipid metabolism and insulin sensitivity. We sought to define potential mechanisms for this association through systematic review of clinical and preclinical studies of CVD in the setting of HIV/cART from the English language literature from 1989 to March 2018. We used PubMed, Web of Knowledge and Google Scholar, and conference abstracts for the years 2015-March 2018. We uncovered three themes: (1) a critical role for the HIV protease inhibitor (PI) ritonavir and certain other PI-based regimens. (2) The importance of platelet activation. Virtually all PIs, and one nucleoside reverse transcriptase inhibitor, abacavir, activate platelets, but a role for this phenomenon in clinical CVD risk may require additional postactivation processes, including: release of platelet transforming growth factor-β1; induction of oxidative stress with production of reactive oxygen species from vascular cells; suppression of extracellular matrix autophagy; and/or sustained proinflammatory signalling, leading to cardiac fibrosis and dysfunction. Cardiac fibrosis may underlie an apparent shift in the character of HIV-linked CVD over the past decade from primarily left ventricular systolic to diastolic dysfunction, possibly driven by cART. (3) Recognition of the need for novel interventions. Switching from cART regimens based on PIs to contemporary antiretroviral agents such as the integrase strand transfer inhibitors, which have not been linked to clinical CVD, may not mitigate CVD risk assumed under prior cART. In conclusion, attention to the effects of specific antiretroviral drugs on platelet activation and related profibrotic signalling pathways should help: guide selection of appropriate anti-HIV therapy; assist in evaluation of CVD risk related to novel antiretrovirals; and direct appropriate interventions.
Collapse
Affiliation(s)
- Jeffrey Laurence
- Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York City, New York, USA
| | - Sonia Elhadad
- Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York City, New York, USA
| | - Jasimuddin Ahamed
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
| |
Collapse
|
|
14
|
Gibellini L, Losi L, De Biasi S, Nasi M, Lo Tartaro D, Pecorini S, Patergnani S, Pinton P, De Gaetano A, Carnevale G, Pisciotta A, Mariani F, Roncucci L, Iannone A, Cossarizza A, Pinti M. LonP1 Differently Modulates Mitochondrial Function and Bioenergetics of Primary Versus Metastatic Colon Cancer Cells. Front Oncol 2018; 8:254. [PMID: 30038898 PMCID: PMC6046640 DOI: 10.3389/fonc.2018.00254] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 06/21/2018] [Indexed: 12/11/2022] Open
Abstract
Mitochondrial Lon protease (LonP1) is a multi-function enzyme that regulates mitochondrial functions in several human malignancies, including colorectal cancer (CRC). The mechanism(s) by which LonP1 contributes to colorectal carcinogenesis is not fully understood. We found that silencing LonP1 leads to severe mitochondrial impairment and apoptosis in colon cancer cells. Here, we investigate the role of LonP1 in mitochondrial functions, metabolism, and epithelial-mesenchymal transition (EMT) in colon tumor cells and in metastasis. LonP1 was almost absent in normal mucosa, gradually increased from aberrant crypt foci to adenoma, and was most abundant in CRC. Moreover, LonP1 was preferentially upregulated in colorectal samples with mutated p53 or nuclear β-catenin, and its overexpression led to increased levels of β-catenin and decreased levels of E-cadherin, key proteins in EMT, in vitro. LonP1 upregulation also induced opposite changes in oxidative phosphorylation, glycolysis, and pentose pathway in SW480 primary colon tumor cells when compared to SW620 metastatic colon cancer cells. In conclusion, basal LonP1 expression is essential for normal mitochondrial function, and increased LonP1 levels in SW480 and SW620 cells induce a metabolic shift toward glycolysis, leading to EMT.
Collapse
Affiliation(s)
- Lara Gibellini
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Lorena Losi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Sara De Biasi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Milena Nasi
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Domenico Lo Tartaro
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Simone Pecorini
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Simone Patergnani
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara, Italy
| | - Paolo Pinton
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara, Italy
| | - Anna De Gaetano
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Gianluca Carnevale
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandra Pisciotta
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Francesco Mariani
- Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Luca Roncucci
- Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Anna Iannone
- Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Marcello Pinti
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| |
Collapse
|
|
15
|
Nicu C, Pople J, Bonsell L, Bhogal R, Ansell DM, Paus R. A guide to studying human dermal adipocytes in situ. Exp Dermatol 2018; 27:589-602. [DOI: 10.1111/exd.13549] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Carina Nicu
- Centre for Dermatology Research; The University of Manchester; Manchester UK
- NIHR Manchester Biomedical Research Centre; Manchester Academic Health Science Centre; Manchester UK
| | | | - Laura Bonsell
- Centre for Dermatology Research; The University of Manchester; Manchester UK
- NIHR Manchester Biomedical Research Centre; Manchester Academic Health Science Centre; Manchester UK
| | | | - David M. Ansell
- Centre for Dermatology Research; The University of Manchester; Manchester UK
- NIHR Manchester Biomedical Research Centre; Manchester Academic Health Science Centre; Manchester UK
| | - Ralf Paus
- Centre for Dermatology Research; The University of Manchester; Manchester UK
- NIHR Manchester Biomedical Research Centre; Manchester Academic Health Science Centre; Manchester UK
- Department of Dermatology and Cutaneous Surgery; Miller School of Medicine; University of Miami; Miami FL USA
| |
Collapse
|
|
16
|
HIV protease inhibitor-induced cardiac dysfunction and fibrosis is mediated by platelet-derived TGF-β1 and can be suppressed by exogenous carbon monoxide. PLoS One 2017; 12:e0187185. [PMID: 29088262 PMCID: PMC5663426 DOI: 10.1371/journal.pone.0187185] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 10/16/2017] [Indexed: 12/24/2022] Open
Abstract
Human immunodeficiency virus (HIV) infection is an independent risk factor for cardiovascular disease. This risk is magnified by certain antiretrovirals, particularly the protease inhibitor ritonavir, but the pathophysiology of this connection is unknown. We postulated that a major mechanism for antiretroviral-associated cardiac disease is pathologic fibrosis linked to platelet activation with release and activation of transforming growth factor (TGF)-β1, and that these changes could be modeled in a murine system. We also sought to intervene utilizing inhaled carbon monoxide (CO) as proof-of-concept for therapeutics capable of regulating TGF-β1 signaling and collagen autophagy. We demonstrate decreased cardiac function indices, including cardiac output, ejection fraction and stroke volume, and prominent cardiac fibrosis, in mice exposed to pharmacological doses of ritonavir. Cardiac output and fibrosis correlated with plasma TGF-β1 levels. Mice with targeted deletion of TGF-β1 in megakaryocytes/platelets (PF4CreTgfb1flox/flox) were partially protected from ritonavir-induced cardiac dysfunction and fibrosis. Inhalation of low dose CO (250ppm), used as a surrogate for upregulation of inducible heme oxygenase/endogenous CO pathways, suppressed ritonavir-induced cardiac fibrosis. This occurred in association with modulation of canonical (Smad2) and non-canonical (p38) TGF-β1 signaling pathways. In addition, CO treatment suppressed the M1 pro-inflammatory subset of macrophages and increased M2c regulatory cells in the hearts of RTV-exposed animals. The effects of CO were dependent upon autophagy as CO did not mitigate ritonavir-induced fibrosis in autophagy-deficient LC3-/- mice. These results suggest that platelet-derived TGF-β1 contributes to ritonavir-associated cardiac dysfunction and fibrosis, extending the relevance of our findings to other antiretrovirals that also activate platelets. The anti-fibrotic effects of CO are linked to alterations in TGF-β1 signaling and autophagy, suggesting a proof-of-concept for novel interventions in HIV/antiretroviral therapy-mediated cardiovascular disease.
Collapse
|
|
17
|
Kobayashi N, Nakahara M, Oka M, Saeki K. Additional attention to combination antiretroviral therapy-related lipodystrophy. World J Virol 2017; 6:49-52. [PMID: 28868242 PMCID: PMC5561498 DOI: 10.5501/wjv.v6.i3.49] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 07/21/2017] [Accepted: 08/03/2017] [Indexed: 02/06/2023] Open
Abstract
The occurrence of lipodystrophy in patients taking anti-human immunodeficiency virus (HIV) medications is a serious problem as it is irreversible even after drug withdrawal. Although it was first recognized in patients taking proteinase inhibitors, other types of anti-HIV agents can also cause lipodystrophy. In a recent publication by Jones et al entitled "Highly active antiretroviral therapy dysregulates proliferation and differentiation of human pre-adipocytes" in World Journal of Virology, it was reported that simultaneous treatment of human subcutaneous adipocytes with anti-HIV drugs with different mechanisms of action synergistically exerted anti-adipogenesis effects in vitro, warning us to take utmost care in every case receiving combination antiretroviral therapy (cART). For elucidation of the molecular basis for cART-related lipodystrophy, multi-faceted approaches should be taken, based on a deeper understanding of the development and organization of adipose tissues.
Collapse
|
|
18
|
Non LR, Escota GV, Powderly WG. HIV and its relationship to insulin resistance and lipid abnormalities. Transl Res 2017; 183:41-56. [PMID: 28068521 DOI: 10.1016/j.trsl.2016.12.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 11/18/2016] [Accepted: 12/15/2016] [Indexed: 12/19/2022]
Abstract
Antiretroviral therapy has revolutionized the care of people with human immunodeficiency virus (HIV) by reducing morbidity and mortality from acquired immunodeficiency syndrome-related conditions. Despite longer life expectancy, however, HIV-infected individuals continue to have a higher risk of death compared with the general population. This has been attributed to the increasing incidence of noncommunicable diseases, in particular, atherosclerotic cardiovascular diseases. This is driven, in part, by the emergence of metabolic disorders, particularly dyslipidemia, insulin resistance, and lipodystrophy, in those on antiretroviral therapy. The pathogenesis of these metabolic derangements is complex and multifactorial, and could be a consequence of an interplay between traditional age-related risk factors, HIV infection, antiretroviral therapy effects, and the inflammatory state and immune activation in this population. Understanding the contributions of each of these factors could not just impact the current management of these individuals and help mitigate the risk for premature cardiovascular disease, but also shape the future direction of research in HIV.
Collapse
Affiliation(s)
- Lemuel R Non
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Mo.
| | - Gerome V Escota
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Mo
| | - William G Powderly
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Mo
| |
Collapse
|
|
19
|
Carnevale G, Pisciotta A, Riccio M, Bertoni L, De Biasi S, Gibellini L, Zordani A, Cavallini GM, La Sala GB, Bruzzesi G, Ferrari A, Cossarizza A, de Pol A. Human dental pulp stem cells expressing STRO-1, c-kit and CD34 markers in peripheral nerve regeneration. J Tissue Eng Regen Med 2017; 12:e774-e785. [PMID: 27943583 DOI: 10.1002/term.2378] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 10/10/2016] [Accepted: 12/06/2016] [Indexed: 12/16/2022]
Abstract
Peripheral nerve injuries are a commonly encountered clinical problem and often result in long-term functional defects. The application of stem cells able to differentiate in Schwann cell-like cells in vitro and in vivo, could represent an attractive therapeutic approach for the treatment of nerve injuries. Further, stem cells sources sharing the same embryological origin as Schwann cells might be considered a suitable tool. The aim of this study was to demonstrate the ability of a neuroectodermal subpopulation of human STRO-1+ /c-Kit+ /CD34+ DPSCs, expressing P75NTR , nestin and SOX-10, to differentiate into Schwann cell-like cells in vitro and to promote axonal regeneration in vivo, which led to functional recovery as measured by sustained gait improvement, in animal rat model of peripheral nerve injury. Transplanted human dental pulp stem cells (hDPSCs) engrafted into sciatic nerve defect, as revealed by the positive staining against human nuclei, showed the expression of typical Schwann cells markers, S100b and, noteworthy, a significant number of myelinated axons was detected. Moreover, hDPSCs promoted axonal regeneration from proximal to distal stumps 1 month after transplantation. This study demonstrates that STRO-1+ /c-Kit+ /CD34+ hDPSCs, associated with neural crest derivation, represent a promising source of stem cells for the treatment of demyelinating disorders and might provide a valid alternative tool for future clinical applications to achieve functional recovery after injury or peripheral neuropathies besides minimizing ethical issues. Copyright © 2016 John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Gianluca Carnevale
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandra Pisciotta
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Riccio
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Laura Bertoni
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Sara De Biasi
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Lara Gibellini
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessio Zordani
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Gian Maria Cavallini
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | | | - Giacomo Bruzzesi
- Oro-Maxillo-Facial Department, AUSL Baggiovara, Baggiovara, Modena, Italy
| | - Adriano Ferrari
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.,Children Rehabilitation Special Unit, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
| | - Andrea Cossarizza
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Anto de Pol
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| |
Collapse
|
|
20
|
Erlandson KM, Lake JE. Fat Matters: Understanding the Role of Adipose Tissue in Health in HIV Infection. Curr HIV/AIDS Rep 2016; 13:20-30. [PMID: 26830284 DOI: 10.1007/s11904-016-0298-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
More than one-third of adults in the USA are obese and obesity-related disease accounts for some of the leading causes of preventable death. Mid-life obesity may be a strong predictor of physical function impairment later in life regardless of body mass index (BMI) in older age, highlighting the benefits of obesity prevention on health throughout the lifespan. Adipose tissue disturbances including lipodystrophy and obesity are prevalent in the setting of treated and untreated HIV infection. This article will review current knowledge on fat disturbances in HIV-infected persons, including therapeutic options and future directions.
Collapse
Affiliation(s)
- Kristine M Erlandson
- University of Colorado-Anschutz Medical Center, 12700 E 19th Ave, Mailstop B168, Aurora, CO, USA.
| | - Jordan E Lake
- University of California, Los Angeles, 11075 Santa Monica Blvd., Ste. 100, Los Angeles, CA, USA.
| |
Collapse
|
|
21
|
Casarini L, Reiter E, Simoni M. β-arrestins regulate gonadotropin receptor-mediated cell proliferation and apoptosis by controlling different FSHR or LHCGR intracellular signaling in the hGL5 cell line. Mol Cell Endocrinol 2016; 437:11-21. [PMID: 27502035 DOI: 10.1016/j.mce.2016.08.005] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 07/08/2016] [Accepted: 08/03/2016] [Indexed: 01/01/2023]
Abstract
Gonadotropin signaling classically involves proliferative, steroidogenic and apoptotic stimuli. In this study, we used the human granulosa cell line hGL5 to demonstrate how follicle-stimulating hormone (FSH) and luteinizing hormone (LH) differently control proliferative or apoptotic signals, revealing novel intrinsic properties of their receptors (FSHR, LHCGR). We found that, in this tumor-like cell line, the expression of endogenous FSHR and LHCGR is serum-dependent, but both receptors were unable to activate the canonical cAMP/PKA pathway upon gonadotropin stimulation, failing to produce cAMP, progesterone and G protein-coupled receptor (GPCR)-mediated apoptosis in vitro. Conversely, ligand treatment resulted in FSHR- and LHCGR-mediated ERK1/2 phosphorylation and cell proliferation due to receptor coupling to β-arrestins. The inactive cAMP/PKA pathway was unlocked by siRNA-mediated knock-down of β-arrestin 1 and 2, leading to progesterone synthesis and apoptosis. Surprisingly, FSH, but not LH treatment accelerated the cAMP/PKA-mediated apoptosis after β-arrestin silencing, an effect which could be reproduced by overexpressing the FSHR, but not the LHCGR. This work demonstrates that the expression of FSHR and LHCGR can be induced in hGL5 cells but that the FSHR-dependent cAMP/PKA pathway is constitutively silenced, possibly to protect cells from FSHR-cAMP-PKA-induced apoptosis. Also, we revealed previously unrecognized features intrinsic to the two structurally similar gonadotropin receptors, oppositely resulting in the regulation of life and death signals in vitro.
Collapse
Affiliation(s)
- Livio Casarini
- Unit of Endocrinology, Dept. of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy.
| | - Eric Reiter
- PRC, INRA, CNRS, IFCE, Université de Tours, 37380, Nouzilly, France
| | - Manuela Simoni
- Unit of Endocrinology, Dept. of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy; Azienda USL, NOCSAE, Modena, Italy
| |
Collapse
|
|
22
|
Role of Autophagy in HIV Pathogenesis and Drug Abuse. Mol Neurobiol 2016; 54:5855-5867. [PMID: 27660273 DOI: 10.1007/s12035-016-0118-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 09/12/2016] [Indexed: 12/27/2022]
Abstract
Autophagy is a highly regulated process in which excessive cytoplasmic materials are captured and degraded during deprivation conditions. The unique nature of autophagy that clears invasive microorganisms has made it an important cellular defense mechanism in a variety of clinical situations. In recent years, it has become increasingly clear that autophagy is extensively involved in the pathology of HIV-1. To ensure survival of the virus, HIV-1 viral proteins modulate and utilize the autophagy pathway so that biosynthesis of the virus is maximized. At the same time, the abuse of illicit drugs such as methamphetamine, cocaine, morphine, and alcohol is thought to be a significant risk factor for the acquirement and progression of HIV-1. During drug-induced toxicity, autophagic activity has been proved to be altered in various cell types. Here, we review the current literature on the interaction between autophagy, HIV-1, and drug abuse and discuss the complex role of autophagy during HIV-1 pathogenesis in co-exposure to illicit drugs.
Collapse
|
|
23
|
De Biasi S, Gibellini L, Bianchini E, Nasi M, Pinti M, Salvioli S, Cossarizza A. Quantification of mitochondrial reactive oxygen species in living cells by using multi-laser polychromatic flow cytometry. Cytometry A 2016; 89:1106-1110. [DOI: 10.1002/cyto.a.22936] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 07/26/2016] [Accepted: 08/14/2016] [Indexed: 12/26/2022]
Affiliation(s)
- Sara De Biasi
- Department of Surgery; Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia; Modena Italy
| | - Lara Gibellini
- Department of Surgery; Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia; Modena Italy
| | - Elena Bianchini
- Department of Life Sciences; University of Modena and Reggio Emilia; Modena Italy
| | - Milena Nasi
- Department of Surgery; Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia; Modena Italy
| | - Marcello Pinti
- Department of Life Sciences; University of Modena and Reggio Emilia; Modena Italy
| | - Stefano Salvioli
- Department of Experimental; Diagnostic and Specialty Medicine, University of Bologna; Italy
| | - Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children and Adults; University of Modena and Reggio Emilia; Modena Italy
| |
Collapse
|
|
24
|
Marsit CJ, Brummel SS, Kacanek D, Seage GR, Spector SA, Armstrong DA, Lester BM, Rich K. Infant peripheral blood repetitive element hypomethylation associated with antiretroviral therapy in utero. Epigenetics 2016; 10:708-16. [PMID: 26067216 DOI: 10.1080/15592294.2015.1060389] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
The use of combination antiretroviral therapy (cART) to prevent HIV mother-to-child transmission during pregnancy and delivery is generally considered safe. However, vigilant assessment of potential risks of these agents remains warranted. Epigenetic changes including DNA methylation are considered potential mechanisms linking the in utero environment with long-term health outcomes. Few studies have examined the epigenetic effects of prenatal exposure to pharmaceutical agents, including antiretroviral therapies, on children. In this study, we examined the methylation status of the LINE-1 and ALU-Yb8 repetitive elements as markers of global DNA methylation alteration in peripheral blood mononuclear cells obtained from newborns participating in the Pediatric HIV/AIDS Cohort Study SMARTT cohort of HIV-exposed, cART-exposed uninfected infants compared to a historical cohort of HIV-exposed, antiretroviral-unexposed infants from the Women and Infants Transmission Study Cohort. In linear regression models controlling for potential confounders, we found the adjusted mean difference of AluYb8 methylation of the cART-exposed compared to the -unexposed was -0.568 (95% CI: -1.023, -0.149) and for LINE-1 methylation was -1.359 (95% CI: -1.860, -0.857). Among those exposed to cART, subjects treated with atazanavir (ATV), compared to those on other treatments, had less AluYb8 methylation (-0.524, 95% CI: -0.025, -1.024). Overall, these results suggest a small but statistically significant reduction in the methylation of these repetitive elements in an HIV-exposed, cART-exposed cohort compared to an HIV-exposed, cART-unexposed historic cohort. The potential long-term implications of these differences are worthy of further examination.
Collapse
Affiliation(s)
- Carmen J Marsit
- a Departments of Pharmacology and Toxicology and of Epidemiology; Geisel School of Medicine at Dartmouth ; Hanover , NH USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Ahamed J, Terry H, Choi ME, Laurence J. Transforming growth factor-β1-mediated cardiac fibrosis: potential role in HIV and HIV/antiretroviral therapy-linked cardiovascular disease. AIDS 2016; 30:535-42. [PMID: 26605511 PMCID: PMC4738098 DOI: 10.1097/qad.0000000000000982] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
HIV infection elevates the incidence of cardiovascular disease (CVD) independent of traditional risk factors. Autopsy series document cardiac inflammation and endomyocardial fibrosis in the HIV+ treatment naïve, and gadolinium enhancement magnetic resonance imaging has identified prominent myocardial fibrosis in the majority of HIV+ individuals despite use of suppressive antiretroviral therapies (ART). The extent of such disease may correlate with specific ART regimens. For example, HIV-infected patients receiving ritonavir (RTV)-boosted protease inhibitors have the highest prevalence of CVD, and RTV-exposed rodents exhibit cardiac dysfunction coupled with cardiac and vascular fibrosis, independent of RTV-mediated lipid alterations. We recently showed that platelet transforming growth factor (TGF)-β1 is a key contributor to cardiac fibrosis in murine models. We hypothesize that in the HIV+/ART naïve, cardiac fibrosis is a consequence of proinflammatory cytokine and/or ART-linked platelet activation with release of TGF-β1. Resultant TGF-β1/Smad signaling would promote collagen synthesis and organ fibrosis. We document these changes in a pilot immunohistochemical evaluation of cardiac tissue from two ART-naive pediatric AIDS patients. In terms of ART, we showed that RTV inhibits immunoproteasome degradation of TRAF6, a nuclear adapter signaling molecule critical to the regulation of proinflammatory cytokine signaling pathways involved in osteoclast differentiation and accelerated osteoporosis. We now present a model illustrating how RTV could similarly amplify TGF-β1 signaling in the promotion of cardiac fibrosis and accelerated CVD. Supportive clinical data correlate RTV use with elevation of NT-proBNP, a biomarker for CVD. We discuss potential interventions involving intrinsic modulators of inflammation and collagen degradation, including carbon monoxide-based therapeutics.
Collapse
Affiliation(s)
- Jasimuddin Ahamed
- aDivision of Hematology and Medical OncologybDivision of Nephrology and Hypertension, Weill Cornell Medical College, New YorkcCardiovascular Biology Research Program, Oklahoma Medical Research Foundation and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | | | | | | |
Collapse
|
|
26
|
Carnevale G, Pisciotta A, Riccio M, De Biasi S, Gibellini L, Ferrari A, La Sala GB, Bruzzesi G, Cossarizza A, de Pol A. Optimized Cryopreservation and Banking of Human Bone-Marrow Fragments and Stem Cells. Biopreserv Biobank 2016; 14:138-48. [PMID: 26828565 DOI: 10.1089/bio.2015.0001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Adult mesenchymal stem cells are a promising source for cell therapies and tissue engineering applications. Current procedures for banking of human bone-marrow mesenchymal stem cells (hBM-MSCs) require cell isolation and expansion, and thus the use of large amounts of animal sera. However, animal-derived culture supplements have the potential to trigger infections and severe immune reactions. The aim of this study was to investigate an optimized method for cryopreservation of human bone-marrow fragments for application in cell banking procedures where stem-cell expansion and use are not immediately needed. Whole trabecular fragments enclosing the bone marrow were stored in liquid nitrogen for 1 year in a cryoprotective solution containing a low concentration of dimethyl sulfoxide and a high concentration of human serum (HuS). After thawing, the isolation, colony-forming-unit ability, proliferation, morphology, stemness-related marker expression, cell senescence, apoptosis, and multi-lineage differentiation potential of hBM-MSCs were tested in media containing HuS compared with hBM-MSCs isolated from fresh fragments. Human BM-MSCs isolated from cryopreserved fragments expressed MSC markers until later passages, had a good proliferation rate, and exhibited the capacity to differentiate toward osteogenic, adipogenic, and myogenic lineages similar to hBM-MSCs isolated from fresh fragments. Moreover, the cryopreservation method did not induce cell senescence or cell death. These results imply that minimal processing may be adequate for the banking of tissue samples with no requirement for the immediate isolation and use of hBM-MSCs, thus limiting cost and the risk of contamination, and facilitating banking for clinical use. Furthermore, the use of HuS for cryopreservation and expansion/differentiation has the potential for clinical application in compliance with good manufacturing practice standards.
Collapse
Affiliation(s)
- Gianluca Carnevale
- 1 Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia , Modena, Italy .,2 Dipartimento Sperimentale Interaziendale, University of Modena and Reggio Emilia , Modena, Italy
| | - Alessandra Pisciotta
- 1 Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia , Modena, Italy
| | - Massimo Riccio
- 1 Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia , Modena, Italy
| | - Sara De Biasi
- 1 Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia , Modena, Italy
| | - Lara Gibellini
- 1 Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia , Modena, Italy
| | - Adriano Ferrari
- 2 Dipartimento Sperimentale Interaziendale, University of Modena and Reggio Emilia , Modena, Italy .,3 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia , Modena, Italy
| | - Giovanni B La Sala
- 2 Dipartimento Sperimentale Interaziendale, University of Modena and Reggio Emilia , Modena, Italy .,4 Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia , Modena, Italy
| | - Giacomo Bruzzesi
- 5 Oro-Maxillo-Facial Department, AUSL Baggiovara , Modena, Italy
| | - Andrea Cossarizza
- 1 Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia , Modena, Italy .,2 Dipartimento Sperimentale Interaziendale, University of Modena and Reggio Emilia , Modena, Italy
| | - Anto de Pol
- 1 Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia , Modena, Italy .,2 Dipartimento Sperimentale Interaziendale, University of Modena and Reggio Emilia , Modena, Italy
| |
Collapse
|
|
27
|
Fernández-Galilea M, Tapia P, Cautivo K, Morselli E, Cortés VA. AGPAT2 deficiency impairs adipogenic differentiation in primary cultured preadipocytes in a non-autophagy or apoptosis dependent mechanism. Biochem Biophys Res Commun 2015; 467:39-45. [DOI: 10.1016/j.bbrc.2015.09.128] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 09/23/2015] [Indexed: 11/26/2022]
|
|
28
|
Different origin of adipogenic stem cells influences the response to antiretroviral drugs. Exp Cell Res 2015; 337:160-9. [PMID: 26238601 DOI: 10.1016/j.yexcr.2015.07.031] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 07/28/2015] [Accepted: 07/30/2015] [Indexed: 12/31/2022]
Abstract
Lipodystrophy (LD) is a main side effect of antiretroviral therapy for HIV infection, and can be provoked by nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs). LD exists in different forms, characterized by fat loss, accumulation, or both, but its pathogenesis is still unclear. In particular, few data exist concerning the effects of antiretroviral drugs on adipocyte differentiation. Adipose tissue can arise either from mesenchymal stem cells (MSCs), that include bone marrow-derived MSCs (hBM-MSCs), or from ectodermal stem cells, that include dental pulp stem cells (hDPSCs). To analyze whether the embryonal origin of adipocytes might impact the occurrence of different phenotypes in LD, we quantified the effects of several antiretroviral drugs on the adipogenic differentiation of hBM-MSCs and hDPSCs. hBM-MSCs and hDPSCs were isolated from healthy donors. Cells were treated with 10 and 50 μM stavudine (d4T), efavirenz (EFV), atazanavir (ATV), ritonavir (RTV), and ATV-boosted RTV. Viability and adipogenesis were evaluated by staining with propidium iodide, oil red, and adipoRed; mRNA levels of genes involved in adipocyte differentiation, i.e. CCAAT/enhancer-binding protein alpha (CEBPα) and peroxisome proliferator-activated receptor gamma (PPARγ), and in adipocyte functions, i.e. fatty acid synthase (FASN), fatty acid binding protein-4 (FABP4), perilipin-1 (PLIN1) and 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2), were quantified by real time PCR. We found that ATV, RTV, EFV, and ATV-boosted RTV, but not d4T, caused massive cell death in both cell types. EFV and d4T affected the accumulation of lipid droplets and induced changes in mRNA levels of genes involved in adipocyte functions in hBM-MSCs, while RTV and ATV had little effects. All drugs stimulated the accumulation of lipid droplets in hDPSCs. Thus, the adipogenic differentiation of human stem cells can be influenced by antiretroviral drugs, and depends, at least in part, on their embryonal origin.
Collapse
|
|
29
|
De Biasi S, Gibellini L, Cossarizza A. Uncompensated Polychromatic Analysis of Mitochondrial Membrane Potential Using JC‐1 and Multilaser Excitation. ACTA ACUST UNITED AC 2015; 72:7.32.1-7.32.11. [DOI: 10.1002/0471142956.cy0732s72] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Sara De Biasi
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia Modena Italy
| | - Lara Gibellini
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia Modena Italy
| | - Andrea Cossarizza
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia Modena Italy
| |
Collapse
|
|
30
|
Human dental pulp stem cells (hDPSCs): isolation, enrichment and comparative differentiation of two sub-populations. BMC DEVELOPMENTAL BIOLOGY 2015; 15:14. [PMID: 25879198 PMCID: PMC4377026 DOI: 10.1186/s12861-015-0065-x] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 02/27/2015] [Indexed: 02/07/2023]
Abstract
Background Human dental pulp represents a suitable alternative source of stem cells for the purpose of cell-based therapies in regenerative medicine, because it is relatively easy to obtain it, using low invasive procedures. This study characterized and compared two subpopulations of adult stem cells derived from human dental pulp (hDPSCs). Human DPSCs, formerly immune-selected for STRO-1 and c-Kit, were separated for negativity and positivity to CD34 expression respectively, and evaluated for cell proliferation, stemness maintenance, cell senescence and multipotency. Results The STRO-1+/c-Kit+/CD34+ hDPSCs showed a slower proliferation, gradual loss of stemness, early cell senescence and apoptosis, compared to STRO-1+/c-Kit+/CD34− hDPSCs. Both the subpopulations demonstrated similar abilities to differentiate towards mesoderm lineages, whereas a significant difference was observed after the neurogenic induction, with a greater commitment of STRO-1+/c-Kit+/CD34+ hDPSCs. Moreover, undifferentiated STRO-1+/c-Kit+/CD34− hDPSCs did not show any expression of CD271 and nestin, typical neural markers, while STRO-1+/c-Kit+/CD34+ hDPSCs expressed both. Conclusions These results suggest that STRO-1+/c-Kit+/CD34− hDPSCs and STRO-1+/c-Kit+/CD34+ hDPSCs might represent two distinct stem cell populations, with different properties. These results trigger further analyses to deeply investigate the hypothesis that more than a single stem cell population resides within the dental pulp, to better define the flexibility of application of hDPSCs in regenerative medicine.
Collapse
|
|
31
|
The Fas/Fas ligand apoptosis pathway underlies immunomodulatory properties of human biliary tree stem/progenitor cells. J Hepatol 2014; 61:1097-105. [PMID: 24953023 DOI: 10.1016/j.jhep.2014.06.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 05/14/2014] [Accepted: 06/11/2014] [Indexed: 12/28/2022]
Abstract
BACKGROUND & AIMS Human biliary tree stem/progenitor cells (hBTSCs) are multipotent epithelial stem cells, easily obtained from the biliary tree, with the potential for regenerative medicine in liver, biliary tree, and pancreas diseases. Recent reports indicate that human mesenchymal stem cells are able to modulate the T cell immune response. However, no information exists on the capabilities of hBTSCs to control the allogeneic response. The aims of this study were to evaluate FasL expression in hBTSCs, to study the in vitro interaction between hBTSCs and human lymphocytes, and the role of Fas/FasL modulation in inducing T cell apoptosis in hBTSCs/T cell co-cultures. METHODS Fas and FasL expression were evaluated in situ and in vitro by immunofluorescence and western blotting. Co-cultures of hBTSCs with human leukocytes were used to analyze the influence of hBTSCs on lymphocytes activation and apoptosis. RESULTS hBTSCs expressed HLA antigens and FasL in situ and in vitro. Western blot data demonstrated that hBTSCs constitutively expressed high levels of FasL that increased after co-culture with T cells. Confocal microscopy demonstrated that FasL expression was restricted to EpCAM(+)/LGR5(+) cells. FACS analysis of T cells co-cultured with hBTSCs indicated that hBTSCs were able to induce apoptosis in activated CD4(+) and CD8(+) T cell populations. Moreover, the Fas receptor appears to be more expressed in T cells co-cultured with hBTSCs than in resting T cells. CONCLUSIONS Our data suggest that hBTSCs could modulate the T cell response through the production of FasL, which influences the lymphocyte Fas/FasL pathway by inducing "premature" apoptosis in CD4(+) and CD8(+) T cells.
Collapse
|
|
32
|
O’Connor JE, Herrera G, Martínez-Romero A, de Oyanguren FS, Díaz L, Gomes A, Balaguer S, Callaghan RC. Systems Biology and immune aging. Immunol Lett 2014; 162:334-45. [DOI: 10.1016/j.imlet.2014.09.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Accepted: 09/12/2014] [Indexed: 10/24/2022]
|
|
33
|
O'Connor JE, Herrera G, Martínez-Romero A, Oyanguren FSD, Díaz L, Gomes A, Balaguer S, Callaghan RC. WITHDRAWN: Systems Biology and Immune Aging. Immunol Lett 2014:S0165-2478(14)00197-7. [PMID: 25251659 DOI: 10.1016/j.imlet.2014.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 09/12/2014] [Indexed: 10/24/2022]
Abstract
The Publisher regrets that this article is an accidental duplication of anarticle that has already been published, http://dx.doi.org/10.1016/j.imlet.2014.09.009. The duplicate article has therefore been withdrawn.
Collapse
Affiliation(s)
- José-Enrique O'Connor
- Laboratory of Translational Cytomics, Joint Research Unit, The University of Valencia and Principe Felipe Research Center, Valencia, Spain; Cytometry Laboratory, Incliva Foundation, Clinical University Hospital, The University of Valencia, Valencia, Spain.
| | - Guadalupe Herrera
- Laboratory of Translational Cytomics, Joint Research Unit, The University of Valencia and Principe Felipe Research Center, Valencia, Spain; Cytometry Laboratory, Incliva Foundation, Clinical University Hospital, The University of Valencia, Valencia, Spain
| | - Alicia Martínez-Romero
- Cytometry Technological Service, Principe Felipe Research Center, Valencia, Spain; Cytometry Laboratory, Incliva Foundation, Clinical University Hospital, The University of Valencia, Valencia, Spain
| | - Francisco Sala-de Oyanguren
- Laboratory of Translational Cytomics, Joint Research Unit, The University of Valencia and Principe Felipe Research Center, Valencia, Spain; Cytometry Laboratory, Incliva Foundation, Clinical University Hospital, The University of Valencia, Valencia, Spain
| | - Laura Díaz
- Laboratory of Translational Cytomics, Joint Research Unit, The University of Valencia and Principe Felipe Research Center, Valencia, Spain; Cytometry Laboratory, Incliva Foundation, Clinical University Hospital, The University of Valencia, Valencia, Spain
| | - Angela Gomes
- Laboratory of Translational Cytomics, Joint Research Unit, The University of Valencia and Principe Felipe Research Center, Valencia, Spain; Cytometry Laboratory, Incliva Foundation, Clinical University Hospital, The University of Valencia, Valencia, Spain
| | - Susana Balaguer
- Laboratory of Translational Cytomics, Joint Research Unit, The University of Valencia and Principe Felipe Research Center, Valencia, Spain; Cytometry Laboratory, Incliva Foundation, Clinical University Hospital, The University of Valencia, Valencia, Spain
| | - Robert C Callaghan
- Department of Pathology, Faculty of Medicine, The University of Valencia, Valencia, Spain; Cytometry Laboratory, Incliva Foundation, Clinical University Hospital, The University of Valencia, Valencia, Spain
| |
Collapse
|
|
34
|
Squillace N, Bresciani E, Torsello A, Bandera A, Sabbatini F, Giovannetti C, Giunta G, Rovati L, Del Bene M, Locatelli V, Gori A. Changes in subcutaneous adipose tissue microRNA expression in HIV-infected patients. J Antimicrob Chemother 2014; 69:3067-75. [PMID: 25063777 DOI: 10.1093/jac/dku264] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES We evaluated the possibility that a pattern of abnormal microRNA (miRNA) expression could be fuelling the mechanisms causing HIV-associated lipodystrophy (HAL). METHODS In this case-control study, samples of subcutaneous adipose tissue from eight consecutive HIV-infected patients on combination antiretroviral therapy with HAL (cases) were compared with those of eight HIV-negative subjects (controls). Human miRNA microarrays were used to probe the transcriptomes of the samples. Analysis of differentially expressed miRNAs was performed using DataAssist v2.0 software, applying a paired Student's t-test. RESULTS Data showed that 21 miRNAs out of 754 were overexpressed in the patient group. Ten of these (i.e. miR-186, miR-199a-3p, miR-214, miR-374a, miR-487b, miR-532-5p, miR-628-5p, miR-874, miR-125-b-1* and miR-374b*) were up-regulated to a significant degree (fold change >2.5; P < 0.01). Eleven other miRNAs (i.e. miR-let-7d, miR-24, miR-30c, miR-125a-3p, miR-149, miR-191, miR-196-b, miR-218, miR-342-3p, miR-452 and miR-454*) were 2- to 2.5-fold more expressed in HIV+ samples than in controls. Levels of mRNA for lipin 1, the target of miR-218, were significantly lower in subcutaneous adipose tissue from HIV patients. CONCLUSIONS In adipocytes of HIV-infected patients, the up-regulation of specific miRNAs could lead to an increased 'activation' that might contribute to the pathogenesis of HAL by increasing cell turnover and/or promotion of apoptosis.
Collapse
Affiliation(s)
- Nicola Squillace
- Division of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital, Monza, Italy
| | - Elena Bresciani
- Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy
| | - Antonio Torsello
- Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy
| | - Alessandra Bandera
- Division of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital, Monza, Italy
| | - Francesca Sabbatini
- Division of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital, Monza, Italy
| | - Chiara Giovannetti
- Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy
| | | | - Luca Rovati
- Plastic Surgery Unit, San Gerardo Hospital, Monza, Italy
| | | | - Vittorio Locatelli
- Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy
| | - Andrea Gori
- Division of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital, Monza, Italy Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy
| |
Collapse
|
|
35
|
Abstract
The treatment of metabolic disease is becoming an increasingly important component of the long-term management of patients with well controlled HIV on antiretroviral therapy (ART). Metabolic diseases probably develop at the intersection of traditional risk factors (such as obesity, tobacco use, and genetic predisposition) and HIV-specific and ART-specific contributors (including chronic inflammation and immune activation). This Review discusses present knowledge on adipose tissue dysfunction, insulin-glucose homoeostasis, lipid disturbances, and cardiovascular disease risk in people with HIV on ART. Although new antiretroviral drugs are believed to induce fewer short-term metabolic perturbations than do older drugs, the long-term effects of these drugs are not fully understood. Additionally, patients remain at increased risk of cardiovascular disease and other metabolic comorbidities. Research and treatment should focus on selection of ART that is both virologically effective and has minimum metabolic effects, minimisation of traditional risk factors for metabolic disease, and development of novel therapies to treat metabolic disease in patients with HIV, including use of anti-inflammatory and immunomodulatory drugs.
Collapse
Affiliation(s)
- Jordan E Lake
- David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | | |
Collapse
|
|
36
|
Nolis T. Exploring the pathophysiology behind the more common genetic and acquired lipodystrophies. J Hum Genet 2013; 59:16-23. [PMID: 24152769 DOI: 10.1038/jhg.2013.107] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 08/31/2013] [Accepted: 09/10/2013] [Indexed: 01/16/2023]
Abstract
Lipodystrophies are an immense group of genetic or acquired metabolic disorders that are characterized by varying degrees of body fat loss and in some instances localized accumulation of subcutaneous fat. Lipodystrophies are often tightly linked with profound metabolic complications; this strong bond emphasizes and reinforces the significance of adipose tissue as a dynamic endocrine organ. The extent of fat loss determines the severity of associated metabolic complications such as diabetes mellitus, hypertriglyceridemia and hepatic steatosis. The lipodystrophies can be divided into generalized, partial or local, depending on the degree and locality of the observable fat loss; moreover, the generalized and partial divisions can be partitioned further into inherited or acquired forms. The major genetic factors in the generalized forms of the lipodystrophies, particularly Congenital generalized lipodystrophy (CGL)-Berardinelli-Seip syndrome, are the AGPAT2, BSCL2, caveolin 1 (CAV1) and polymerase-I-and-transcriptrelease factor (PTRF) genes. In the acquired forms, genes such as LMNA, PPARG, CIDEC (cell-death-inducing DNA fragmentation factor a-like effector c) and PLIN1 are heavily involved in familial partial lipodystrophy (FPLD) type 2 (also known as the Dunnigan-Variety) and WRN along with RECQL5 in Werner Syndrome (WS). Autoimmune causes are particularly noted in acquired partial lipodystrophy (APL)-Barraquer-Simons syndrome and in AGL-Lawrence syndrome; panniculitis has been shown to have a substantial role in the former as well as in other forms of localized lipodystrophies. Patients with human immunodeficiency virus (HIV) exposed to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) (for example, zidovudine and stavudine) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) (for example, efavirenz) while undergoing Highly Active Antiretroviral Therapy (HAART) have led to the current most-prevalent form of the lipodystrophies: lipodystrophy in HIV-infected patients (LD-HIV) and HAART-associated lipodystrophy syndrome (HALS).
Collapse
Affiliation(s)
- Tom Nolis
- Graduate Entry Medical School, Richmond Hill, Ontario, Canada
| |
Collapse
|
|
37
|
Tovilovic G, Ristic B, Milenkovic M, Stanojevic M, Trajkovic V. The Role and Therapeutic Potential of Autophagy Modulation in Controlling Virus-Induced Cell Death. Med Res Rev 2013; 34:744-67. [DOI: 10.1002/med.21303] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Gordana Tovilovic
- Institute for Biological Research; University of Belgrade; Despot Stefan Boulevard 142 11000 Belgrade Serbia
| | - Biljana Ristic
- Institute of Microbiology and Immunology; School of Medicine; University of Belgrade; Dr. Subotica 1 11000 Belgrade Serbia
| | - Marina Milenkovic
- Institute of Microbiology and Immunology; School of Medicine; University of Belgrade; Dr. Subotica 1 11000 Belgrade Serbia
| | - Maja Stanojevic
- Institute of Microbiology and Immunology; School of Medicine; University of Belgrade; Dr. Subotica 1 11000 Belgrade Serbia
| | - Vladimir Trajkovic
- Institute of Microbiology and Immunology; School of Medicine; University of Belgrade; Dr. Subotica 1 11000 Belgrade Serbia
| |
Collapse
|
|
38
|
Carnevale G, Riccio M, Pisciotta A, Beretti F, Maraldi T, Zavatti M, Cavallini GM, La Sala GB, Ferrari A, De Pol A. In vitro differentiation into insulin-producing β-cells of stem cells isolated from human amniotic fluid and dental pulp. Dig Liver Dis 2013; 45:669-76. [PMID: 23643565 DOI: 10.1016/j.dld.2013.02.007] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Revised: 01/21/2013] [Accepted: 02/06/2013] [Indexed: 12/11/2022]
Abstract
AIM To investigate the ability of human amniotic fluid stem cells and human dental pulp stem cells to differentiate into insulin-producing cells. METHODS Human amniotic fluid stem cells and human dental pulp stem cells were induced to differentiate into pancreatic β-cells by a multistep protocol. Islet-like structures were assessed in differentiated human amniotic fluid stem cells and human dental pulp stem cells after 21 days of culture by dithizone staining. Pancreatic and duodenal homebox-1, insulin and Glut-2 expression were detected by immunofluorescence and confocal microscopy. Insulin secreted from differentiated cells was tested with SELDI-TOF MS and by enzyme-linked immunosorbent assay. RESULTS Human amniotic fluid stem cells and human dental pulp stem cells, after 7 days of differentiation started to form islet-like structures that became evident after 14 days of induction. SELDI-TOF MS analysis, revealed the presence of insulin in the media of differentiated cells at day 14, further confirmed by enzyme-linked immunosorbent assay after 7, 14 and 21 days. Both stem cell types expressed, after differentiation, pancreatic and duodenal homebox-1, insulin and Glut-2 and were positively stained by dithizone. Either the cytosol to nucleus translocation of pancreatic and duodenal homebox-1, either the expression of insulin, are regulated by glucose concentration changes. Day 21 islet-like structures derived from both human amniotic fluid stem cells and human dental pulp stem cell release insulin in a glucose-dependent manner. CONCLUSION The present study demonstrates the ability of human amniotic fluid stem cells and human dental pulp stem cell to differentiate into insulin-producing cells, offering a non-pancreatic, low-invasive source of cells for islet regeneration.
Collapse
Affiliation(s)
- Gianluca Carnevale
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Zha BS, Wan X, Zhang X, Zha W, Zhou J, Wabitsch M, Wang G, Lyall V, Hylemon PB, Zhou H. HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes. PLoS One 2013; 8:e59514. [PMID: 23533630 PMCID: PMC3606318 DOI: 10.1371/journal.pone.0059514] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Accepted: 02/15/2013] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND HIV protease inhibitors (PI) are core components of Highly Active Antiretroviral Therapy (HAART), the most effective treatment for HIV infection currently available. However, HIV PIs have now been linked to lipodystrophy and dyslipidemia, which are major risk factors for cardiovascular disease and metabolic syndrome. Our previous studies have shown that HIV PIs activate endoplasmic reticulum (ER) stress and disrupt lipid metabolism in hepatocytes and macrophages. Yet, little is known on how HIV PIs disrupt lipid metabolism in adipocytes, a major cell type involved in the pathogenesis of metabolic syndrome. METHODOLOGY AND PRINCIPAL FINDINGS Cultured and primary mouse adipocytes and human adipocytes were used to examine the effect of frequently used HIV PIs in the clinic, lopinavir/ritonavir, on adipocyte differentiation and further identify the underlying molecular mechanism of HIV PI-induced dysregulation of lipid metabolism in adipocytes. The results indicated that lopinavir alone or in combination with ritonavir, significantly activated the ER stress response, inhibited cell differentiation, and induced cell apoptosis in adipocytes. In addition, HIV PI-induced ER stress was closely linked to inhibition of autophagy activity. We also identified through the use of primary adipocytes of CHOP(-/-) mice that CHOP, the major transcriptional factor of the ER stress signaling pathway, is involved in lopinavir/ritonavir-induced inhibition of cell differentiation in adipocytes. In addition, lopinavir/ritonavir-induced ER stress appears to be associated with inhibition of autophagy activity in adipocytes. CONCLUSION AND SIGNIFICANCE Activation of ER stress and impairment of autophagy activity are involved in HIV PI-induced dysregulation of lipid metabolism in adipocytes. The key components of ER stress and autophagy signaling pathways are potential therapeutic targets for HIV PI-induced metabolic side effects in HIV patients.
Collapse
Affiliation(s)
- Beth S. Zha
- Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Xiaoshan Wan
- School of Pharmacy, Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China
| | - Xiaoxuan Zhang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
| | - Weibin Zha
- Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
| | - Jun Zhou
- School of Pharmacy, Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, University of Ulm, Ulm, Germany
| | - Guangji Wang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
| | - Vijay Lyall
- Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Phillip B. Hylemon
- Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America
- McGuire Veterans Affairs Medical Center, Richmond, Virginia, United States of America
| | - Huiping Zhou
- Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America
- School of Pharmacy, Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China
- McGuire Veterans Affairs Medical Center, Richmond, Virginia, United States of America
| |
Collapse
|