|
1
|
Zhou E, Bhoora S, Pillay TS, Punchoo R. Induction of Cell Death and Regulation of Autocrine Vitamin D Metabolism in Cervical Cancer by Physiological and GI20 Doses of 25-Hydroxycholecalciferol. Int J Mol Sci 2025; 26:4008. [PMID: 40362248 PMCID: PMC12071354 DOI: 10.3390/ijms26094008] [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: 03/06/2025] [Revised: 04/12/2025] [Accepted: 04/14/2025] [Indexed: 05/15/2025] Open
Abstract
Vitamin D and its metabolites exert anti-cancer properties in various cancers; however, their effects on cervical cancer remain largely unexplored. To investigate this gap, we exposed HeLa adenocarcinoma cervical cells to physiological and the growth inhibition 20% (GI20) concentration of 25-hydroxycholecalciferol, the precursor hormone of active 1,25-dihydroxycholecalciferol. We then assessed its impact on cell health, and the expression of the genes and proteins involved in the activation and catabolism of vitamin D at the cellular level by autocrine vitamin D metabolism via the vitamin D metabolizing system (VDMS). Cell health was evaluated by crystal violet and alamarBlue assays, while cell cycle progression and apoptotic cell death markers were assessed by flow cytometry. Gross morphology and ultrastructure were observed using brightfield microscopy and transmission electron microscopy. Gene and protein analyses of the autocrine VDMS were assessed using reverse transcription polymerase chain reaction and Western blot, respectively. Our findings reveal that 25(OH)D3 inhibits cell growth and induces apoptosis in HeLa cervical cells in a dose-dependent manner through the autocrine upregulation of CYP27B1 and VDR. These autocrine effects most likely promote the bioactivation of 25(OH)D3 and intracellular signaling of pro-apoptotic genomic pathways by liganded VDR. Furthermore, the upregulation of CYP24A1 at GI20 treatment likely increases the catabolism of 25(OH)D3 and 1,25(OH)2D3, and therefore may mitigate the anti-cancer action of the high-treatment dose. In summary, 25(OH)D3 holds immense potential as a complementary therapeutic treatment for cervical cancer.
Collapse
Affiliation(s)
- Esther Zhou
- Department of Chemical Pathology, University of Pretoria, Pretoria 0084, South Africa; (E.Z.); (T.S.P.)
| | - Sachin Bhoora
- Division of Chemical Pathology, Department of Pathology, University of Cape Town, Cape Town 7935, South Africa;
| | - Tahir S. Pillay
- Department of Chemical Pathology, University of Pretoria, Pretoria 0084, South Africa; (E.Z.); (T.S.P.)
- Division of Chemical Pathology, Department of Pathology, University of Cape Town, Cape Town 7935, South Africa;
- National Health Laboratory Service (NHLS), Tshwane Academic Division, Pretoria 0084, South Africa
| | - Rivak Punchoo
- Department of Chemical Pathology, University of Pretoria, Pretoria 0084, South Africa; (E.Z.); (T.S.P.)
- Division of Chemical Pathology, Department of Pathology, University of Cape Town, Cape Town 7935, South Africa;
| |
Collapse
|
|
2
|
Stevens CM, Weeks K, Jain SK. Potential of Vitamin D and l-Cysteine Co-supplementation to Downregulate Mammalian Target of Rapamycin: A Novel Therapeutic Approach to Diabetes. Metab Syndr Relat Disord 2025; 23:13-22. [PMID: 39279596 PMCID: PMC12021770 DOI: 10.1089/met.2024.0146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/18/2024] Open
Abstract
Diabetes, a metabolic disease associated with an increased health care burden and mortality, is currently on the rise. Both upregulation of the mammalian target of rapamycin (mTOR) and decreased levels of vitamin D (VD) and l-cysteine (LC) have been associated with diabetes. The overactivation of mTOR leads to insulin desensitization and metabolic dysfunction including uncontrolled hyperglycemia. This review summarizes various studies that have shown an inhibitory effect of VD or LC on mTOR activity. Findings from preclinical studies suggest that optimizing the VD and LC status in patients with diabetes can result in mTOR suppression, which has the potential to protect these individuals from microvascular and macrovascular complications while enhancing the regulation of their blood glucose. Given this information, finding ways to suppress mTOR signaling and also increasing VD and LC status is a possible therapeutic approach that might aid patients with diabetes. Future clinical trials are needed to investigate whether VD and LC co-supplementation can successfully downregulate mTOR and can be used as adjuvant therapy in patients with diabetes.
Collapse
Affiliation(s)
- Christopher M. Stevens
- Departments of Pediatrics and Medicine, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
| | - Kathrine Weeks
- Department of Chemistry, Centenary College of Louisiana, Shreveport, Louisiana, USA
| | - Sushil K. Jain
- Departments of Pediatrics and Medicine, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
| |
Collapse
|
|
3
|
Wakle KS, Mokale SN, Sakle NS. Emerging perspectives: unraveling the anticancer potential of vitamin D 3. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:2877-2933. [PMID: 37994947 DOI: 10.1007/s00210-023-02819-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 10/26/2023] [Indexed: 11/24/2023]
Abstract
Vitamin D3, a fat-soluble vitamin known for its critical function in calcium homeostasis and bone health, is gaining interest for its anticancer properties. Observational studies have suggested a negative relationship between vitamin D levels and the incidence of some malignancies throughout the years, prompting substantial investigation to find its anticancer effects. The purpose of this comprehensive review is to investigate the diverse function of vitamin D3 in cancer prevention and therapy. We explored the molecular mechanism underlying its effects on cancer cells, which range from cell cycle control and death to angiogenesis and immune response modulation. Insights from in vitro and in vivo studies provide valuable evidence supporting its anticancer potential. Furthermore, we look at epidemiological and clinical studies that investigate the relationship between vitamin D3 levels and cancer risk or treatment results. Vitamin D3 supplementation's safety profile and cost-effectiveness increase its attractiveness as an adjuvant therapy in conjunction with traditional treatment regimens. Our critical review of the current literature provides an in-depth understanding of vitamin D3's anticancer effect, covering the obstacles and possibilities in realizing its promise for cancer prevention and therapy. The findings of this study might pave the way for the development of innovative treatment techniques that take use of the advantages of vitamin D3 to fight cancer and improve patient care. As research progresses, a better understanding of vitamin D3's anticancer processes will surely simplify its incorporation into personalized cancer care techniques, hence enhancing patient outcomes in the battle against cancer.
Collapse
Affiliation(s)
- Komal S Wakle
- Y. B. Chavan College of Pharmacy, Aurangabad, Maharashtra, 431001, India
| | - Santosh N Mokale
- Y. B. Chavan College of Pharmacy, Aurangabad, Maharashtra, 431001, India
| | - Nikhil S Sakle
- Y. B. Chavan College of Pharmacy, Aurangabad, Maharashtra, 431001, India.
| |
Collapse
|
|
4
|
Sobhi P, Bahrami M, Mahdizadeh F, Fazaeli A, Babaei G, Rezagholizadeh L. Vitamin D and potential effects on cancers: a review. Mol Biol Rep 2024; 51:190. [PMID: 38270702 DOI: 10.1007/s11033-023-09111-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 12/05/2023] [Indexed: 01/26/2024]
Abstract
Cancer is characterized by the abnormal and uncontrollable division and growth of cells that can infiltrate tissues and alter normal physiological function, which will become crucial and life-threatening if left untreated. Cancer can be a result of genetics, such as mutations or environmental causes, including smoking, lack of physical activity, as well as nutritional imbalance in the body. Vitamin D is one of the foremost nutrients that play a crucial role in a variety of biochemical pathways, and it is an important key factor in several diseases. Vitamin D is an essential nutrient for preventing malignancies and a complementary treatment for cancer through direct and indirect biochemical pathways. In this article, we summarized the correlation between vitamin D and various cancers using an extensive search on PubMed, Google Scholar, and Scopus. This paper reviews the role of vitamin D in different types of cancer.
Collapse
Affiliation(s)
- Pouria Sobhi
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mohammad Bahrami
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Faraz Mahdizadeh
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Aliakbar Fazaeli
- Department of Biochemistry, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Ghader Babaei
- Department of Clinical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Lotfollah Rezagholizadeh
- Department of Biochemistry, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.
| |
Collapse
|
|
5
|
Popli P, Tang S, Chadchan SB, Talwar C, Rucker EB, Guan X, Monsivais D, Lydon JP, Stallings CL, Moley KH, Kommagani R. Beclin-1-dependent autophagy, but not apoptosis, is critical for stem-cell-mediated endometrial programming and the establishment of pregnancy. Dev Cell 2023; 58:885-897.e4. [PMID: 37040770 PMCID: PMC10289806 DOI: 10.1016/j.devcel.2023.03.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 01/31/2023] [Accepted: 03/16/2023] [Indexed: 04/13/2023]
Abstract
The human endometrium shows a remarkable regenerative capacity that enables cyclical regeneration and remodeling throughout a woman's reproductive life. Although early postnatal uterine developmental cues direct this regeneration, the vital factors that govern early endometrial programming are largely unknown. We report that Beclin-1, an essential autophagy-associated protein, plays an integral role in uterine morphogenesis during the early postnatal period. We show that conditional depletion of Beclin-1 in the uterus triggers apoptosis and causes progressive loss of Lgr5+/Aldh1a1+ endometrial progenitor stem cells, with concomitant loss of Wnt signaling, which is crucial for stem cell renewal and epithelial gland development. Beclin-1 knockin (Becn1 KI) mice with disabled apoptosis exhibit normal uterine development. Importantly, the restoration of Beclin-1-driven autophagy, but not apoptosis, promotes normal uterine adenogenesis and morphogenesis. Together, the data suggest that Beclin-1-mediated autophagy acts as a molecular switch that governs the early uterine morphogenetic program by maintaining the endometrial progenitor stem cells.
Collapse
Affiliation(s)
- Pooja Popli
- Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Suni Tang
- Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Sangappa B Chadchan
- Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Chandni Talwar
- Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Edmund B Rucker
- Department of Biology, University of Kentucky, Lexington, KY 40506, USA
| | - Xiaoming Guan
- Department of Obstetrics and Gynecology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Diana Monsivais
- Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - John P Lydon
- Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Christina L Stallings
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Kelle H Moley
- Department Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Reproductive Health Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ramakrishna Kommagani
- Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
| |
Collapse
|
|
6
|
Lesko P, Vlkova B, Kalavska K, De Angelis V, Novotna V, Obertova J, Orszaghova Z, Palacka P, Rejlekova K, Sycova-Mila Z, Kollarik B, Aziri R, Pindak D, Mardiak J, Chovanec M, Celec P, Mego M. Prognostic role of plasma vitamin D and its association with disease characteristics in germ cell tumours. Front Oncol 2023; 13:1149432. [PMID: 37114140 PMCID: PMC10126247 DOI: 10.3389/fonc.2023.1149432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 03/23/2023] [Indexed: 04/29/2023] Open
Abstract
Background Testicular cancer is the most common malignancy among young men. Vitamin D has pluripotent effects on cancer pathogenesis and plays a role in the metastatic cascade. The aim of this study is to analyze plasma vitamin D in association with clinico-pathological findings and prognosis in patients with germ-cell tumors (GCTs). Methods This study included 120 newly diagnosed and/or relapsed GCT patients treated from April 2013 to July 2020, for whom plasma was available in the biobank. Blood samples were drawn the 1st chemotherapy cycle as well as before the 2nd cycle. Plasma vitamin D was measured using ELISA and correlated with disease characteristics and the outcome. For survival analysis, the cohort was dichotomized into "low" and "high" based on median vitamin D. Results There was no significant difference in vitamin D plasma levels between healthy donors and GCT patients (p = 0.71). Vitamin D level was not associated with disease characteristics except for brain metastases, where patients with brain metastases had a vitamin D level that was 32% lower compared to patients without brain metastases, p = 0.03. Vitamin D was also associated with response to chemotherapy, with an approximately 32% lower value in patients with an unfavorable response compared to a favorable response, p = 0.02. Moreover, low plasma levels of vitamin D were significantly associated with disease recurrence and inferior progression-free survival (PFS), but not with overall survival (OS) (HR = 3.02, 95% CI 1.36-6.71, p = 0.01 for PFS and HR = 2.06, 95% CI 0.84-5.06, p = 0.14 for OS, respectively). Conclusion Our study suggests the prognostic value of pretreatment vitamin D concentrations in GCT patients. Low plasma vitamin D was associated with an unfavorable response to therapy and disease recurrence. However, it remains to be determined whether the biology of the disease confirms a causative role for low vitamin D and whether its supplementation affects the outcome.
Collapse
Affiliation(s)
- Peter Lesko
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
- *Correspondence: Peter Lesko,
| | - Barbora Vlkova
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Katarina Kalavska
- Translation Research Unit, Comenius University, National Cancer Institute, Bratislava, Slovakia
| | - Valentina De Angelis
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Vera Novotna
- 1st Department of Oncology, Faculty of Medicine Comenius University (FMCU) and St. Elizabeth Cancer Institute, Bratislava, Slovakia
| | - Jana Obertova
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Zuzana Orszaghova
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Patrik Palacka
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Katarina Rejlekova
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Zuzana Sycova-Mila
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Boris Kollarik
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Ramadan Aziri
- Department of Surgical Oncology, National Institute for Oncology, Bratislava, Slovakia
| | - Daniel Pindak
- Department of Surgical Oncology, National Institute for Oncology, Bratislava, Slovakia
| | - Jozef Mardiak
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Michal Chovanec
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Peter Celec
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Michal Mego
- Translation Research Unit, Comenius University, National Cancer Institute, Bratislava, Slovakia
| |
Collapse
|
|
7
|
Wang H, Wu T, Huang Z, Huang J, Geng Z, Cui B, Yan Y, Zhang Y, Wang Y. Channel HCN4 mutation R666Q associated with sporadic arrhythmia decreases channel electrophysiological function and increases protein degradation. J Biol Chem 2022; 298:102599. [PMID: 36244448 PMCID: PMC9663530 DOI: 10.1016/j.jbc.2022.102599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 10/06/2022] [Accepted: 10/10/2022] [Indexed: 11/07/2022] Open
Abstract
Mutations in the hyperpolarization-activated nucleotide-gated channel 4 (HCN4) are known to be associated with arrhythmias in which QT prolongation (delayed ventricular repolarization) is rare. Here, we identified a HCN4 mutation, HCN4-R666Q, in two sporadic arrhythmia patients with sinus bradycardia, QT prolongation, and short bursts of ventricular tachycardia. To determine the functional effect of the mutation, we conducted clinical, genetic, and functional analyses using whole-cell voltage-clamp, qPCR, Western blot, confocal microscopy, and co-immunoprecipitation. The mean current density of HEK293T cells transfected with HCN4-R666Q was lower in 24 to 36 h after transfection and was much lower in 36 to 48 h after transfection relative to cells transfected with wildtype HCN4. Additionally, we determined that the HCN4-R666Q mutant was more susceptible to ubiquitin-proteasome system–mediated protein degradation than wildtype HCN4. This decreased current density for HCN4-R666Q could be partly rescued by treatment with a proteasome inhibitor. Therefore, we conclude that HCN4-R666Q had an effect on HCN4 function in two aspects, including decreasing the current density of the channel as a biophysical effect and weakening its protein stability. Our findings provide new insights into the pathogenesis of the HCN4-R666Q mutation.
Collapse
|
|
8
|
Muñoz A, Grant WB. Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms. Nutrients 2022; 14:1448. [PMID: 35406059 PMCID: PMC9003337 DOI: 10.3390/nu14071448] [Citation(s) in RCA: 140] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/28/2022] [Accepted: 03/28/2022] [Indexed: 02/07/2023] Open
Abstract
This is a narrative review of the evidence supporting vitamin D's anticancer actions. The first section reviews the findings from ecological studies of cancer with respect to indices of solar radiation, which found a reduced risk of incidence and mortality for approximately 23 types of cancer. Meta-analyses of observational studies reported the inverse correlations of serum 25-hydroxyvitamin D [25(OH)D] with the incidence of 12 types of cancer. Case-control studies with a 25(OH)D concentration measured near the time of cancer diagnosis are stronger than nested case-control and cohort studies as long follow-up times reduce the correlations due to changes in 25(OH)D with time. There is no evidence that undiagnosed cancer reduces 25(OH)D concentrations unless the cancer is at a very advanced stage. Meta-analyses of cancer incidence with respect to dietary intake have had limited success due to the low amount of vitamin D in most diets. An analysis of 25(OH)D-cancer incidence rates suggests that achieving 80 ng/mL vs. 10 ng/mL would reduce cancer incidence rates by 70 ± 10%. Clinical trials have provided limited support for the UVB-vitamin D-cancer hypothesis due to poor design and execution. In recent decades, many experimental studies in cultured cells and animal models have described a wide range of anticancer effects of vitamin D compounds. This paper will review studies showing the inhibition of tumor cell proliferation, dedifferentiation, and invasion together with the sensitization to proapoptotic agents. Moreover, 1,25-(OH)2D3 and other vitamin D receptor agonists modulate the biology of several types of stromal cells such as fibroblasts, endothelial and immune cells in a way that interferes the apparition of metastases. In sum, the available mechanistic data support the global protective action of vitamin D against several important types of cancer.
Collapse
Affiliation(s)
- Alberto Muñoz
- Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, CIBERONC and IdiPAZ, 28029 Madrid, Spain;
| | - William B. Grant
- Sunlight, Nutrition and Health Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA
| |
Collapse
|
|
9
|
Jhun J, Woo JS, Kwon JY, Na HS, Cho KH, Kim SA, Kim SJ, Moon SJ, Park SH, Cho ML. Vitamin D Attenuates Pain and Cartilage Destruction in OA Animals via Enhancing Autophagic Flux and Attenuating Inflammatory Cell Death. Immune Netw 2022; 22:e34. [PMID: 36081528 PMCID: PMC9433191 DOI: 10.4110/in.2022.22.e34] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 03/28/2022] [Accepted: 04/10/2022] [Indexed: 01/15/2023] Open
Affiliation(s)
- JooYeon Jhun
- Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Korea
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jin Seok Woo
- Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Korea
| | - Ji Ye Kwon
- Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Korea
| | - Hyun Sik Na
- Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Korea
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Keun-Hyung Cho
- Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Korea
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Seon Ae Kim
- Department of Orthopedic Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Seok Jung Kim
- Department of Orthopedic Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Su-Jin Moon
- Division of Rheumatology, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 11765, Korea
| | - Sung-Hwan Park
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Mi-La Cho
- Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Korea
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| |
Collapse
|
|
10
|
Valle MS, Russo C, Malaguarnera L. Protective role of vitamin D against oxidative stress in diabetic retinopathy. Diabetes Metab Res Rev 2021; 37:e3447. [PMID: 33760363 DOI: 10.1002/dmrr.3447] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 02/01/2021] [Accepted: 02/15/2021] [Indexed: 02/06/2023]
Abstract
Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus. There is much evidence showing that a high level of mitochondrial overproduction of reactive oxygen species in the diabetic retina contributes in modifying cellular signalling and leads to retinal cell damage and finally to the development of DR pathogenesis. In the last few decades, it has been reported that vitamin D is involved in DR pathogenesis. Vitamin D, traditionally known as an essential nutrient crucial in bone metabolism, has also been proven to be a very effective antioxidant. It has been demonstrated that it modulates the production of advanced glycosylated end products, as well as several pathways including protein kinase C, the polyol pathway leading to the reduction of free radical formation. It prevents the translocation of nuclear factor kappa B, preventing the inflammatory response, acting as an immunomodulator, and modulates autophagy and apoptosis. In this review, we explore the molecular mechanisms by which vitamin D protects the eye from oxidative stress, in order to evaluate whether vitamin D supplementation may be useful to mitigate the deleterious effects of free radicals in DR.
Collapse
Affiliation(s)
- Maria Stella Valle
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Cristina Russo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Lucia Malaguarnera
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| |
Collapse
|
|
11
|
Mongy NNE, Hilal RF. How far is vitamin D implicated in cutaneous infections. Clin Dermatol 2021; 40:198-205. [PMID: 34893391 DOI: 10.1016/j.clindermatol.2021.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Vitamin D is an important cornerstone in the immunologic cascade of many skin infections, systemic infections with cutaneous presentations, and other infectious dermatologic diseases where infections could be a culprit. Vitamin D supplementation is proposed as a protective measure against their occurrence and exacerbation, especially with the emergence of several viral pandemics in recent years. Vitamin D plays a key role in the maintenance of a balanced immunologic profile which could be reflected by a lowered incidence and morbidity of infections. Vitamin D screening and supplementation in patients with deficiencies or insufficiencies should be a part of the dermatologic approach to patients with these diseases.
Collapse
Affiliation(s)
- Naglaa Nabil El Mongy
- Professor of Dermatology, Kasr Al Ainy Teaching Hospital, Cairo University, Cairo, Egypt
| | - Rana Fathy Hilal
- Associate Professor of Dermatology, Kasr Al Ainy Teaching Hospital, Cairo University, Cairo, Egypt.
| |
Collapse
|
|
12
|
The effects of dietary vitamin D supplementation and in vitro 1,25 dihydroxyvitamin D 3 treatment on autophagy in bone marrow-derived dendritic cells from high-fat diet-induced obese mice. J Nutr Biochem 2021; 100:108880. [PMID: 34655755 DOI: 10.1016/j.jnutbio.2021.108880] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 06/18/2021] [Accepted: 09/22/2021] [Indexed: 12/11/2022]
Abstract
Obesity is associated with the dysregulation of vitamin D metabolism and altered immune responses in bone marrow-derived dendritic cells (BMDCs). Vitamin D can affect the differentiation, maturation, and activation of dendritic cells (DCs) and regulate autophagy via vitamin D receptor signaling. Autophagy was shown to be involved in the functions of DCs. We investigated the effects of dietary vitamin D supplementation and in vitro 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on autophagy in BMDCs from control diet (CON)-fed lean and high-fat diet (HFD)-induced obese mice. C57BL/6 male mice were fed CON or HFD with 10% or 45% kcal fat, respectively, supplemented with 1,000 or 10,000 IU vitamin D/kg diet (vDC or vDS) for 12 weeks. BMDCs were generated by culturing bone marrow cells from the mice with 20 ng/mL rmGM-CSF and treated with 1 nM 1,25(OH)2D3. Maturation of BMDCs was induced by lipopolysaccharide (50 ng/mL) stimulation. Treatment with 1,25(OH)2D3 inhibited the expression of phenotypes related to DC function (MHC class Ⅱ, CD86, CD80) and production of IL-12p70 by BMDCs from control and obese mice, regardless of dietary vitamin D supplementation. LC3Ⅱ/Ⅰ and VPS34 protein levels increased, and p62 expression decreased, after 1,25(OH)2D3 treatment of the BMDCs in CON-vDC only. Vdr mRNA levels decreased following 1,25(OH)2D3 treatment of BMDCs in the HFD-vDC. In conclusion, autophagy flux was increased by 1,25(OH)2D3 treatment of the BMDCs in CON-vDC but not in the HFD-vDC group. This suggests that the decreased expression of Vdr following 1,25(OH)2D3 treatment might have affected autophagy flux in BMDCs from obese mice.
Collapse
|
|
13
|
Li A, Yi B, Han H, Yang S, Hu Z, Zheng L, Wang J, Liao Q, Zhang H. Vitamin D-VDR (vitamin D receptor) regulates defective autophagy in renal tubular epithelial cell in streptozotocin-induced diabetic mice via the AMPK pathway. Autophagy 2021; 18:877-890. [PMID: 34432556 PMCID: PMC9037529 DOI: 10.1080/15548627.2021.1962681] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Diabetic nephropathy (DN) has become a major cause of end-stage renal disease, and autophagy disorder is implicated in the pathogenesis of DN. Our previous studies found that vitamin D (VD) and VDR (vitamin D receptor) played a renoprotective role by inhibiting inflammation and fibrosis. However, whether VD-VDR regulates autophagy disorders in DN remains unclear. In this study, we established a streptozotocin (STZ)-induced diabetic model in vdr knockout (vdr-KO) mice and VDR specifically overexpressed in renal proximal tubular epithelial cells (Vdr-OE) mice. Our results showed that paricalcitol (an activated vitamin D analog) or Vdr-OE could alleviate STZ-induced ALB (albumin) excretion, renal tubule injury and inflammation, while these were worsened in vdr-KO mice. Defective autophagy was observed in the kidneys of STZ mice, which was more pronounced in vdr-KO mice and could be partially restored by paricalcitol or Vdr-OE. In high glucose-induced HK-2 cells, defective autophagy and decreased PRKAA1/AMPK phosphorylation was observed, which could be partially restored by paricalcitol in a VDR-dependent manner. AMPK inhibitor abolished paricalcitol-induced autophagy activation, and AMPK activator restored the defective autophagy in high glucose-induced HK-2 cells. Furthermore, paricalcitol-mediated AMPK activation was abrogated by CAMKK2/CaMKKβ inhibition, but not by STK11/LKB1 knockout. Meanwhile, paricalcitol rescued the decreased Ca2+ concentration induced by high glucose. In conclusion, VD-VDR can restore defective autophagy in the kidney of STZ-induced diabetic mice, which could be attributed to the activation of the Ca2+-CAMKK2-AMPK pathway in renal tubular epithelial cells. Abbreviations: ACTB/β-actin: actin beta;AGE: advanced glycation end-products;AMPK: AMP-activated protein kinase;CAMKK2/CaMKKβ: calcium-calmodulin dependent protein kinase kinase 2;CQ: chloroquine;DN: diabetic nephropathy;HG: high levels of glucose;KO: knockout;LG: low levels of glucose;MAP1LC3/LC3: microtubule associated protein 1 light chain 3;NOD2: nucleotide binding oligomerization domain containing 2;OE: overexpression;PAS: periodic acid Schiff; Pari: paricalcitol;PTECs: proximal renal tubule epithelial cells;RT: room temperature;SQSTM1/p62: sequestosome 1;STK11/LKB1: serine/threonine kinase 11;STZ: streptozotocin;TEM: transmission electron microscopy;VD: vitamin D;VDR: vitamin D receptor;WT: wild-type
Collapse
Affiliation(s)
- Aimei Li
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Bin Yi
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hailong Han
- Centre For Medical Genetics And Hunan Key Laboratory of Medical Genetics, School Of Life Sciences, Central South University, Changsha, Hunan, China.,Department of Neuroscience, Postdoctoral Station For Basic Medicine, Hengyang School of Medicine, University of South China, Hengyang, Hunan, China
| | - Shikun Yang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaoxin Hu
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Li Zheng
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jianwen Wang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qin Liao
- Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hao Zhang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| |
Collapse
|
|
14
|
Perrelli A, Retta SF. Polymorphisms in genes related to oxidative stress and inflammation: Emerging links with the pathogenesis and severity of Cerebral Cavernous Malformation disease. Free Radic Biol Med 2021; 172:403-417. [PMID: 34175437 DOI: 10.1016/j.freeradbiomed.2021.06.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/03/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023]
Abstract
Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin affecting 0.5% of the population and characterized by abnormally enlarged and leaky capillaries that predispose to seizures, neurological deficits, and intracerebral hemorrhage (ICH). CCM occurs sporadically or is inherited as dominant condition with incomplete penetrance and highly variable expressivity. Three disease genes have been identified: KRIT1 (CCM1), CCM2 and CCM3. Previous results demonstrated that loss-of-function mutations of CCM genes cause pleiotropic effects, including defective autophagy, altered reactive oxygen species (ROS) homeostasis, and enhanced sensitivity to oxidative stress and inflammatory events, suggesting a novel unifying pathogenetic mechanism, and raising the possibility that CCM disease onset and severity are influenced by the presence of susceptibility and modifier genes. Consistently, genome-wide association studies (GWAS) in large and homogeneous cohorts of patients sharing the familial form of CCM disease and identical mutations in CCM genes have led to the discovery of distinct genetic modifiers of major disease severity phenotypes, such as development of numerous and large CCM lesions, and susceptibility to ICH. This review deals with the identification of genetic modifiers with a significant impact on inter-individual variability in CCM disease onset and severity, including highly polymorphic genes involved in oxidative stress, inflammatory and immune responses, such as cytochrome P450 monooxygenases (CYP), matrix metalloproteinases (MMP), and Toll-like receptors (TLR), pointing to their emerging prognostic value, and opening up new perspectives for risk stratification and personalized medicine strategies.
Collapse
Affiliation(s)
- Andrea Perrelli
- Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy; CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy.
| | - Saverio Francesco Retta
- Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy; CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy.
| |
Collapse
|
|
15
|
Bhutia SK. Vitamin D in autophagy signaling for health and diseases: Insights on potential mechanisms and future perspectives. J Nutr Biochem 2021; 99:108841. [PMID: 34403722 DOI: 10.1016/j.jnutbio.2021.108841] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 06/08/2021] [Accepted: 08/10/2021] [Indexed: 02/07/2023]
Abstract
Vitamin D regulates the pleiotropic effect to maintain cellular homeostasis and epidemiological evidence establishes an association between vitamin D deficiency and various human diseases. Here, the role of autophagy, the cellular self-degradation process, in vitamin D-dependent function is documented in different cellular settings and discussed the molecular aspects for treating chronic inflammatory, infectious diseases, and cancer. Vitamin D activates autophagy through a genomic and non-genomic signaling pathway to influence a wide variety of physiological functions of different body organs along with bone health and calcium metabolism. Moreover, it induces autophagy as a protective mechanism to inhibit oxidative stress and apoptosis to regulate cell proliferation, differentiation, and immune modulation. Furthermore, vitamin D and its receptor regulate autophagy signaling to control inflammation and host immunity by activating antimicrobial defense mechanisms. Vitamin D has been revealed as a potent anticancer agent and induces autophagy to increase the response to radiation and chemotherapeutic drugs for potential cancer therapy. Increasing vitamin D levels in the human body through timely exposure to sunlight or vitamin D supplements could activate autophagy as part of the homeostasis mechanism to prevent multiple human diseases and aging-associated dysfunctions.
Collapse
Affiliation(s)
- Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, 769008, India.
| |
Collapse
|
|
16
|
Li Y, Gao S, Du X, Ji J, Xi Y, Zhai G. Advances in autophagy as a target in the treatment of tumours. J Drug Target 2021; 30:166-187. [PMID: 34319838 DOI: 10.1080/1061186x.2021.1961792] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Autophagy is a multi-step lysosomal degradation process, which regulates energy and material metabolism and has been used to maintain homeostasis. Autophagy has been shown to be involved in the regulation of health and disease. But at present, there is no consensus on the relationship between autophagy and tumour, and we consider that it plays a dual role in the occurrence and development of tumour. That is to say, under certain conditions, it can inhibit the occurrence of tumour, but it can also promote the process of tumour. Therefore, autophagy could be used as a target for tumour treatment. The regulation of autophagy plays a synergistic role in the radiotherapy, chemotherapy, phototherapy and immunotherapy of tumour, and nano drug delivery system provides a promising strategy for improving the efficacy of autophagy regulation. This review summarised the progress in the regulatory pathways and factors of autophagy as well as nanoformulations as carriers for the delivery of autophagy modulators.
Collapse
Affiliation(s)
- Yingying Li
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Shan Gao
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Xiyou Du
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Jianbo Ji
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Yanwei Xi
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Guangxi Zhai
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| |
Collapse
|
|
17
|
Wang W, Liu J, Chen K, Wang J, Dong Q, Xie J, Yuan Y. Vitamin D promotes autophagy in AML cells by inhibiting miR-17-5p-induced Beclin-1 overexpression. Mol Cell Biochem 2021; 476:3951-3962. [PMID: 34185245 DOI: 10.1007/s11010-021-04208-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 06/14/2021] [Indexed: 11/24/2022]
Abstract
MicroRNA (miR)-17-5p has been investigated in many diseases as a regulator of disease progression and is highly expressed in acute myeloid leukemia (AML). However, potential mechanisms underlying the function of miR-17-5p in AML need more elucidation. MiR-17-5p expression was augmented, while 25(OH)D3 and Beclin-1 levels were decreased in AML patients with the highest risk for disease progression. MiR-17-5p, 25(OH)D3 and Beclin-1 were determined to be clinically important in AML based on ROC curve analysis. Higher miR-17-5p expression as well as lower 25(OH)D3 and Beclin-1 expression were relevant with poor prognosis in AML. In addition, miR-17-5p was negatively correlated with and bound to BECN1. Vitamin D was found to diminish cell proliferation and enhance autophagy. Finally, through rescue assays, miR-17-5p facilitated the ability of cell proliferation, inhibited autophagy and apoptosis by modulating Beclin-1 in HL-60 cells following the treatment of 4 μM vitamin D. Vitamin D promoted autophagy in AML cells by modulating miR-17-5p and Beclin-1.
Collapse
Affiliation(s)
- Weijia Wang
- Department of Laboratory Diagnosis, Zhongshan People's Hospital, No. 2, Sunwen East Road, Zhongshan City, 528403, Guangdong, China
| | - Jing Liu
- Ethics Committee, Zhongshan People's Hospital, Zhongshan City, 528403, Guangdong, China
| | - Kang Chen
- Department of Laboratory Diagnosis, Zhongshan People's Hospital, No. 2, Sunwen East Road, Zhongshan City, 528403, Guangdong, China
| | - Juan Wang
- Department of Laboratory Diagnosis, Zhongshan People's Hospital, No. 2, Sunwen East Road, Zhongshan City, 528403, Guangdong, China
| | - Qian Dong
- Department of Laboratory Diagnosis, Zhongshan People's Hospital, No. 2, Sunwen East Road, Zhongshan City, 528403, Guangdong, China
| | - Jinye Xie
- Department of Laboratory Diagnosis, Zhongshan People's Hospital, No. 2, Sunwen East Road, Zhongshan City, 528403, Guangdong, China
| | - Yong Yuan
- Department of Laboratory Diagnosis, Zhongshan People's Hospital, No. 2, Sunwen East Road, Zhongshan City, 528403, Guangdong, China.
| |
Collapse
|
|
18
|
Verma AK, Bharti PS, Rafat S, Bhatt D, Goyal Y, Pandey KK, Ranjan S, Almatroodi SA, Alsahli MA, Rahmani AH, Almatroudi A, Dev K. Autophagy Paradox of Cancer: Role, Regulation, and Duality. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8832541. [PMID: 33628386 PMCID: PMC7892237 DOI: 10.1155/2021/8832541] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 01/14/2021] [Accepted: 01/29/2021] [Indexed: 12/12/2022]
Abstract
Autophagy, a catabolic process, degrades damaged and defective cellular materials through lysosomes, thus working as a recycling mechanism of the cell. It is an evolutionarily conserved and highly regulated process that plays an important role in maintaining cellular homeostasis. Autophagy is constitutively active at the basal level; however, it gets enhanced to meet cellular needs in various stress conditions. The process involves various autophagy-related genes that ultimately lead to the degradation of targeted cytosolic substrates. Many factors modulate both upstream and downstream autophagy pathways like nutritional status, energy level, growth factors, hypoxic conditions, and localization of p53. Any problem in executing autophagy can lead to various pathological conditions including neurodegeneration, aging, and cancer. In cancer, autophagy plays a contradictory role; it inhibits the formation of tumors, whereas, during advanced stages, autophagy promotes tumor progression. Besides, autophagy protects the tumor from various therapies by providing recycled nutrition and energy to the tumor cells. Autophagy is stimulated by tumor suppressor proteins, whereas it gets inhibited by oncogenes. Due to its dynamic and dual role in the pathogenesis of cancer, autophagy provides promising opportunities in developing novel and effective cancer therapies along with managing chemoresistant cancers. In this article, we summarize different strategies that can modulate autophagy in cancer to overcome the major obstacle, i.e., resistance developed in cancer to anticancer therapies.
Collapse
Affiliation(s)
- Amit Kumar Verma
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Prahalad Singh Bharti
- Department of Biophysics, All India Institutes of Medical Sciences, New Delhi, India
| | - Sahar Rafat
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Deepti Bhatt
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Yamini Goyal
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Kamlesh Kumar Pandey
- Department of Anatomy, All India Institutes of Medical Sciences, New Delhi, India
| | - Sanjeev Ranjan
- Institute of Biomedicine, Cell and Tissue Imaging Unit, Finland
| | - Saleh A. Almatroodi
- Department of Medical Laboratories, College of Applied Medical Science, Qassim University, Buraidah, Saudi Arabia
| | - Mohammed A. Alsahli
- Department of Medical Laboratories, College of Applied Medical Science, Qassim University, Buraidah, Saudi Arabia
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Science, Qassim University, Buraidah, Saudi Arabia
| | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Science, Qassim University, Buraidah, Saudi Arabia
| | - Kapil Dev
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| |
Collapse
|
|
19
|
Currò M, Visalli G, Pellicanò GF, Ferlazzo N, Costanzo MG, D’Andrea F, Caccamo D, Nunnari G, Ientile R. Vitamin D Status Modulates Inflammatory Response in HIV+ Subjects: Evidence for Involvement of Autophagy and TG2 Expression in PBMC. Int J Mol Sci 2020; 21:ijms21207558. [PMID: 33066266 PMCID: PMC7588966 DOI: 10.3390/ijms21207558] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/09/2020] [Accepted: 10/11/2020] [Indexed: 12/11/2022] Open
Abstract
Conflicting results on the involvement of vitamin D deficiency in inflammatory and immune response in HIV+ subjects are reported. We aimed to characterize the possible influence of vitamin D status on changes in expression of tissue transglutaminase gene (TGM2) and other genes involved in inflammatory response and autophagy in peripheral blood mononuclear cells (PBMC) from HIV+ subjects. HIV+ subjects (n = 57) under antiretroviral therapy (ART) and healthy controls (n = 40) were enrolled. mRNA levels of 1-alpha-hydroxylase (CYP27B1), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), TGM2, microtubule-associated protein 1A/1B-light chain 3 (LC3), autophagy-related 5 homolog (ATG5), and Beclin 1 (BECN1) were quantified by real-time PCR. In HIV+ subjects, 25(OH)D3 plasma levels were negatively correlated with time since HIV diagnosis. In PBMC from HIV+ subjects, increases in gene expression of TNF-α and IFN-γ in comparison to controls were observed. The highest increase in TNF-α transcripts was observed in HIV+ subjects with deficient 25(OH)D3 levels. Autophagy-related genes LC3, ATG5, and BECN1 were down-regulated in HIV+ subjects. Moreover, TGM2 transcripts were up-regulated in PBMC from HIV+ subjects with 25(OH)D3 deficiency. Changes observed in PBMC from HIV+ subjects appeared to be dependent on vitamin D status. The present results suggest that vitamin D deficiency is associated with changes in the expression of markers of inflammation and autophagy, resulting in immune cell dysfunction.
Collapse
Affiliation(s)
- Monica Currò
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (M.C.); (G.V.); (N.F.); (M.G.C.); (D.C.)
| | - Giuseppa Visalli
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (M.C.); (G.V.); (N.F.); (M.G.C.); (D.C.)
| | - Giovanni Francesco Pellicanò
- Unit of Infectious Diseases, Department of Human Pathology of Adult and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy;
| | - Nadia Ferlazzo
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (M.C.); (G.V.); (N.F.); (M.G.C.); (D.C.)
| | - Maria Giovanna Costanzo
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (M.C.); (G.V.); (N.F.); (M.G.C.); (D.C.)
| | - Flavia D’Andrea
- Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (F.D.); (G.N.)
| | - Daniela Caccamo
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (M.C.); (G.V.); (N.F.); (M.G.C.); (D.C.)
| | - Giuseppe Nunnari
- Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (F.D.); (G.N.)
| | - Riccardo Ientile
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (M.C.); (G.V.); (N.F.); (M.G.C.); (D.C.)
- Correspondence: ; Tel.: +39-090-2213383
| |
Collapse
|
|
20
|
Guizzardi S, Picotto G, Rodriguez V, Welsh J, Narvaez C, Bohl L, Tolosa de Talamoni N. Combined treatment of menadione and calcitriol increases the antiproliferative effect by promoting oxidative/nitrosative stress, mitochondrial dysfunction, and autophagy in breast cancer MCF-7 cells. Can J Physiol Pharmacol 2020; 98:548-556. [PMID: 32762631 DOI: 10.1139/cjpp-2019-0585] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The aim of this study was to determine new insights into the molecular mechanisms involved in the antiproliferative action of menadione + calcitriol (MEN+D) on MCF-7 cells. After 24 h, MEN+D inhibited the cell growth but was not observed with each single treatment. The combined drugs reduced the mitochondrial respiration at that time, as judged by an increase in the proton leak and a decrease in the ATP generation and coupling efficiency. At longer times, 48 or 96 h, either D or MEN reduced the proliferation, but the effect was higher when both drugs were used together. The combined treatment increased the superoxide anion ([Formula: see text]) and nitric oxide (NO•) contents as well as acidic vesicular organelles (AVOs) formation. The percentage of cells showing the lower mitochondrial membrane potential (ΔΨm) was highly increased by the combined therapy. LC3-II protein expression was enhanced by any treatment. In conclusion, the antiproliferative action of MEN+D involves oxidative/nitrosative stress, mitochondrial alteration, and autophagy. This combined therapy could be useful to treat breast cancer cells because it inhibits multiple oncogenic pathways more effectively than each single agent.
Collapse
Affiliation(s)
- Solange Guizzardi
- Laboratorio "Dr. Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-UNC), Córdoba, Argentina
| | - Gabriela Picotto
- Laboratorio "Dr. Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-UNC), Córdoba, Argentina
| | - Valeria Rodriguez
- Laboratorio "Dr. Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-UNC), Córdoba, Argentina
| | - JoEllen Welsh
- University at Albany Cancer Research Center, Rensselaer, NY, USA
| | - Carmen Narvaez
- University at Albany Cancer Research Center, Rensselaer, NY, USA
| | - Luciana Bohl
- Centro de Investigaciones y Transferencia Villa María (CITVM-CONICET), Universidad Nacional Villa María, Villa María, Argentina
| | - Nori Tolosa de Talamoni
- Laboratorio "Dr. Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-UNC), Córdoba, Argentina
| |
Collapse
|
|
21
|
Biesalski HK. Vitamin D deficiency and co-morbidities in COVID-19 patients – A fatal relationship? NFS JOURNAL 2020. [PMCID: PMC7276229 DOI: 10.1016/j.nfs.2020.06.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
|
|
22
|
Vitamin D Signaling in Inflammation and Cancer: Molecular Mechanisms and Therapeutic Implications. Molecules 2020; 25:molecules25143219. [PMID: 32679655 PMCID: PMC7397283 DOI: 10.3390/molecules25143219] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 03/28/2020] [Accepted: 04/03/2020] [Indexed: 12/12/2022] Open
Abstract
Vitamin D and its active metabolites are important nutrients for human skeletal health. UV irradiation of skin converts 7-dehydrocholesterol into vitamin D3, which metabolized in the liver and kidneys into its active form, 1α,25-dihydroxyvitamin D3. Apart from its classical role in calcium and phosphate regulation, scientists have shown that the vitamin D receptor is expressed in almost all tissues of the body, hence it has numerous biological effects. These includes fetal and adult homeostatic functions in development and differentiation of metabolic, epidermal, endocrine, neurological and immunological systems of the body. Moreover, the expression of vitamin D receptor in the majority of immune cells and the ability of these cells to actively metabolize 25(OH)D3 into its active form 1,25(OH)2D3 reinforces the important role of vitamin D signaling in maintaining a healthy immune system. In addition, several studies have showed that vitamin D has important regulatory roles of mechanisms controlling proliferation, differentiation and growth. The administration of vitamin D analogues or the active metabolite of vitamin D activates apoptotic pathways, has antiproliferative effects and inhibits angiogenesis. This review aims to provide an up-to-date overview on the effects of vitamin D and its receptor (VDR) in regulating inflammation, different cell death modalities and cancer. It also aims to investigate the possible therapeutic benefits of vitamin D and its analogues as anticancer agents.
Collapse
|
|
23
|
Noura M, Matsuo H, Koyama A, Adachi S, Masutani H. TXNIP induces growth arrest and enhances ABT263-induced apoptosis in mixed-lineage leukemia-rearranged acute myeloid leukemia cells. FEBS Open Bio 2020; 10:1532-1541. [PMID: 32511893 PMCID: PMC7396447 DOI: 10.1002/2211-5463.12908] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/26/2020] [Accepted: 06/04/2020] [Indexed: 01/20/2023] Open
Abstract
Thioredoxin‐interacting protein (TXNIP) has been widely recognized as a tumor suppressor in various cancers, including liver, breast, and thyroid cancers. Although TXNIP is epigenetically silenced in acute myeloid leukemia (AML) cells, as in many cancer cells, its role in leukemogenesis remains elusive. Mixed‐lineage leukemia (MLL) gene rearrangements in AML are associated with poor prognosis, and the development of a new treatment method is eagerly anticipated. In this study, we first reveal that lower expression of TXNIP is correlated with shortened overall survival periods in AML patients. Moreover, we demonstrated that TXNIP overexpression significantly suppresses proliferation in AML cells harboring MLL fusion genes. TXNIP promotes autophagy by increasing expression of the autophagy protein, Beclin 1, and lipidation of LC3B. We also show that TXNIP overexpression combined with ABT263, a potent inhibitor of Bcl‐2 and Bcl‐xL, is highly effective at inducing cell death in MLL‐rearranged (MLL‐r) AML cells. In summary, this study provides insights into the molecular mechanism of TXNIP‐mediated tumor suppression and furthermore underscores the potential of TXNIP as a promising therapeutic target for MLL‐r AML.
Collapse
Affiliation(s)
- Mina Noura
- Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Clinical Laboratory Sciences, Tenri Health Care University, Tenri, Japan
| | - Hidemasa Matsuo
- Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Asami Koyama
- Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Souichi Adachi
- Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Masutani
- Department of Clinical Laboratory Sciences, Tenri Health Care University, Tenri, Japan
| |
Collapse
|
|
24
|
Constantinovits M, Sipos F, L Kiss A, Műzes G. Preconditioning with cell-free DNA prevents DSS-colitis by promoting cell protective autophagy. J Investig Med 2020; 68:992-1001. [PMID: 32393477 DOI: 10.1136/jim-2020-001296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/17/2020] [Indexed: 02/05/2023]
Abstract
Presence of cell-free DNA (cfDNA) in sera of patients with inflammatory bowel diseases (IBD) is a long-known fact. The biological effect of cfDNA administration on cellular autophagy within normal and inflammatory circumstances remains unclear. In this study, the effects of intravenous cfDNA pretreatment on autophagy response were studied in dextran sulfate sodium (DSS)-induced acute experimental colitis. Selected proinflammatory cytokine and autophagy-related gene and protein expressions were compared with clinical and histological activity parameters, and with transmission electron microscopic evaluations. A single intravenous dose of cfDNA pretreatment with cfDNA from colitis exhibited beneficial response concerning the clinical and histological severity of DSS-colitis as compared with effects of normal cfDNA. Pretreatment with colitis-derived cfDNA substantially altered the gene and protein expression of several autophagy and inflammatory cytokine genes in a clinically favorable manner. Autophagy in splenocytes is also altered after colitis-derived cfDNA pretreatment. During the process of acute colitis, the subsequent inflammatory environment presumably results in changes of cfDNA with the potential to facilitate cell protective autophagy. Understanding the molecular mechanisms behind the impact of colitis-associated autophagy, and elucidating alterations of the interaction between autophagy and innate immunity caused by nucleic acids may provide further insight into the etiology of IBD. By targeting or modifying cfDNA, novel anti-inflammatory therapies may be developed.
Collapse
Affiliation(s)
- Miklós Constantinovits
- Immunology Research Team, 2nd Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Ferenc Sipos
- Immunology Research Team, 2nd Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Anna L Kiss
- Department of Human Morphology and Developmental Biology, Semmelweis University, Budapest, Hungary
| | - Györgyi Műzes
- Immunology Research Team, 2nd Department of Medicine, Semmelweis University, Budapest, Hungary
| |
Collapse
|
|
25
|
Meghil MM, Cutler CW. Oral Microbes and Mucosal Dendritic Cells, "Spark and Flame" of Local and Distant Inflammatory Diseases. Int J Mol Sci 2020; 21:E1643. [PMID: 32121251 PMCID: PMC7084622 DOI: 10.3390/ijms21051643] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 02/24/2020] [Accepted: 02/25/2020] [Indexed: 12/20/2022] Open
Abstract
Mucosal health and disease is mediated by a complex interplay between the microbiota ("spark") and the inflammatory response ("flame"). Pathobionts, a specific class of microbes, exemplified by the oral microbe Porphyromonas gingivalis, live mostly "under the radar" in their human hosts, in a cooperative relationship with the indigenous microbiota. Dendritic cells (DCs), mucosal immune sentinels, often remain undisturbed by such microbes and do not alert adaptive immunity to danger. At a certain tipping point of inflammation, an "awakening" of pathobionts occurs, wherein their active growth and virulence are stimulated, leading to a dysbiosis. Pathobiont becomes pathogen, and commensal becomes accessory pathogen. The local inflammatory outcome is the Th17-mediated degenerative bone disease, periodontitis (PD). In systemic circulation of PD subjects, inflammatory DCs expand, carrying an oral microbiome and promoting Treg and Th17 responses. At distant peripheral sites, comorbid diseases including atherosclerosis, Alzheimer's disease, macular degeneration, chronic kidney disease, and others are reportedly induced. This review will review the immunobiology of DCs, examine the complex interplay of microbes and DCs in the pathogenesis of PD and its comorbid inflammatory diseases, and discuss the role of apoptosis and autophagy in this regard. Overall, the pathophysiological mechanisms of DC-mediated chronic inflammation and tissue destruction will be summarized.
Collapse
Affiliation(s)
| | - Christopher W. Cutler
- Department of Periodontics, The Dental College of Georgia at Augusta University, Augusta, GA 30912, USA;
| |
Collapse
|
|
26
|
Seranova E, Palhegyi AM, Verma S, Dimova S, Lasry R, Naama M, Sun C, Barrett T, Rosenstock TR, Kumar D, Cohen MA, Buganim Y, Sarkar S. Human Induced Pluripotent Stem Cell Models of Neurodegenerative Disorders for Studying the Biomedical Implications of Autophagy. J Mol Biol 2020; 432:2754-2798. [PMID: 32044344 DOI: 10.1016/j.jmb.2020.01.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 01/22/2020] [Accepted: 01/23/2020] [Indexed: 12/12/2022]
Abstract
Autophagy is an intracellular degradation process that is essential for cellular survival, tissue homeostasis, and human health. The housekeeping functions of autophagy in mediating the clearance of aggregation-prone proteins and damaged organelles are vital for post-mitotic neurons. Improper functioning of this process contributes to the pathology of myriad human diseases, including neurodegeneration. Impairment in autophagy has been reported in several neurodegenerative diseases where pharmacological induction of autophagy has therapeutic benefits in cellular and transgenic animal models. However, emerging studies suggest that the efficacy of autophagy inducers, as well as the nature of the autophagy defects, may be context-dependent, and therefore, studies in disease-relevant experimental systems may provide more insights for clinical translation to patients. With the advancements in human stem cell technology, it is now possible to establish disease-affected cellular platforms from patients for investigating disease mechanisms and identifying candidate drugs in the appropriate cell types, such as neurons that are otherwise not accessible. Towards this, patient-derived human induced pluripotent stem cells (hiPSCs) have demonstrated considerable promise in constituting a platform for effective disease modeling and drug discovery. Multiple studies have utilized hiPSC models of neurodegenerative diseases to study autophagy and evaluate the therapeutic efficacy of autophagy inducers in neuronal cells. This review provides an overview of the regulation of autophagy, generation of hiPSCs via cellular reprogramming, and neuronal differentiation. It outlines the findings in various neurodegenerative disorders where autophagy has been studied using hiPSC models.
Collapse
Affiliation(s)
- Elena Seranova
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
| | - Adina Maria Palhegyi
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
| | - Surbhi Verma
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India
| | - Simona Dimova
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
| | - Rachel Lasry
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, 91120, Israel
| | - Moriyah Naama
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, 91120, Israel
| | - Congxin Sun
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
| | - Timothy Barrett
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
| | - Tatiana Rosado Rosenstock
- Department of Physiological Science, Santa Casa de São Paulo School of Medical Sciences, São Paulo, SP, 01221-020, Brazil
| | - Dhiraj Kumar
- Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India
| | - Malkiel A Cohen
- Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA
| | - Yosef Buganim
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, 91120, Israel
| | - Sovan Sarkar
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
| |
Collapse
|
|
27
|
Hu X, Niu L, Ma C, Huang Y, Yang X, Shi Y, Pan C, Liu J, Wang H, Li Q, Geng F, Tang X. Calcitriol decreases live
Porphyromonas gingivalis
internalized into epithelial cells and monocytes by promoting autophagy. J Periodontol 2019; 91:956-966. [DOI: 10.1002/jper.19-0510] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/09/2019] [Accepted: 11/07/2019] [Indexed: 12/25/2022]
Affiliation(s)
- Xinyue Hu
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
- Department of Pediatric DentistryShenyang Stomatological Hospital Shenyang Liaoning Province China
| | - Li Niu
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
| | - Chunliang Ma
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
| | - Yuehua Huang
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
- Department of PeriodontologyHangzhou Dental Hospital Hangzhou Zhejiang Province China
| | - Xue Yang
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
| | - Yakun Shi
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
| | - Chunling Pan
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
| | - Jingbo Liu
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
| | - Hongyan Wang
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
| | - Qian Li
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
| | - Fengxue Geng
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
| | - Xiaolin Tang
- Department of PeriodontologySchool of StomatologyChina Medical University Shenyang Liaoning Province China
| |
Collapse
|
|
28
|
Suares A, Tapia C, González-Pardo V. VDR agonists down regulate PI3K/Akt/mTOR axis and trigger autophagy in Kaposi's sarcoma cells. Heliyon 2019; 5:e02367. [PMID: 31497671 PMCID: PMC6722267 DOI: 10.1016/j.heliyon.2019.e02367] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/14/2019] [Accepted: 08/21/2019] [Indexed: 12/21/2022] Open
Abstract
The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor (KSHV/vGPCR) is a key molecule in the pathogenesis of Kaposi's sarcoma. We have previously shown that 1α,25(OH)2D3 or its less-calcemic analog TX 527 inhibits the proliferation of endothelial cells expressing vGPCR, NF-κB activity and induces apoptosis in a VDR dependent manner. In this work, we further explored whether 1α,25(OH)2D3 or TX 527 regulates PI3K/Akt/mTOR axis and induces autophagy as part of its antineoplastic mechanism of action. Proliferation assays indicated that vGPCR cell number decreased in presence of LY294002 (PI3K/Akt inhibitor) likewise 1α,25(OH)2D3 or TX 527 (10 nM, 48 h). Also, Akt phosphorylation was found decreased in dose (0.1-100 nM) and time response studies (12-72 h) after both compounds treatments. In addition, decreased phosphorylated Akt was significantly observed in the nucleus. Moreover, regulation of Akt phosphorylation was NF-κB and VDR dependent. TNFAIP3/A20, an ubiquitin-editing enzyme, a direct NF-κB target gene and a negative regulator of Beclin-1, was down-regulated whereas Beclin-1 was up-regulated after 10 nM of 1α,25(OH)2D3 or TX 527 treatment. Decrement in Akt phosphorylation was accompanied by a reduced mTOR phosphorylation and an increase in the autophagy marker LC3-II. Since increment in autophagosomes not always indicates increment in autophagy activity, we used Chloroquine (CQ, 1 μM), an inhibitor of autophagy flow, to confirm autophagy after both VDR agonists treatment. In conclusion, VDR agonists, 1α,25(OH)2D3 or TX 527, inhibited PI3K/Akt/mTOR axis and induced autophagy in endothelial cells expressing vGPCR by a VDR-dependent mechanism.
Collapse
Affiliation(s)
- Alejandra Suares
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Departamento de Biología Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, San Juan 670, 8000, Bahía Blanca, Argentina
- IFIBYNE – Instituto de Fisiología, Biología Molecular y Neurociencias (UBA-CONICET), Ciudad Universitaria, 1428, Ciudad Autónoma de Buenos Aires, Argentina
| | - Cinthya Tapia
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Departamento de Biología Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, San Juan 670, 8000, Bahía Blanca, Argentina
| | - Verónica González-Pardo
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Departamento de Biología Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, San Juan 670, 8000, Bahía Blanca, Argentina
| |
Collapse
|
|
29
|
Dutta S, Mahalanobish S, Saha S, Ghosh S, Sil PC. Natural products: An upcoming therapeutic approach to cancer. Food Chem Toxicol 2019; 128:240-255. [PMID: 30991130 DOI: 10.1016/j.fct.2019.04.012] [Citation(s) in RCA: 162] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/08/2019] [Accepted: 04/09/2019] [Indexed: 12/28/2022]
Abstract
Cancer is one of the leading causes of death across the world. Different environmental and anthropogenic factors initiate mutations in different functional genes of growth factors and their receptors, anti-apoptotic proteins, self-renewal developmental proteins, tumor suppressors, transcription factors, etc. This phenomenon leads to altered protein homeostasis of the cell which in turn induces cancer initiation, development, progression and survival. From ancient times various natural products have been used as traditional medicine against different diseases. Natural products are readily applicable, inexpensive, accessible and acceptable therapeutic approach with minimum cytotoxicity. As most of the target-specific anticancer drugs failed to achieve the expected result so far, new multi-targeted therapies using natural products have become significant. In this review, we have summarized the efficacy of different natural compounds against cancer. They are capable of modulating cancer microenvironment and diverse cell signaling cascades; thus playing a major role in combating cancer. These compounds are found to be effective against several signaling pathways, mainly cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch pathway, Wnt pathway and Hedgehog pathway). This review article is expected to be helpful in understanding the recent progress of natural product research for the development of anticancer drug.
Collapse
Affiliation(s)
- Sayanta Dutta
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Sushweta Mahalanobish
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Sukanya Saha
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Shatadal Ghosh
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Parames C Sil
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India.
| |
Collapse
|
|
30
|
Meghil MM, Hutchens L, Raed A, Multani NA, Rajendran M, Zhu H, Looney S, Elashiry M, Arce RM, Peacock ME, Dong Y, Cutler CW. The influence of vitamin D supplementation on local and systemic inflammatory markers in periodontitis patients: A pilot study. Oral Dis 2019; 25:1403-1413. [PMID: 30912231 DOI: 10.1111/odi.13097] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 02/27/2019] [Accepted: 03/18/2019] [Indexed: 01/09/2023]
Abstract
OBJECTIVES Vitamin D deficiency/insufficiency is a worldwide public health issue that has been linked to numerous inflammatory disorders, including periodontitis. There is increasing support for a role for adequate vitamin D levels in overall health. Populations with darker skin color have a higher prevalence of vitamin D deficiency/insufficiency and periodontitis. The purpose of this small pilot study was to investigate the influence of 12 weeks of 25(OH)D vitamin D supplementation (VDS) on mediators of systemic inflammation in dark-skinned, periodontitis patients. MATERIALS AND METHODS A total of 23 patients with moderate to severe periodontitis were randomly assigned to the vitamin D group or placebo group and received intensive single visit scaling and root planning to elicit a systemic inflammatory response. RESULTS Vitamin D supplementation increased serum 25(OH)D levels approximately 2-fold over baseline levels; moreover, VDS group had reduced peripheral blood CD3 and CD3+CD8+ cytotoxic T lymphocyte (CTLs) counts and reduced pro-inflammatory salivary cytokines. In contrast, VDS group had higher levels of the autophagy-related proteins and other proteins crucial for anti-microbial autophagy in whole blood PBMCs. CONCLUSION In conclusion, VDS has multiple benefits for reducing systemic inflammation and promoting induction of autophagy-related proteins related to anti-microbial functions.
Collapse
Affiliation(s)
- Mohamed M Meghil
- Department of Periodontics, The Dental College of Georgia at Augusta University, Augusta, Georgia.,Department of Oral Biology, The Dental College of Georgia at Augusta University, Augusta, Georgia
| | - Lance Hutchens
- Department of Periodontics, The Dental College of Georgia at Augusta University, Augusta, Georgia
| | - Anas Raed
- Georgia Prevention Institute, Augusta University, Augusta, Georgia
| | - Neha A Multani
- Department of General Dentistry, Eastman Institute for Oral Health, University of Rochester, Rochester, New York
| | - Mythilypriya Rajendran
- Department of Periodontics, The Dental College of Georgia at Augusta University, Augusta, Georgia
| | - Haidong Zhu
- Georgia Prevention Institute, Augusta University, Augusta, Georgia
| | - Stephen Looney
- Department of Biostatistics and Epidemiology, Medical College of Georgia at Augusta University, Augusta, Georgia
| | - Mahmoud Elashiry
- Department of Periodontics, The Dental College of Georgia at Augusta University, Augusta, Georgia.,Department of Oral Biology, The Dental College of Georgia at Augusta University, Augusta, Georgia
| | - Roger M Arce
- Department of Periodontics, The Dental College of Georgia at Augusta University, Augusta, Georgia
| | - Mark E Peacock
- Department of Periodontics, The Dental College of Georgia at Augusta University, Augusta, Georgia
| | - Yanbin Dong
- Georgia Prevention Institute, Augusta University, Augusta, Georgia
| | - Christopher W Cutler
- Department of Periodontics, The Dental College of Georgia at Augusta University, Augusta, Georgia
| |
Collapse
|
|
31
|
Panda PK, Fahrner A, Vats S, Seranova E, Sharma V, Chipara M, Desai P, Torresi J, Rosenstock T, Kumar D, Sarkar S. Chemical Screening Approaches Enabling Drug Discovery of Autophagy Modulators for Biomedical Applications in Human Diseases. Front Cell Dev Biol 2019; 7:38. [PMID: 30949479 PMCID: PMC6436197 DOI: 10.3389/fcell.2019.00038] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 03/01/2019] [Indexed: 12/12/2022] Open
Abstract
Autophagy is an intracellular degradation pathway for malfunctioning aggregation-prone proteins, damaged organelles, unwanted macromolecules and invading pathogens. This process is essential for maintaining cellular and tissue homeostasis that contribute to organismal survival. Autophagy dysfunction has been implicated in the pathogenesis of diverse human diseases, and therefore, therapeutic exploitation of autophagy is of potential biomedical relevance. A number of chemical screening approaches have been established for the drug discovery of autophagy modulators based on the perturbations of autophagy reporters or the clearance of autophagy substrates. These readouts can be detected by fluorescence and high-content microscopy, flow cytometry, microplate reader and immunoblotting, and the assays have evolved to enable high-throughput screening and measurement of autophagic flux. Several pharmacological modulators of autophagy have been identified that act either via the classical mechanistic target of rapamycin (mTOR) pathway or independently of mTOR. Many of these autophagy modulators have been demonstrated to exert beneficial effects in transgenic models of neurodegenerative disorders, cancer, infectious diseases, liver diseases, myopathies as well as in lifespan extension. This review describes the commonly used chemical screening approaches in mammalian cells and the key autophagy modulators identified through these methods, and highlights the therapeutic benefits of these compounds in specific disease contexts.
Collapse
Affiliation(s)
- Prashanta Kumar Panda
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Alexandra Fahrner
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Somya Vats
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
| | - Elena Seranova
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Vartika Sharma
- Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Miruna Chipara
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Priyal Desai
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Jorge Torresi
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- Department of Physiological Science, Santa Casa de São Paulo School of Medical Sciences, São Paulo, Brazil
| | - Tatiana Rosenstock
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- Department of Physiological Science, Santa Casa de São Paulo School of Medical Sciences, São Paulo, Brazil
| | - Dhiraj Kumar
- Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Sovan Sarkar
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| |
Collapse
|
|
32
|
Li J, Frederick AM, Jin Y, Guo C, Xiao H, Wood RJ, Liu Z. The Prevention of a High Dose of Vitamin D or Its Combination with Sulforaphane on Intestinal Inflammation and Tumorigenesis in
Apc
1638N
Mice Fed a High‐Fat Diet. Mol Nutr Food Res 2018; 63:e1800824. [DOI: 10.1002/mnfr.201800824] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 11/10/2018] [Indexed: 12/14/2022]
Affiliation(s)
- Jinchao Li
- Department of Nutrition School of Public Health and Health Sciences University of Massachusetts Amherst MA 01002 USA
| | - Armina‐Lyn M. Frederick
- Department of Nutrition School of Public Health and Health Sciences University of Massachusetts Amherst MA 01002 USA
| | - Yu Jin
- Department of Nutrition School of Public Health and Health Sciences University of Massachusetts Amherst MA 01002 USA
- Department of Gastroenterology Shengjing Hospital China Medical University Shenyang Liaoning 110004 China
| | - Chi Guo
- Department of Nutrition School of Public Health and Health Sciences University of Massachusetts Amherst MA 01002 USA
- Department of Molecular Medicine Hunan University Changsha Hunan 410006 China
| | - Hang Xiao
- Department of Food Science University of Massachusetts Amherst MA 01002 USA
| | - Richard J. Wood
- Department of Nutrition School of Public Health and Health Sciences University of Massachusetts Amherst MA 01002 USA
| | - Zhenhua Liu
- Department of Nutrition School of Public Health and Health Sciences University of Massachusetts Amherst MA 01002 USA
- Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University Boston MA 02153 USA
| |
Collapse
|
|
33
|
Serum vitamin D level in patients with viral warts. JOURNAL OF THE EGYPTIAN WOMEN’S DERMATOLOGIC SOCIETY 2018. [DOI: 10.1097/01.ewx.0000544897.93500.a8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
34
|
Guo W, Jin J, Pan J, Yao R, Li X, Huang X, Ma Z, Huang S, Yan X, Jin J, Dong A. The change of nuclear LC3 distribution in acute myeloid leukemia cells. Exp Cell Res 2018; 369:69-79. [PMID: 29752949 DOI: 10.1016/j.yexcr.2018.05.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Revised: 04/27/2018] [Accepted: 05/07/2018] [Indexed: 01/07/2023]
Abstract
Making sure the change of nuclear LC3 distribution in the autophagy of acute myeloid leukemia (AML) cell and finding out the regulation mechanism may lead to a breakthrough for killing AML cells. Western blots were performed to assess the expression of autophagy proteins. Changes in the LC3 distribution were monitored by immunofluorescence assays together with western blots, and the expression levels of Sirt1, DOR, Beclin1, HMGB1, and AMPK mRNA were detected via fluorescent quantitative PCR. The effects of Sirt1 and DOR on cell proliferation and survival were analyzed by MTT, flow cytometry, and western blotting assays. We found that treating AML cells with Ara-c or Sorafenib resulted in autophagy enhancement, and when autophagy was enhanced, nuclear LC3 moved into the cytoplasm. Notably, when autophagy was inhibited by blocking the nuclear LC3 shift, the cytotoxicity of drugs was enhanced. Our results also identified Sirt1 and DOR as regulatory molecules for the observed nuclear LC3 shift, and these molecules further affected the expression of Beclin1, HMGB1, and AMPK. Our results suggest the distribution of nuclear LC3 can be a novel way for further studying death of AML cells,and the regulatory molecules may be new targets for treating AML.
Collapse
Affiliation(s)
- Wenjian Guo
- Department of Hematology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China; Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, PR China; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, PR China; Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Jingrui Jin
- Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, PR China; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, PR China; Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Jiajia Pan
- Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, PR China; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, PR China; Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Rongxing Yao
- Department of Hematology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China
| | - Xia Li
- Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, PR China; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, PR China; Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Xin Huang
- Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, PR China; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, PR China; Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Zhixing Ma
- Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, PR China; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, PR China; Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Sujuan Huang
- Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, PR China; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, PR China; Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Xiao Yan
- Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, PR China; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, PR China; Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, PR China; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, PR China; Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China.
| | - Aishu Dong
- Department of Emergency, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China.
| |
Collapse
|
|
35
|
Low Autophagy (ATG) Gene Expression Is Associated with an Immature AML Blast Cell Phenotype and Can Be Restored during AML Differentiation Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:1482795. [PMID: 29743969 PMCID: PMC5878891 DOI: 10.1155/2018/1482795] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 12/21/2017] [Accepted: 12/31/2017] [Indexed: 02/06/2023]
Abstract
Autophagy is an intracellular degradation system that ensures a dynamic recycling of a variety of building blocks required for self-renewal, homeostasis, and cell survival under stress. We used primary acute myeloid leukemia (AML) samples and human AML cell lines to investigate the regulatory mechanisms of autophagy and its role in AML differentiation. We found a significantly lower expression of key autophagy- (ATG-) related genes in primary AML as compared to healthy granulocytes, an increased autophagic activity during all-trans retinoic acid- (ATRA-) induced neutrophil differentiation, and an impaired AML differentiation upon inhibition of ATG3, ATG4D, and ATG5. Supporting the notion of noncanonical autophagy, we found that ATRA-induced autophagy was Beclin1-independent compared to starvation- or arsenic trioxide- (ATO-) induced autophagy. Furthermore, we identified PU.1 as positive transcriptional regulator of ATG3, ATG4D, and ATG5. Low PU.1 expression in AML may account for low ATG gene expression in this disease. Low expression of the autophagy initiator ULK1 in AML can partially be attributed to high expression of the ULK1-targeting microRNA-106a. Our data clearly suggest that granulocytic AML differentiation relies on noncanonical autophagy pathways and that restoring autophagic activity might be beneficial in differentiation therapies.
Collapse
|
|
36
|
Abdel-Mohsen MA, El-Braky AAA, Ghazal AAER, Shamseya MM. Autophagy, apoptosis, vitamin D, and vitamin D receptor in hepatocellular carcinoma associated with hepatitis C virus. Medicine (Baltimore) 2018; 97:e0172. [PMID: 29561429 PMCID: PMC5895342 DOI: 10.1097/md.0000000000010172] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The aims of this study were to investigate the interplay between autophagy and apoptosis and to investigate the association between both of autophagy and apoptosis and vitamin D and its receptor in hepatitis C virus (HCV) viral infection and its implication in the progression into hepatocellular carcinoma (HCC).A cross-sectional study where serum levels of microtubule-associated protein 1A/1B-light chain 3 (LC3); marker of autophagy, caspase-3; marker of apoptosis, vitamin D3 and vitamin D receptor (VDR) were measured in healthy subjects as well as HCV and HCV-HCC patients using enzyme-linked immunosorbent assay technique.Collectively, the liver profile revealed hepatic dysfunctions in HCV patients with or without HCC. A significant reduction in the serum concentration levels LC3 and caspase-3 were observed referring to the down regulation of autophagy and host-mediated apoptosis in HCV patients with or without HCC. Deficiency of vitamin D and decreased levels of its receptor were observed in HCV and HCV-HCC patients.The perturbation in vitamin D/VDR axis, which modulates both of autophagy and apoptosis in HCV infection, may point out to its involvement and implication in the pathogenesis of HCV infection and the development of HCV-related HCC. Therefore, supplementation with vitamin D may not be the only solution to restore the vital biological functions of vitamin D but VDR-targeted therapy may be of great importance in this respect.
Collapse
Affiliation(s)
| | | | | | - Mohammed Mohammed Shamseya
- Department of Clinical and Experimental Internal Medicine, Medical Research Institute, Alexandria University, Alexandria, Egypt
| |
Collapse
|
|
37
|
Abstract
Ageing is the gradual decline in biological function both at the cellular and organismal level. One of the key characteristics of cellular ageing is the accumulation of damaged proteins and organelles which, in turn, can cause cellular toxicity and death. Autophagy is an evolutionarily conserved process that is responsible for the sequestration of damaged or surplus cytoplasmic components which are then delivered to the lysosome for degradation. This house-keeping mechanism is essential to maintain cellular homeostasis and survival, particularly during stress. A decline or loss of sensitivity/responsiveness of autophagy is intimately linked with an accelerated rate of ageing as well as many age-related diseases including neurodegeneration, cancer and metabolic disease where damage accumulation exceeds damage removal. This chapter summarises current knowledge regarding the relationship between autophagy and ageing and outlines some strategies that can be implemented to promote the anti-ageing effects of autophagy to improve human health and lifespan.
Collapse
Affiliation(s)
- Charlotte J Pattison
- Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK
| | | |
Collapse
|
|
38
|
Fakhimahmadi A, Nazmi F, Rahmati M, Bonab NM, Hashemi M, Moosavi MA. Nucleostemin silencing induces differentiation and potentiates all-trans-retinoic acid effects in human acute promyelocytic leukemia NB4 cells via autophagy. Leuk Res 2017; 63:15-21. [PMID: 29096331 DOI: 10.1016/j.leukres.2017.10.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 10/19/2017] [Accepted: 10/24/2017] [Indexed: 12/15/2022]
Abstract
Here, we report that targeting Nucleostemin (NS), a recently discovered stem cells-enriched gene, by a specific small interference RNA (siNS), decreases the rate of proliferation of acute promyelocytic leukemia (APL) NB4 cells and induces differentiation and autophagy. In addition, NS silencing promotes the effects of all-trans-retinoic acid (ATRA)-based differentiation therapy in NB4 cells. Autophagy inhibitors 3-methyladenine and bafilomycin block the effect of NS targeting on differentiation, indicating a new functional link between NS and autophagy as an important regulator of differentiation in NB4 cells. The capability of NS in modulating autophagy and differentiation, alone or in combination with ATRA, may help to broaden the range of treatment options available to treat leukemia.
Collapse
Affiliation(s)
- Aila Fakhimahmadi
- Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, P.O. Box:14965/161, Tehran, Iran; Islamic Azad University Tehran Medical Branch, Tehran, Iran
| | - Farinaz Nazmi
- Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, P.O. Box:14965/161, Tehran, Iran; Department of Biology, Faculty of Natural Science, University of Tabriz, P.O. Box 51666-16471, Tabriz, Iran
| | - Marveh Rahmati
- Cancer Biology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazila Moghtaran Bonab
- Department of Biology, Faculty of Natural Science, University of Tabriz, P.O. Box 51666-16471, Tabriz, Iran
| | | | - Mohammad Amin Moosavi
- Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, P.O. Box:14965/161, Tehran, Iran.
| |
Collapse
|
|
39
|
Vitamin D as a Novel Regulator of Tumor Metabolism: Insights on Potential Mechanisms and Implications for Anti-Cancer Therapy. Int J Mol Sci 2017; 18:ijms18102184. [PMID: 29048387 PMCID: PMC5666865 DOI: 10.3390/ijms18102184] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 10/14/2017] [Accepted: 10/16/2017] [Indexed: 02/07/2023] Open
Abstract
1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], the bioactive form of vitamin D, has been shown to possess significant anti-tumor potential. While most studies so far have focused on the ability of this molecule to influence the proliferation and apoptosis of cancer cells, more recent data indicate that 1,25(OH)₂D₃ also impacts energy utilization in tumor cells. In this article, we summarize and review the evidence that demonstrates the targeting of metabolic aberrations in cancers by 1,25(OH)₂D₃, and highlight potential mechanisms through which these effects may be executed. We shed light on the ability of this molecule to regulate metabolism-related tumor suppressors and oncogenes, energy- and nutrient-sensing pathways, as well as cell death and survival mechanisms such as autophagy.
Collapse
|
|
40
|
Dembitz V, Lalic H, Visnjic D. 5-Aminoimidazole-4-carboxamide ribonucleoside-induced autophagy flux during differentiation of monocytic leukemia cells. Cell Death Discov 2017; 3:17066. [PMID: 28975042 PMCID: PMC5624282 DOI: 10.1038/cddiscovery.2017.66] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 07/29/2017] [Accepted: 08/18/2017] [Indexed: 12/30/2022] Open
Abstract
Pharmacological modulators of AMP-dependent kinase (AMPK) have been suggested in treatment of cancer. The biguanide metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) have been reported to inhibit proliferation of solid tumors and hematological malignancies, but their role in differentiation is less explored. Our previous study demonstrated that AICAR alone induced AMPK-independent expression of differentiation markers in monocytic U937 leukemia cells, and no such effects were observed in response to metformin. The aim of this study was to determine the mechanism of AICAR-mediated effects and to test for the possible role of autophagy in differentiation of leukemia cells. The results showed that AICAR-mediated effects on the expression of differentiation markers were not mimicked by A769662, a more specific direct AMPK activator. Long-term incubation of U937 cells with AICAR and other differentiation agents, all-trans-retinoic acid (ATRA) and phorbol 12-myristate 13-acetate, increased the expression of the autophagy marker LC3B-II, and these effects were not observed in response to metformin. Western blot and immunofluorescence analyses of U937 cells treated with bafilomycin A1 or transfected with mRFP-GFP-LC3 proved that the increase in the expression of LC3B-II was due to an increase in autophagy flux, and not to a decrease in lysosomal degradation. 3-Methyladenine inhibited the expression of differentiation markers in response to all inducers, but had stimulatory effects on autophagy flux at dose that effectively inhibited the production of phosphatidylinositol 3-phosphate. The small inhibitory RNA-mediated down-modulation of Beclin 1 and hVPS34 had no effects on AICAR and ATRA-mediated increase in the expression of differentiation markers. These results show that AICAR and other differentiation agents induce autophagy flux in U937 cells and that the effects of AICAR and ATRA on the expression of differentiation markers do not depend on the normal levels of key proteins of the classical or canonical autophagy pathway.
Collapse
Affiliation(s)
- Vilma Dembitz
- Department of Physiology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, Zagreb 10 000, Croatia
| | - Hrvoje Lalic
- Department of Physiology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, Zagreb 10 000, Croatia
| | - Dora Visnjic
- Department of Physiology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, Zagreb 10 000, Croatia
| |
Collapse
|
|
41
|
Effect of 1,25(OH)2D3 on high glucose‑induced autophagy inhibition in peritoneum. Mol Med Rep 2017; 16:7080-7085. [PMID: 28901396 DOI: 10.3892/mmr.2017.7408] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 07/14/2017] [Indexed: 11/05/2022] Open
Abstract
High glucose (HG) may damage the structure and function of the peritoneal membrane, and is considered to be one of the most important factors that leads to peritoneal fibrosis and ultrafiltration failure. Recently, 1,25(OH)2D3, the active form of vitamin D, was demonstrated to protect against epithelial‑mesenchymal transition and fibrosis in peritoneal mesothelium and other organs. Accumulating evidence has suggested that autophagy serves a protective role in certain diseases by regulating cell survival. The present study examined whether 1,25(OH)2D3 has an effect on autophagy in peritoneal mesothelial cells. The protein level of Beclin, anti‑ubiquitin‑binding protein p62 (p62), microtubule‑associated proteins 1A/1B light chain 3B (LC3-II), mechanistic target of rapamycin (mTOR) and phosphorylated mTOR were evaluated by western blot analysis. Autophagosomes were detected under transmission electron microscopy. It was revealed that exposure to HG inhibited autophagy in peritoneal mesothelial cells. However, 1,25(OH)2D3 alleviated autophagy inhibition induced by HG in human peritoneal mesothelial cells, which activated expression of autophagy‑associated genes encoding Beclin‑1 and LC3-II downregulated the expression of p62 via mTOR signaling pathway. In a mouse model of HG‑treated peritoneal mesothelium, autophagy inhibition was observed in peritoneum, 1,25(OH)2D3 attenuated HG‑induced autophagy inhibition in peritoneal mesothelium via the mTOR signaling pathway. These findings suggested that 1,25(OH)2D3 may be a potential therapy for peritoneal injury.
Collapse
|
|
42
|
Dang J, Bian X, Ma X, Li J, Long F, Shan S, Yuan Q, Xin Q, Li Y, Gao F, Gong Y, Liu Q. ORMDL3 Facilitates the Survival of Splenic B Cells via an ATF6α-Endoplasmic Reticulum Stress-Beclin1 Autophagy Regulatory Pathway. THE JOURNAL OF IMMUNOLOGY 2017; 199:1647-1659. [PMID: 28747345 DOI: 10.4049/jimmunol.1602124] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 06/21/2017] [Indexed: 01/25/2023]
Abstract
The genetic association of orosomucoid-like 3 (ORMDL3) with an array of immunoinflammatory disorders has been recently unraveled in multiple ethnic groups, and functional exploration has received attention of the particular relevance of this gene in endoplasmic reticulum stress, lipid metabolism, and inflammatory response. In this study, we demonstrated the upregulation of ORMDL3 in both patients with systemic lupus erythematosus and lupus mice compared with controls. By establishing ORMDL3 knockout mice (Ormdl3-/-), we showed that silencing Ormdl3 in vivo significantly decreased the proportions of mature B lymphocytes and transitional 2B cells in spleen and B1a cells from abdominal cavity perfusion fluid, the secretion of IgG and IgM, and the expression of Baff. Additionally, knockdown of Ormdl3 augmented the apoptosis of total splenic cells and splenic CD19+ B cells but did not affect B cell proliferation and cell cycle. Subsequently, we in vitro and in vivo demonstrated that ORMDL3 potentially mediates the autophagy via the ATF 6-Beclin1 autophagy pathway, and it facilitates the survival of splenic B cells via promoting autophagy and suppressing apoptosis. Taken together, we uncovered a role of ORMDL3 in fine-tuning B cell development and survival, besides highlighting a potential mechanism by which ORMDL3 regulates autophagy via ATF6 pathway.
Collapse
Affiliation(s)
- Jie Dang
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics and Cell Biology, Ningxia Medical University, Yinchuan, Ningxia 750004, China; and.,Key Laboratory for Fertility Preservation and Maintenance of the Ministry of Education, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Xianli Bian
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Xiaochun Ma
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Jiangxia Li
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Feng Long
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Shan Shan
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Qianqian Yuan
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Qian Xin
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Yan Li
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Fei Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Yaoqin Gong
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Qiji Liu
- Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; .,Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China
| |
Collapse
|
|
43
|
Moukayed M, Grant WB. The roles of UVB and vitamin D in reducing risk of cancer incidence and mortality: A review of the epidemiology, clinical trials, and mechanisms. Rev Endocr Metab Disord 2017; 18:167-182. [PMID: 28213657 DOI: 10.1007/s11154-017-9415-2] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Global cancer incidence and mortality rates are high and increasing. Thus, it is imperative to find novel solutions to preventing cancer incidence and treating it at an affordable yet efficacious manner. The solar UVB-vitamin D-cancer hypothesis was first proposed in 1980 based on a geographical ecological study. Since then, numerous ecological and observational studies as well as studies of mechanisms have provided support for the hypothesis. However, observational studies have not provided consistent support, in part due to using a single blood draw from any season to use for serum 25-hydroxyvitamin D [25(OH)D] concentration in prospective studies with long follow-up times. Case-controls studies, in which blood is drawn near time of diagnosis, and prospective studies in which blood is drawn in the sunnier half of the year, are more likely to find significant inverse relations between 25(OH)D and cancer incidence. Three vitamin D plus calcium clinical trials have found significant reduction in all-cancer incidence. This paper reviews the evidence for vitamin D in reducing incidence of and increasing survival from breast, colorectal, lung, ovarian, pancreatic, and prostate cancer. The epidemiological evidence provides strong support for all of these types of cancer except for non-aggressive prostate cancer. Studies of the cellular mechanisms of vitamin D action in different cancer cell types, strongly indicate that vitamin D can exert protective and anti-tumorigenic activities that would retard cellular transformation, hyperplasia and cancer progression. Based on the scientific evidence reviewed in this paper, individuals and health providers can consider increasing 25(OH)D concentrations through sensible sun exposure and/or vitamin D supplementation to reduce risk of and, in conjunction with standard care, treat cancer. Public health acceptance of vitamin D for cancer prevention and treatment requires stronger support from vitamin D clinical trials.
Collapse
Affiliation(s)
- Meis Moukayed
- School of Arts and Sciences, American University in Dubai, P.O. Box 28282, Dubai, United Arab Emirates
| | - William B Grant
- Sunlight, Nutrition, and Health Research Center, P.O. Box 641603, San Francisco, CA, 94164-1603, USA.
| |
Collapse
|
|
44
|
Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1-dependent manner. Blood 2017; 129:2782-2792. [PMID: 28381396 DOI: 10.1182/blood-2016-10-745034] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 03/16/2017] [Indexed: 12/13/2022] Open
Abstract
AML1-ETO (AE), a fusion oncoprotein generated by t(8;21), can trigger acute myeloid leukemia (AML) in collaboration with mutations including c-Kit, ASXL1/2, FLT3, N-RAS, and K-RAS. Caspase-3, a key executor among its family, plays multiple roles in cellular processes, including hematopoietic development and leukemia progression. Caspase-3 was revealed to directly cleave AE in vitro, suggesting that AE may accumulate in a Caspase-3-compromised background and thereby accelerate leukemogenesis. Therefore, we developed a Caspase-3 knockout genetic mouse model of AML and found that loss of Caspase-3 actually delayed AML1-ETO9a (AE9a)-driven leukemogenesis, indicating that Caspase-3 may play distinct roles in the initiation and/or progression of AML. We report here that loss of Caspase-3 triggers a conserved, adaptive mechanism, namely autophagy (or macroautophagy), which acts to limit AE9a-driven leukemia. Furthermore, we identify ULK1 as a novel substrate of Caspase-3 and show that upregulation of ULK1 drives autophagy initiation in leukemia cells and that inhibition of ULK1 can rescue the phenotype induced by Caspase-3 deletion in vitro and in vivo. Collectively, these data highlight Caspase-3 as an important regulator of autophagy in AML and demonstrate that the balance and selectivity between its substrates can dictate the pace of disease.
Collapse
|
|
45
|
Song JH, Park E, Kim MS, Cho KM, Park SH, Lee A, Song J, Kim HJ, Koh JT, Kim TS. l-Asparaginase-mediated downregulation of c-Myc promotes 1,25(OH) 2 D 3 -induced myeloid differentiation in acute myeloid leukemia cells. Int J Cancer 2017; 140:2364-2374. [PMID: 28224619 DOI: 10.1002/ijc.30662] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 02/06/2017] [Accepted: 02/08/2017] [Indexed: 01/29/2023]
Abstract
Treatment of acute myeloid leukemia (AML) largely depends on chemotherapy, but current regimens have been unsatisfactory for long-term remission. Although differentiation induction therapy utilizing 1,25(OH)2 D3 (VD3) has shown great promise for the improvement of AML treatment efficacy, severe side effects caused by its supraphysiological dose limit its clinical application. Here we investigated the combinatorial effect of l-asparaginase (ASNase)-mediated amino acid depletion and the latent alternation of VD3 activity on the induction of myeloid differentiation. ASNase treatment enhanced VD3-driven phenotypic and functional differentiation of three-different AML cell lines into monocyte/macrophages, along with c-Myc downregulation. Using gene silencing with shRNA and a chemical blocker, we found that reduced c-Myc is a critical factor for improving VD3 efficacy. c-Myc-dependent inhibition of mTORC1 signaling and induction of autophagy were involved in the enhanced AML cell differentiation. In addition, in a postculture of AML cells after each treatment, ASNase supports the antileukemic effect of VD3 by inhibiting cell growth and inducing apoptosis. Finally, we confirmed that the administration of ASNase significantly improved VD3 efficacy in the prolongation of survival time in mice bearing tumor xenograft. Our results are the first to demonstrate the extended application of ASNase, which is currently used for acute lymphoid leukemia, in VD3-mediated differentiation induction therapy for AML, and suggest that this drug combination may be a promising novel strategy for curing AML.
Collapse
Affiliation(s)
- Ju Han Song
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Eunchong Park
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Myun Soo Kim
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Kyung-Min Cho
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Su-Ho Park
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Arim Lee
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Jiseon Song
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Hyeoung-Joon Kim
- Department of Hematology, Chonnam National University Hwasun Hospital, Hwasun, 58128, Republic of Korea
| | - Jeong-Tae Koh
- Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Tae Sung Kim
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| |
Collapse
|
|
46
|
Sinha RA, Singh BK, Yen PM. Reciprocal Crosstalk Between Autophagic and Endocrine Signaling in Metabolic Homeostasis. Endocr Rev 2017; 38:69-102. [PMID: 27901588 DOI: 10.1210/er.2016-1103] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 11/28/2016] [Indexed: 12/19/2022]
Abstract
Autophagy is a cellular quality control and energy-providing process that is under strict control by intra- and extracellular stimuli. Recently, there has been an exponential increase in autophagy research and its implications for mammalian physiology. Autophagy deregulation is now being implicated in many human diseases, and its modulation has shown promising results in several preclinical studies. However, despite the initial discovery of autophagy as a hormone-regulated process by De Duve in the early 1960s, endocrine regulation of autophagy still remains poorly understood. In this review, we provide a critical summary of our present understanding of the basic mechanism of autophagy, its regulation by endocrine hormones, and its contribution to endocrine and metabolic homeostasis under physiological and pathological settings. Understanding the cross-regulation of hormones and autophagy on endocrine cell signaling and function will provide new insight into mammalian physiology as well as promote the development of new therapeutic strategies involving modulation of autophagy in endocrine and metabolic disorders.
Collapse
Affiliation(s)
- Rohit A Sinha
- Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School Singapore, Singapore 169016
| | - Brijesh K Singh
- Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School Singapore, Singapore 169016
| | - Paul M Yen
- Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School Singapore, Singapore 169016
| |
Collapse
|
|
47
|
Tian G, Liang X, Chen D, Mao X, Yu J, Zheng P, He J, Huang Z, Yu B. Vitamin D3 supplementation alleviates rotavirus infection in pigs and IPEC-J2 cells via regulating the autophagy signaling pathway. J Steroid Biochem Mol Biol 2016; 163:157-63. [PMID: 27174720 DOI: 10.1016/j.jsbmb.2016.05.004] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 04/06/2016] [Accepted: 05/03/2016] [Indexed: 11/23/2022]
Abstract
Vitamin D had an anti-infection effect and benefited to the intestinal health. Autophagy signaling pathway was regulated by vitamin D3 to inhibit the infection of human immunodeficiency virus type-1. Rotavirus (RV) was a major cause of the severe diarrheal disease in young children and young animals. Although evidence suggested that vitamin D3 attenuates the negative effects of RV infection via the retinoic acid-inducible gene I signaling pathway, little is known of its antiviral effect whether through the regulation of autophagy. The present study was performed to investigate whether vitamin D3 alleviates RV infection in pig and porcine small intestinal epithelial cell line (IPEC-J2) models via regulating the autophagy signaling pathway. RV administration increased the Beclin 1 mRNA abundance in porcine jejunum and ileum. 5000 IU/kg dietary vitamin D3 supplementation greatly up-regulated LC3-II/LC3-I ratios and PR-39 mRNA expression under the condition of RV challenged. The viability of IPEC-J2 was significantly inhibited by RV infection. Incubation with 25-hydroxyvitamin D3 significantly decreased the concentrations of RV antigen and non-structural protein 4 (NSP4), and up-regulated the mRNA expression of Beclin 1 and PR-39 in the RV-infected IPEC-J2 cells. And then, based on the 25-hydroxyvitamin D3 treatment and RV infection, LC3-II mRNA expression in cells was inhibited by an autophagy inhibitor 3-methyladenine (3-MA). Bafilomycin A1 (Baf A1, a class of inhibitors of membrane ATPases, inhibits maturation of autophagic vacuoles) treatment numerically enhanced the LC3-II mRNA abundance, but had no effect on NSP4 concentration. Furthermore, 25-hydroxyvitamin D3 decreased the p62 mRNA expression and increased porcine cathelicidins (PMAP23, PG1-5 and PR-39) mRNA expression in the RV-infected cells. Taken together, these results indicated that vitamin D3 attenuates RV infection through regulating autophagic maturation and porcine cathelicidin genes expression.
Collapse
Affiliation(s)
- Gang Tian
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, Sichuan 625014, China
| | - Xiaofang Liang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, Sichuan 625014, China
| | - Daiwen Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, Sichuan 625014, China
| | - Xiangbing Mao
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, Sichuan 625014, China
| | - Jie Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, Sichuan 625014, China
| | - Ping Zheng
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, Sichuan 625014, China
| | - Jun He
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, Sichuan 625014, China
| | - Zhiqing Huang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, Sichuan 625014, China
| | - Bing Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, Sichuan 625014, China.
| |
Collapse
|
|
48
|
Fernandes Â, Azevedo MM, Pereira O, Sampaio-Marques B, Paiva A, Correia-Neves M, Castro I, Ludovico P. Proteolytic systems and AMP-activated protein kinase are critical targets of acute myeloid leukemia therapeutic approaches. Oncotarget 2016; 6:31428-40. [PMID: 25537507 PMCID: PMC4741616 DOI: 10.18632/oncotarget.2947] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 12/09/2014] [Indexed: 12/19/2022] Open
Abstract
The therapeutic strategies against acute myeloid leukemia (AML) have hardly been modified over four decades. Although resulting in a favorable outcome in young patients, older individuals, the most affected population, do not respond adequately to therapy. Intriguingly, the mechanisms responsible for AML cells chemoresistance/susceptibility are still elusive. Mounting evidence has shed light on the relevance of proteolytic systems (autophagy and ubiquitin-proteasome system, UPS), as well as the AMPK pathway, in AML biology and treatment, but their exact role is still controversial. Herein, two AML cell lines (HL-60 and KG-1) were exposed to conventional chemotherapeutic agents (cytarabine and/or doxorubicin) to assess the relevance of autophagy and UPS on AML cells’ response to antileukemia drugs. Our results clearly showed that the antileukemia agents target both proteolytic systems and the AMPK pathway. Doxorubicin enhanced UPS activity while drugs’ combination blocked autophagy specifically on HL-60 cells. In contrast, KG-1 cells responded in a more subtle manner to the drugs tested consistent with the higher UPS activity of these cells. In addition, the data demonstrates that autophagy may play a protective role depending on AML subtype. Specific modulators of autophagy and UPS are, therefore, promising targets for combining with standard therapeutic interventions in some AML subtypes.
Collapse
Affiliation(s)
- Ângela Fernandes
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Maria M Azevedo
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Olga Pereira
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Belém Sampaio-Marques
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Artur Paiva
- Blood and Transplantation Center of Coimbra, Portuguese Institute of Blood and Transplantation, Coimbra, Portugal
| | - Margarida Correia-Neves
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Isabel Castro
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Paula Ludovico
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| |
Collapse
|
|
49
|
Cao Y, Fang Y, Cai J, Li X, Xu F, Yuan N, Zhang S, Wang J. ROS functions as an upstream trigger for autophagy to drive hematopoietic stem cell differentiation. ACTA ACUST UNITED AC 2016; 21:613-618. [PMID: 27077779 DOI: 10.1080/10245332.2016.1165446] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND AND OBJECTIVES We have recently described a mechanistic action of autophagy on hematopoiesis in which autophagy sustains hematopoietic stem cell multilineage differentiation by direct targeting of intracellular Notch. However, the upstream signal that triggers autophagy to degrade Notch during hematopoiesis remains elusive. METHODS Conditional autophagy-essential gene Atg7 knockout mouse model is used for identifying signals regulating autophagy in the promotion of hematopoiesis. RESULTS We find here that generation of reactive oxygen species (ROS) is progressively increased during hematopoietic stem cell differentiation, and inhibition of ROS production was found to attenuate the differentiation of hematopoietic stem cells. In hematopoietic stem and progenitor cells (HSPCs) of wild-type mice, inhibition of ROS production downregulated autophagy activity but upregulated intracellular Notch and its downstream effectors. In contrast, in the HSPCs of autophagy fully defective mice, ROS inhibition did not alter myeloid differentiation, and hematopoietic stem cell differentiation to multi-lineages no longer responded to ROS inhibition. DISCUSSION The ROS-regulating hematopoiesis is mitochondrial origin, and this action depends on intact autophagy machinery capable of degrading intracellular Notch. CONCLUSION ROS functions as an upstream signal in the autophagic promotion of hematopoietic stem cell differentiation.
Collapse
Affiliation(s)
- Yan Cao
- a Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology , Soochow University School of Medicine , Suzhou , China
| | - Yixuan Fang
- a Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology , Soochow University School of Medicine , Suzhou , China
| | - Jinyang Cai
- a Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology , Soochow University School of Medicine , Suzhou , China
| | - Xin Li
- a Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology , Soochow University School of Medicine , Suzhou , China
| | - Fei Xu
- a Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology , Soochow University School of Medicine , Suzhou , China
| | - Na Yuan
- a Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology , Soochow University School of Medicine , Suzhou , China
| | - Suping Zhang
- a Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology , Soochow University School of Medicine , Suzhou , China
| | - Jianrong Wang
- a Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology , Soochow University School of Medicine , Suzhou , China
| |
Collapse
|
|
50
|
Gomez-Puerto MC, Folkerts H, Wierenga ATJ, Schepers K, Schuringa JJ, Coffer PJ, Vellenga E. Autophagy Proteins ATG5 and ATG7 Are Essential for the Maintenance of Human CD34(+) Hematopoietic Stem-Progenitor Cells. Stem Cells 2016; 34:1651-63. [PMID: 26930546 DOI: 10.1002/stem.2347] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 01/08/2016] [Indexed: 01/07/2023]
Abstract
Autophagy is a highly regulated catabolic process that involves sequestration and lysosomal degradation of cytosolic components such as damaged organelles and misfolded proteins. While autophagy can be considered to be a general cellular housekeeping process, it has become clear that it may also play cell type-dependent functional roles. In this study, we analyzed the functional importance of autophagy in human hematopoietic stem/progenitor cells (HSPCs), and how this is regulated during differentiation. Western blot-based analysis of LC3-II and p62 levels, as well as flow cytometry-based autophagic vesicle quantification, demonstrated that umbilical cord blood-derived CD34(+) /CD38(-) immature hematopoietic progenitors show a higher autophagic flux than CD34(+) /CD38(+) progenitors and more differentiated myeloid and erythroid cells. This high autophagic flux was critical for maintaining stem and progenitor function since knockdown of autophagy genes ATG5 or ATG7 resulted in reduced HSPC frequencies in vitro as well as in vivo. The reduction in HSPCs was not due to impaired differentiation, but at least in part due to reduced cell cycle progression and increased apoptosis. This is accompanied by increased expression of p53, proapoptotic genes BAX and PUMA, and the cell cycle inhibitor p21, as well as increased levels of cleaved caspase-3 and reactive oxygen species. Taken together, our data demonstrate that autophagy is an important regulatory mechanism for human HSCs and their progeny, reducing cellular stress and promoting survival. Stem Cells 2016;34:1651-1663.
Collapse
Affiliation(s)
- Maria Catalina Gomez-Puerto
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.,Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Hendrik Folkerts
- Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University Groningen, Groningen, The Netherlands
| | - Albertus T J Wierenga
- Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University Groningen, Groningen, The Netherlands
| | - Koen Schepers
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jan Jacob Schuringa
- Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University Groningen, Groningen, The Netherlands
| | - Paul J Coffer
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.,Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Edo Vellenga
- Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University Groningen, Groningen, The Netherlands
| |
Collapse
|