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Guo Y, Li J, Liu X, Ding H, Zhang W. Potential therapeutic targets for ischemic stroke in pre-clinical studies: Epigenetic-modifying enzymes DNMT/TET and HAT/HDAC. Front Pharmacol 2025; 16:1571276. [PMID: 40356977 PMCID: PMC12066669 DOI: 10.3389/fphar.2025.1571276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 04/15/2025] [Indexed: 05/15/2025] Open
Abstract
Ischemic stroke (IS) remains a leading cause of mortality and disability worldwide, driven by genetic predispositions and environmental interactions, with epigenetics playing a pivotal role in mediating these processes. Specific modifying enzymes that regulate epigenetic changes have emerged as promising targets for IS treatment. DNA methyltransferases (DNMTs), ten-eleven translocation (TET) dioxygenases, histone acetyltransferases (HATs), and histone deacetylases (HDACs) are central to epigenetic regulation. These enzymes maintain a dynamic balance between DNA methylation/demethylation and histone acetylation/deacetylation, which critically influences gene expression and neuronal survival in IS. This review is based on both in vivo and in vitro experimental studies, exploring the roles of DNMT/TET and HAT/HDAC in IS, evaluating their potential as therapeutic targets, and discussing the use of natural compounds as modulators of these enzymes to develop novel treatment strategies.
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Affiliation(s)
- Yurou Guo
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Jing Li
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Xiaodan Liu
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
- Key Laboratory of Hunan Provincial for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Changsha, China
| | - Huang Ding
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
- Key Laboratory of Hunan Provincial for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Changsha, China
| | - Wei Zhang
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
- Key Laboratory of Hunan Provincial for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Changsha, China
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Wang X, Harty KR, Wan TC, Qu Z, Smith BC, Lough JW, Auchampach JA. Mitigation of Injury from Myocardial Infarction by Pentamidine, an Inhibitor of the Acetyltransferase Tip60. Cardiovasc Drugs Ther 2025:10.1007/s10557-025-07696-z. [PMID: 40202550 DOI: 10.1007/s10557-025-07696-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/31/2025] [Indexed: 04/10/2025]
Abstract
PURPOSE There is an urgent unmet need for new pharmacologic approaches that promote re-muscularization and repair following myocardial infarction (MI). We previously reported that genetic depletion of the acetyltransferase Tip60 after MI in a mouse model activates the CM cell-cycle, reduces scarring, and restores cardiac function, and that these beneficial effects are mimicked by the Tip60-selective inhibitor TH1834. Here, we investigated whether the FDA-approved anti-microbial agent pentamidine, a Tip60 inhibitor from which TH1834 is derived, also protects from the damaging effects of MI. METHODS Adult (10-14 weeks old) C57Bl/6 mice were subjected to permanent left coronary artery ligation to induce MI. Subsequently, echocardiography, electrocardiography, cardiac staining, and molecular analyses were performed to monitor the effects of treatment with pentamidine on cardiac injury and function. RESULTS We report that transient systemic administration of pentamidine on days 3-16 post-MI at a daily dose of 3 mg/kg efficiently improved cardiac function for up to ten months. This was accompanied by improved survival, diminished scarring, and increased activation of cell-cycle markers in CMs located in the infarct border zone in the absence of hypertrophy. Histological assessments suggested that post-MI treatment with pentamidine reduced site-specific acetylation of the minor histone variant H2A.Z at lysines K4 and K7 in CMs, indicative of the dedifferentiation process which must occur prior to CM proliferation. Treating mice with pentamidine post-MI produced no prominent electrophysiological changes. CONCLUSIONS These findings support the translational potential of pentamidine for treatment of MI, and provide evidence that functional improvement is mediated, in part, by CM renewal due to inhibition of the acetyltransferase activity of Tip60.
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Affiliation(s)
- Xinrui Wang
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Katherine R Harty
- Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Tina C Wan
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Zhuocheng Qu
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Brian C Smith
- Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - John W Lough
- Department of Cell Biology Neurobiology & Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
| | - John A Auchampach
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
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Li Z, Lin K, Wang Y, Mao J, Yin Y, Li Z, Wang F, Zeng X, Li Q, Wang X, Li Z, Miao R, Lin C, Mao C. Garcinol promotes wound healing in diabetic mice by regulating inflammation and NLRP3 inflammasome-mediated pyroptosis via the PI3K/Akt/NF-κB pathway. Int Immunopharmacol 2025; 151:114352. [PMID: 40022821 DOI: 10.1016/j.intimp.2025.114352] [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: 01/08/2025] [Revised: 02/14/2025] [Accepted: 02/20/2025] [Indexed: 03/04/2025]
Abstract
Diabetic wounds, characterized by chronic inflammation and impaired angiogenesis, often lead to severe complications such as persistent infections and an elevated risk of amputation, significantly affecting a patient's quality of life. Garcinol, a polyisoprenylated benzophenone derived from the rind of Garcinia indica, exhibits potent anti-inflammatory, angiogenic, and antioxidant effects in various disease models. However, its potential to enhance diabetic wound healing remains unclear. In this research, we firstly used network pharmacology analysis to identify the potential targets of Garcinol in treating diabetic wounds. Cellular study results revealed that Garcinol therapy alleviated high glucose-induced cellular dysfunction and increased the angiogenic potential of human umbilical vein endothelial cells (HUVECs). Additionally, Garcinol substantially downregulated the levels of inflammatory cytokines secreted by macrophages through inhibiting the PI3K/Akt/NF-κB signaling pathway, which was further validated using the PI3K/Akt agonist 740 YP. Furthermore, inhibiting PI3K signaling also resulted in a marked reduction of NLRP3 inflammasome-mediated pyroptosis in macrophages compared to control. In vivo study using a full-thickness diabetic wound model confirmed that Garcinol treatment promoted diabetic wound healing by improving angiogenesis, inhibiting inflammation and pyroptosis, whereas the addition of 740 YP reduced the beneficial effects of Garcinol. Overall, our findings suggested that Garcinol enhanced diabetic wound healing via its anti-inflammatory ability, suppression of pyroptosis, and enhancement of angiogenesis. These results highlight the potential of Garcinol as a therapeutic agent for diabetic wounds.
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Affiliation(s)
- Zihao Li
- Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Department of Burn and Wound Healing Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Kai Lin
- Department of Burn and Wound Healing Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Yilong Wang
- Laboratory Animal Centre, Wenzhou Medical University, Wenzhou 325000, China
| | - Junnan Mao
- Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Department of Burn and Wound Healing Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Yihu Yin
- Department of Burn and Wound Healing Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Zi Li
- Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Fulin Wang
- Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Xiangtao Zeng
- Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Department of Burn and Wound Healing Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Qiubo Li
- Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Department of Burn and Wound Healing Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Xuan Wang
- Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Zhi Li
- Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Ronghui Miao
- Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Cai Lin
- Department of Burn and Wound Healing Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
| | - Cong Mao
- Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.
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Wu X, Zhang X, Tang S, Wang Y. The important role of the histone acetyltransferases p300/CBP in cancer and the promising anticancer effects of p300/CBP inhibitors. Cell Biol Toxicol 2025; 41:32. [PMID: 39825161 PMCID: PMC11742294 DOI: 10.1007/s10565-024-09984-0] [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: 08/13/2024] [Accepted: 12/21/2024] [Indexed: 01/20/2025]
Abstract
Histone acetyltransferases p300 (E1A-associated protein p300) and CBP (CREB binding protein), collectively known as p300/CBP due to shared sequence and functional synergy, catalyze histone H3K27 acetylation and consequently induce gene transcription. p300/CBP over-expression or over-activity activates the transcription of oncogenes, leading to cancer cell growth, resistance to apoptosis, tumor initiation and development. The discovery of small molecule inhibitors targeting p300/CBP histone acetyltransferase activity, bromodomains, dual inhibitors of p300/CBP and BRD4 bromodomains, as well as proteolysis-targeted-chimaera p300/CBP protein degraders, marks significant progress in cancer therapeutics. These inhibitors and degraders induce histone H3K27 deacetylation, reduce oncogene expression and cancer cell proliferation, promote cancer cell death, and decrease tumor progression in mice. Furthermore, p300/CBP inhibitors and protein degraders have been demonstrated to exert synergy when in combination with conventional radiotherapy, chemotherapy and BRD4 inhibitors in vitro as well as in mice. Importantly, two p300/CBP bromodomain inhibitors, CCS1477 and FT-7051, as well as the dual p300/CBP and BRD4 bromodomain inhibitor NEO2734 have entered Phase I and IIa clinical trials in patients with advanced and refractory hematological malignancies or solid tumors. Taken together, the identification of p300/CBP as critical drivers of tumorigenesis and the development of p300/CBP inhibitors and proteolysis-targeted-chimaera protein degraders represent promising avenues for clinical translation of novel cancer therapeutics.
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Affiliation(s)
- Xin Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, 110004, Shenyang, Liaoning, China
| | - Xin Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, 110004, Shenyang, Liaoning, China
| | - Shaoshan Tang
- Department of Ultrasound, Shengjing Hospital of China Medical University, 110004, Shenyang, Liaoning, China.
| | - Yao Wang
- Department of Ultrasound, Shengjing Hospital of China Medical University, 110004, Shenyang, Liaoning, China.
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Jun JH, Cha H, Ko JY, Kim HS, Yoo KH, Park JH. Loss of Kat2b impairs intraflagellar transport and the Hedgehog signaling pathway in primary cilia. Sci Rep 2025; 15:2127. [PMID: 39820844 PMCID: PMC11739504 DOI: 10.1038/s41598-025-86292-5] [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: 08/14/2024] [Accepted: 01/09/2025] [Indexed: 01/19/2025] Open
Abstract
Primary cilia are sensory organelles that regulate various signaling pathways. When microtubules are compared to a highway, motor proteins carry and transport cargo proteins, which are tuned by post-translational modifications, such as acetylation. However, the role of acetylation in primary cilia regulation remains unclear. In this study, histone K (lysine) acetyltransferase 2 B (Kat2b) was identified as a novel regulator of primary cilia. Kat2b, which mainly regulates transcription as a p300/CBP associated factor, is localized to the cytosol, centrosome, and cilium basal body. In addition, basal Kat2b expression gradually increased during ciliogenesis. Kat2b regulates the rate of cilia assembly, particularly in the early stages, and loss of Kat2b reduces the recruitment of intraflagellar transport (IFT) components to the ciliary axoneme and impairs Hedgehog (Hh) signaling activation. In addition, Kat2b-knockout mice showed mild abnormalities and ciliary IFT defects in the kidneys. These results establish a link between acetylation regulated by Kat2b and its relevance to ciliary assembly and function.
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Affiliation(s)
- Jae Hee Jun
- Department of Biological Science, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Hwayeon Cha
- Department of Biological Science, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Je Yeong Ko
- Department of Biological Science, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Ho-Shik Kim
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Kyung Hyun Yoo
- Department of Biological Science, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
| | - Jong Hoon Park
- Department of Biological Science, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
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Patolsky RG, Laiolo J, Díaz-Pérez L, Luna Pizarro G, Mayol GF, Touz MC, Feliziani C, Rópolo AS. Analysis of the role of acetylation in Giardia lamblia and the giardicidal potential of garcinol. Front Microbiol 2025; 15:1513053. [PMID: 39831116 PMCID: PMC11738946 DOI: 10.3389/fmicb.2024.1513053] [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: 10/17/2024] [Accepted: 12/10/2024] [Indexed: 01/22/2025] Open
Abstract
Introduction Post-translational modifications of proteins provide cellular physiology with a broad range of adaptability to the external environment flexibly and rapidly. In the case of the protozoan parasite Giardia lamblia, the study of these modifications has gained relevance in recent years, mainly focusing on methylation and deacetylation of proteins. This study investigates the significance of acetylation in this protozoan parasite. Methods This study explores the role of acetylation in G. lamblia through a combination of immunofluorescence assays, manipulation of acetyltransferase enzymes, and the use of garcinol, an acetylation inhibitor, during the growth phase. Results The acetylation of histone marks H3K9 and H3K27 occurs during growth and is followed by deacetylation during encystation. Transfections modifying acetyltransferase activity induced a latent cellular state, underscoring the importance of protein acetylation for parasite survival. Garcinol treatment during growth caused significant morphological changes, including plasma membrane blebbing and apoptotic-like bodies. Immunofluorescence revealed these bodies contained α-tubulin/acetylated α-tubulin and reactive oxygen species. Flow cytometry and Annexin V staining indicated early apoptosis within 24 hours of treatment. Additionally, garcinol led to the deacetylation of H3K9 and H3K27, with redistribution of tubulin and acetylated tubulin from microtubules to the cytosol. Significantly, garcinol prevented parasite recrudescence after treatment withdrawal. Discussion These results demonstrate that acetylation is essential for trophozoite survival and highlight the natural histone acetyltransferase inhibitor garcinol as a potential candidate for drug development against giardiasis, considering its giardicidal activity.
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Affiliation(s)
- Rocío G. Patolsky
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC – Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Jerónimo Laiolo
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC – Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
- Universidad Católica de Córdoba, Córdoba, Argentina
| | - Luciano Díaz-Pérez
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC – Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Gabriel Luna Pizarro
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC – Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Gonzalo F. Mayol
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC – Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - María C. Touz
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC – Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Constanza Feliziani
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC – Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Andrea S. Rópolo
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC – Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
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Guha S, Jagadeesan Y, Pandey MM, Mittal A, Chitkara D. Targeting the epigenome with advanced delivery strategies for epigenetic modulators. Bioeng Transl Med 2025; 10:e10710. [PMID: 39801754 PMCID: PMC11711227 DOI: 10.1002/btm2.10710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/17/2024] [Accepted: 07/23/2024] [Indexed: 01/16/2025] Open
Abstract
Epigenetics mechanisms play a significant role in human diseases by altering DNA methylation status, chromatin structure, and/or modifying histone proteins. By modulating the epigenetic status, the expression of genes can be regulated without any change in the DNA sequence itself. Epigenetic drugs exhibit promising therapeutic efficacy against several epigenetically originated diseases including several cancers, neurodegenerative diseases, metabolic disorders, cardiovascular disorders, and so forth. Currently, a considerable amount of research is focused on discovering new drug molecules to combat the existing research gap in epigenetic drug therapy. A novel and efficient delivery system can be established as a promising approach to overcome the drawbacks associated with the current epigenetic modulators. Therefore, formulating the existing epigenetic drugs with distinct encapsulation strategies in nanocarriers, including solid lipid nanoparticles, nanogels, bio-engineered nanocarriers, liposomes, surface modified nanoparticles, and polymer-drug conjugates have been examined for therapeutic efficacy. Nonetheless, several epigenetic modulators are untouched for their therapeutic potential through different delivery strategies. This review provides a comprehensive up to date discussion on the research findings of various epigenetics mechanism, epigenetic modulators, and delivery strategies utilized to improve their therapeutic outcome. Furthermore, this review also highlights the recently emerged CRISPR tool for epigenome editing.
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Affiliation(s)
- Sonia Guha
- Department of PharmacyBirla Institute of Technology and Science Pilani (BITS Pilani)JhunjhunuRajasthanIndia
| | - Yogeswaran Jagadeesan
- Department of PharmacyBirla Institute of Technology and Science Pilani (BITS Pilani)JhunjhunuRajasthanIndia
| | - Murali Monohar Pandey
- Department of PharmacyBirla Institute of Technology and Science Pilani (BITS Pilani)JhunjhunuRajasthanIndia
| | - Anupama Mittal
- Department of PharmacyBirla Institute of Technology and Science Pilani (BITS Pilani)JhunjhunuRajasthanIndia
| | - Deepak Chitkara
- Department of PharmacyBirla Institute of Technology and Science Pilani (BITS Pilani)JhunjhunuRajasthanIndia
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Ahmed IA, Zamakshshari NH, Mikail MA, Bello I, Hossain MS. Garcinia flavonoids for healthy aging: Anti-senescence mechanisms and cosmeceutical applications in skin care. Fitoterapia 2025; 180:106282. [PMID: 39489352 DOI: 10.1016/j.fitote.2024.106282] [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: 06/16/2024] [Revised: 10/28/2024] [Accepted: 10/30/2024] [Indexed: 11/05/2024]
Abstract
Cellular senescence, the irreversible arrest of cell division, is a hallmark of aging and a key contributor to age-related disorders. Targeting senescent cells represents a promising therapeutic approach to combat these ailments. This review explores the potential of Garcinia species, a genus rich in flavonoids with established antioxidant and anti-inflammatory properties, as a source of natural anti-senescence agents. We investigate the intricate connections between aging, cellular senescence, and oxidative stress, highlighting the detrimental effects of free radicals on cellular health. Furthermore, we analyze the diverse array of flavonoids identified within Garcinia and their established cellular mechanisms. We critically evaluate the emerging evidence for the anti-senescence potential of flavonoids in general and the limited research on Garcinia flavonoids in this context. By identifying existing knowledge gaps and paving the way for future research, this review underscores the exciting potential of Garcinia flavonoids as natural anti-senescence agents. These agents hold promise for not only promoting healthy aging but also for the development of cosmeceutical products that combat the visible signs of aging.
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Affiliation(s)
- Idris Adewale Ahmed
- Department of Biotechnology, Faculty of Applied Science, Lincoln University College, 47301 Petaling Jaya, Selangor, Malaysia; Mimia Sdn. Bhd., Selangor, Malaysia.
| | - Nor Hisam Zamakshshari
- Department of Chemistry, Faculty of Resource Science and Technology, University Malaysia Sarawak, 94300 Kota Samarahan, Sarawak, Malaysia.
| | | | - Ibrahim Bello
- Agricultural and Biosystems Engineering, North Dakota State University, Fargo, USA.
| | - Md Sanower Hossain
- Centre for Sustainability of Mineral and Resource Recovery Technology (Pusat SMaRRT), University Malaysia Pahang Al-Sultan Abdullah, Kuantan 26300, Malaysia.
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Li N, Gong Y, Zhu Y, Li B, Wang C, Wang Z, Wang J, Huang J, Bian J, Zhang Y. Exogenous acetate attenuates inflammatory responses through HIF-1α-dependent glycolysis regulation in macrophage. Cell Mol Life Sci 2024; 82:21. [PMID: 39725781 DOI: 10.1007/s00018-024-05521-8] [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] [Received: 07/28/2024] [Revised: 10/15/2024] [Accepted: 11/18/2024] [Indexed: 12/28/2024]
Abstract
Cytokine storm is a hallmark for acute systemic inflammatory disease like sepsis. Intrinsic microbiome-derived short-chain fatty acid (SCFAs) like acetate modulates immune cell function and metabolism has been well studied. However, it remains poorly investigated about the effects and the underlying mechanism of exogenous acetate in acute inflammation like sepsis. Here, we observed that serum acetate accumulates in patients undergoing abdominal gastrointestinal surgery and in septic mice. Short exposure to high-dose exogenous acetate protects mice from sepsis by inhibiting glycolysis in macrophages, both in vivo and in vitro. Hypoxia-inducible factor 1 subunit alpha (HIF-1α) stabilization or overexpression reverses the decreased glycolysis and pro-inflammatory cytokine production in macrophages and abrogates acetate's protective effect in septic mice. Meanwhile, we also found acetyl-CoA synthetase-2, but not GPR41 or GPR43, plays a key role in acetate's immunosuppressive effect. Acetate transiently increases acetyl-coenzyme A production, promoting histone acetylation and decreasing acetyl-transfer to NF-κB p65. These findings suggest that short exposure to mM-level acetate inhibits macrophage immune response linked to HIF-1α-dependent glycolysis. Taken together, we demonstrate short-term exposure of exogenous acetate could regulate inflammatory responses through attenuating HIF-1α-dependent glycolysis.
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Affiliation(s)
- Na Li
- Faculty of Anesthesiology, Changhai Hospital (First Affiliated Hospital of Naval Medical University), Naval Medical University, Shanghai, 200433, China
| | - Yi Gong
- Department of Respiratory Diseases and Critical Medicine, Quzhou Hospital Affiliated to Wenzhou Medical University, Quzhou, Zhejiang, 324000, China
- Department of Respiratory Diseases and Critical Medicine, Huashan Hospital Affiliated to Fudan University, Shanghai, 200040, China
| | - Yalin Zhu
- Faculty of Anesthesiology, Changhai Hospital (First Affiliated Hospital of Naval Medical University), Naval Medical University, Shanghai, 200433, China
- Department of Anesthesiology, Naval Hospital of Eastern Theater, Zhoushan, China
| | - Bo Li
- Faculty of Anesthesiology, Changhai Hospital (First Affiliated Hospital of Naval Medical University), Naval Medical University, Shanghai, 200433, China
| | - Changli Wang
- Faculty of Anesthesiology, Changhai Hospital (First Affiliated Hospital of Naval Medical University), Naval Medical University, Shanghai, 200433, China
| | - Zhefan Wang
- Senior High School of Yangpu District, Shanghai, 200433, China
| | - Jun Wang
- Faculty of Anesthesiology, Changhai Hospital (First Affiliated Hospital of Naval Medical University), Naval Medical University, Shanghai, 200433, China
| | - Jie Huang
- Faculty of Anesthesiology, Changhai Hospital (First Affiliated Hospital of Naval Medical University), Naval Medical University, Shanghai, 200433, China
| | - Jinjun Bian
- Faculty of Anesthesiology, Changhai Hospital (First Affiliated Hospital of Naval Medical University), Naval Medical University, Shanghai, 200433, China.
| | - Yan Zhang
- Faculty of Anesthesiology, Changhai Hospital (First Affiliated Hospital of Naval Medical University), Naval Medical University, Shanghai, 200433, China.
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Dansu DK, Selcen I, Sauma S, Prentice E, Huang D, Li M, Moyon S, Casaccia P. Histone H4 acetylation differentially modulates proliferation in adult oligodendrocyte progenitors. J Cell Biol 2024; 223:e202308064. [PMID: 39133301 PMCID: PMC11318668 DOI: 10.1083/jcb.202308064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 06/18/2024] [Accepted: 07/29/2024] [Indexed: 08/13/2024] Open
Abstract
Adult oligodendrocyte progenitors (aOPCs) generate myelinating oligodendrocytes like neonatal progenitors (nOPCs), and they also display unique functional features. Here, using unbiased histone proteomics analysis and ChIP sequencing analysis of PDGFRα+ OPCs sorted from neonatal and adult Pdgfra-H2B-EGFP reporter mice, we identify the activating H4K8ac histone mark as enriched in the aOPCs. We detect increased occupancy of the H4K8ac activating mark at chromatin locations corresponding to genes related to the progenitor state (e.g., Hes5, Gpr17), metabolic processes (e.g., Txnip, Ptdgs), and myelin components (e.g., Cnp, Mog). aOPCs showed higher levels of transcripts related to lipid metabolism and myelin, and lower levels of transcripts related to cell cycle and proliferation compared with nOPCs. In addition, pharmacological inhibition of histone acetylation decreased the expression of the H4K8ac target genes in aOPCs and decreased their proliferation. Overall, this study identifies acetylation of the histone H4K8 as a regulator of the proliferative capacity of aOPCs.
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Affiliation(s)
- David K. Dansu
- Neuroscience Initiative, Advanced Science Research Center at the City University of New York, New York, NY, USA
- Graduate Program in Biochemistry, The Graduate Center of The City University of New York, New York, NY, USA
| | - Ipek Selcen
- Neuroscience Initiative, Advanced Science Research Center at the City University of New York, New York, NY, USA
- Graduate Program in Biochemistry, The Graduate Center of The City University of New York, New York, NY, USA
| | - Sami Sauma
- Neuroscience Initiative, Advanced Science Research Center at the City University of New York, New York, NY, USA
- Graduate Program in Biology, The Graduate Center of The City University of New York, New York, NY, USA
| | - Emily Prentice
- Neuroscience Initiative, Advanced Science Research Center at the City University of New York, New York, NY, USA
- Graduate Program in Biology, The Graduate Center of The City University of New York, New York, NY, USA
| | - Dennis Huang
- Neuroscience Initiative, Advanced Science Research Center at the City University of New York, New York, NY, USA
- Graduate Program in Biology, The Graduate Center of The City University of New York, New York, NY, USA
| | - Meng Li
- Norris Medical Library, University of Southern California, Los Angeles, CA, USA
| | - Sarah Moyon
- Neuroscience Initiative, Advanced Science Research Center at the City University of New York, New York, NY, USA
- Institute of NeuroPhysiopathology (INP) UMR7051, Aix-Marseille University, CNRS, Marseille, France
| | - Patrizia Casaccia
- Neuroscience Initiative, Advanced Science Research Center at the City University of New York, New York, NY, USA
- Graduate Program in Biochemistry, The Graduate Center of The City University of New York, New York, NY, USA
- Graduate Program in Biology, The Graduate Center of The City University of New York, New York, NY, USA
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11
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Pathikonda S, Amirmahani F, Mathew D, Muthukrishnan SD. Histone acetyltransferases as promising therapeutic targets in glioblastoma resistance. Cancer Lett 2024; 604:217269. [PMID: 39326554 DOI: 10.1016/j.canlet.2024.217269] [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: 06/17/2024] [Revised: 09/14/2024] [Accepted: 09/17/2024] [Indexed: 09/28/2024]
Abstract
Glioblastoma (GBM) is a fatal adult brain tumor with an extremely poor prognosis. GBM poses significant challenges for targeted therapies due to its intra- and inter-tumoral heterogeneity, a highly immunosuppressive microenvironment, diffuse infiltration into normal brain parenchyma, protection by the blood-brain barrier and acquisition of therapeutic resistance. Recent studies have implicated epigenetic modifiers as key players driving tumorigenesis, resistance, and progression of GBM. While the vast majority of GBM research on epigenetic modifiers thus far has focused predominantly on elucidating the functional roles and targeting of DNA methyltransferases and histone deacetylases, emerging evidence indicates that histone acetyltransferases (HATs) also play a key role in mediating plasticity and therapeutic resistance in GBM. Here, we will provide an overview of HATs, their dual roles and functions in cancer as both tumor suppressors and oncogenes and focus specifically on their implications in GBM resistance. We also discuss the technical challenges in developing selective HAT inhibitors and highlight their promise as potential anti-cancer therapeutics for treating intractable cancers such as GBM.
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Affiliation(s)
- Spoorthy Pathikonda
- Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
| | - Farzaneh Amirmahani
- Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
| | - Diya Mathew
- Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
| | - Sree Deepthi Muthukrishnan
- Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
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12
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Sun F, Ali NN, Londoño-Vásquez D, Simintiras CA, Qiao H, Ortega MS, Agca Y, Takahashi M, Rivera RM, Kelleher AM, Sutovsky P, Patterson AL, Balboula AZ. Increased DNA damage in full-grown oocytes is correlated with diminished autophagy activation. Nat Commun 2024; 15:9463. [PMID: 39487138 PMCID: PMC11530536 DOI: 10.1038/s41467-024-53559-w] [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] [Received: 08/17/2023] [Accepted: 10/14/2024] [Indexed: 11/04/2024] Open
Abstract
Unlike mild DNA damage exposure, DNA damage repair (DDR) is reported to be ineffective in full-grown mammalian oocytes exposed to moderate or severe DNA damage. The underlying mechanisms of this weakened DDR are unknown. Here, we show that moderate DNA damage in full-grown oocytes leads to aneuploidy. Our data reveal that DNA-damaged oocytes have an altered, closed, chromatin state, and suggest that the failure to repair damaged DNA could be due to the inability of DDR proteins to access damaged loci. Our data also demonstrate that, unlike somatic cells, mouse and porcine oocytes fail to activate autophagy in response to DNA double-strand break-inducing treatment, which we suggest may be the cause of the altered chromatin conformation and inefficient DDR. Importantly, autophagy activity is further reduced in maternally aged oocytes (which harbor severe DNA damage), and its induction is correlated with reduced DNA damage in maternally aged oocytes. Our findings provide evidence that reduced autophagy activation contributes to weakened DDR in oocytes, especially in those from aged females, offering new possibilities to improve assisted reproductive therapy in women with compromised oocyte quality.
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Affiliation(s)
- Fei Sun
- Division of Animal Sciences, University of Missouri, Columbia, MO, USA
| | - Nourhan Nashat Ali
- Division of Animal Sciences, University of Missouri, Columbia, MO, USA
- Department of Physiology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
| | | | - Constantine A Simintiras
- School of Animal Sciences, Agricultural Center, Louisiana State University, Baton Rouge, LA, USA
| | - Huanyu Qiao
- Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - M Sofia Ortega
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Yuksel Agca
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA
| | - Masashi Takahashi
- Research Faculty of Agriculture, Hokkaido University, Hokkaido, Japan
| | - Rocío M Rivera
- Division of Animal Sciences, University of Missouri, Columbia, MO, USA
| | - Andrew M Kelleher
- Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, MO, USA
| | - Peter Sutovsky
- Division of Animal Sciences, University of Missouri, Columbia, MO, USA
- Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, MO, USA
| | - Amanda L Patterson
- Division of Animal Sciences, University of Missouri, Columbia, MO, USA
- Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, MO, USA
| | - Ahmed Z Balboula
- Division of Animal Sciences, University of Missouri, Columbia, MO, USA.
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13
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Barraza SJ, Woll MG. Pre‐mRNA Splicing Modulation. METHODS AND PRINCIPLES IN MEDICINAL CHEMISTRY 2024:151-202. [DOI: 10.1002/9783527840458.ch7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Jia G, Liu J, Hou X, Jiang Y, Li X. Biological function and small molecule inhibitors of histone deacetylase 11. Eur J Med Chem 2024; 276:116634. [PMID: 38972077 DOI: 10.1016/j.ejmech.2024.116634] [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: 04/15/2024] [Revised: 06/16/2024] [Accepted: 06/25/2024] [Indexed: 07/09/2024]
Abstract
HDAC11, as a rising star in the histone deacetylase (HDAC) family, has attracted widespread interest in the biomedical field in recent years specially owing to its high defatty-acylase activity compared its innate deacetylase activity. Numerous studies have provided evidence indicating the crucial involvement of HDAC11 in cancers, immune responses, and metabolic processes. Several potent and selective HDAC11 inhibitors have been discovered and identified, which is crucial for exploring the function of HDAC11 and its potential therapeutic applications. Herein, we present a critical overview of the current advances in the biological function of HDAC11 and its inhibitors. We initially discuss the physiological functions of HDAC11 and its pathological roles in relevant diseases. Subsequently, our main focus centers on the design strategy and development process of HDAC11 inhibitors. Additionally, we address significant challenges and outline future directions in this field. This perspective may provide guidance for the further development of HDAC11 inhibitors and their prospects in disease treatment.
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Affiliation(s)
- Geng Jia
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Jinyu Liu
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Xinlu Hou
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Yuqi Jiang
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
| | - Xiaoyang Li
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
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15
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Lai R, Lin Z, Yang C, Hai L, Yang Z, Guo L, Nie R, Wu Y. Novel berberine derivatives as p300 histone acetyltransferase inhibitors in combination treatment for breast cancer. Eur J Med Chem 2024; 266:116116. [PMID: 38215590 DOI: 10.1016/j.ejmech.2023.116116] [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: 11/03/2023] [Revised: 12/30/2023] [Accepted: 12/30/2023] [Indexed: 01/14/2024]
Abstract
Adenoviral E1A binding protein p300 (EP300 or p300) and its similar paralog, cyclic-AMP response element binding protein (CBP), are important histone acetyltransferases (HAT) and transcriptional co-activators in epigenetics, participating in numerous cellular pathways including proliferation, differentiation and apoptosis. The overexpression or dysregulation of p300/CBP is closely related to oncology-relevant disease. The inhibition of p300 HAT has been found to be a potential drug target. Berberine has been reported to show anticancer activity and synergistic effect in combination with some of the clinical anticancer drugs via modulation of various pathways. Here, the present study sought to discover more chemotypes of berberine derivatives as p300 HAT inhibitors and to examine the combination of these novel analogues with doxorubicin for the treatment of breast cancer. A series of novel berberine derivatives with modifications of A/B/D rings of berberine have been designed, synthesized and screened. Compound 7b was found to exhibit inhibitory potency against p300 HAT with IC50 values of 1.51 μM. Western blotting proved that 7b decreased H3K27Ac and interfered with the expression of oncology-relevant protein in MCF-7 cells. Further bioactive evaluation showed that combination of compound 7b with doxorubicin could significantly inhibit tumor growth and invasion in vitro and in vivo.
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Affiliation(s)
- Ruizhi Lai
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Zhiqian Lin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Chunyan Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Li Hai
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China; Central Nervous System Drug Key Laboratory of Sichuan Province, Luzhou, 646100, China
| | - Zhongzhen Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Li Guo
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Ruifang Nie
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250000, China.
| | - Yong Wu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
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16
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Dansu DK, Sauma S, Huang D, Li M, Moyon S, Casaccia P. The epigenetic landscape of oligodendrocyte progenitors changes with time. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.06.579145. [PMID: 38501119 PMCID: PMC10946295 DOI: 10.1101/2024.02.06.579145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/20/2024]
Abstract
SUMMARY Dansu et al. identify distinct histone H4 modifications as potential mechanism underlying the functional differences between adult and neonatal progenitors. While H4K8ac favors the expression of differentiation genes, their expression is halted by H4K20me3. Adult oligodendrocyte progenitors (aOPCs) generate myelinating oligodendrocytes, like neonatal progenitors (nOPCs), but they also display unique functional features. Here, using RNA-sequencing, unbiased histone proteomics analysis and ChIP-sequencing, we define the transcripts and histone marks underlying the unique properties of aOPCs. We describe the lower proliferative capacity and higher levels of expression of oligodendrocyte specific genes in aOPCs compared to nOPCs, as well as the greater levels of H4 histone marks. We also report increased occupancy of the H4K8ac mark at chromatin locations corresponding to oligodendrocyte-specific transcription factors and lipid metabolism genes. Pharmacological inhibition of H4K8ac deposition reduces the levels of these transcripts in aOPCs, rendering their transcriptome more similar to nOPCs. The repressive H4K20me3 mark is also higher in aOPCs compared to nOPCs and pharmacological inhibition of its deposition results in increased levels of genes related to the mature oligodendrocyte state. Overall, this study identifies two histone marks which are important for the unique transcriptional and functional identity of aOPCs.
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17
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Routh S, Manickam V. Epigenetic alterations dictating the inflammation: A view through pancreatitis. Life Sci 2024; 338:122383. [PMID: 38158041 DOI: 10.1016/j.lfs.2023.122383] [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: 09/28/2023] [Revised: 12/16/2023] [Accepted: 12/20/2023] [Indexed: 01/03/2024]
Abstract
Pancreatitis is a severe inflammation in the pancreas and accounts for one of the leading gastrointestinal disorders worldwide, and presently pacing up with the morbidity and mortality rates. It has been noted that severe recurrences of acute pancreatitis lead to chronic inflammation and fibrosis of the pancreas which may further result to a long-term risk of pancreatic carcinogenesis which has a lower survival rate and worse prognosis. Several genetic and epigenetic mechanisms have been reported to orchestrate disease development. Intriguingly, concurrent epigenetic alterations can also control the genes responsible for the pathophysiology of several inflammatory pathways. Deciphering how epigenetic changes affect the inflammatory processes in pancreatitis and body's response to various therapeutic modalities may help to manage the condition more effectively. The current review will concentrate on several epigenetic changes in general and how specifically they are implicated in pancreatitis pathogenesis. Further, this review summarizes the involvement of inflammation in pancreatitis from an epigenetic perspective.
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Affiliation(s)
- Sreyoshi Routh
- School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
| | - Venkatraman Manickam
- School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India.
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18
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Hatakeyama D, Tanii H, Nishikawa E, Takahira M, Honjo T, Ebisuda N, Abe N, Shinohara Y, Mitomo S, Tsutsui A, Fujita T, Kuzuhara T. Anacardic Acid Derivatives Isolated from Fungal Species Tyromyces fissilis as New Histone Acetyltransferase Inhibitors. Biol Pharm Bull 2024; 47:2076-2082. [PMID: 39675962 DOI: 10.1248/bpb.b24-00112] [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] [Indexed: 12/17/2024]
Abstract
Anacardic acid (AA) was first detected in the shells of cashew nuts, Anacardium occidentale, and is known to possess inhibitory activity against acetyltransferases. Recently, several anacardic acid derivatives (AAds) were isolated from the wild fungus, Tyromyces fissilis, which has been reported as xanthine oxidase inhibitors. In the present study, we investigated whether nine AAds function as acetyltransferase inhibitors. Screening analyses were performed by incubating the enzyme protein (P300/CBP-associated factor; PCAF) and the substrate protein (histone H1) with radioisotope-marked acetyl-CoA, showing that two of the nine derivatives, namely, AAd7 and AAd11, inhibited the acetyltransferase activity of PCAF at concentrations of 50 and 100 µM, respectively. The inhibition intensities were similar to those of the original compound, AA, and the inhibitory effects of these derivatives increased in a concentration-dependent manner. Docking simulations suggested the possibility that AA, AAd7, and AAd11 might bind the same active pocket of PCAF. These results suggest that the AAds can be used as acetyltransferase inhibitors. In contrast, there were no significant differences in the molecular structure of AA and its derivatives; however, these small differences in the functional groups on the alkyl side chain on salicylic acid reduced the acetyltransferase inhibitor activity or newly produced proteolytic activity.
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Affiliation(s)
- Dai Hatakeyama
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University
| | - Hina Tanii
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University
| | - Erina Nishikawa
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University
| | - Mizuki Takahira
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University
| | - Tsugumi Honjo
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University
| | - Nao Ebisuda
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University
| | - Naoya Abe
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University
| | - Yasuo Shinohara
- Institute of Advanced Medical Sciences, Tokushima University
- Graduate School of Pharmaceutical Sciences, Tokushima University
| | - Shunsuke Mitomo
- Graduate School of Science and Technology, Department of Agriculture, Shinshu University
| | - Ayumi Tsutsui
- Graduate School of Science and Technology, Department of Agriculture, Shinshu University
| | - Tomoyuki Fujita
- Graduate School of Science and Technology, Department of Agriculture, Shinshu University
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19
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Gabbianelli R, Shahar E, de Simone G, Rucci C, Bordoni L, Feliziani G, Zhao F, Ferrati M, Maggi F, Spinozzi E, Mahajna J. Plant-Derived Epi-Nutraceuticals as Potential Broad-Spectrum Anti-Viral Agents. Nutrients 2023; 15:4719. [PMID: 38004113 PMCID: PMC10675658 DOI: 10.3390/nu15224719] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 10/29/2023] [Accepted: 10/31/2023] [Indexed: 11/26/2023] Open
Abstract
Although the COVID-19 pandemic appears to be diminishing, the emergence of SARS-CoV-2 variants represents a threat to humans due to their inherent transmissibility, immunological evasion, virulence, and invulnerability to existing therapies. The COVID-19 pandemic affected more than 500 million people and caused over 6 million deaths. Vaccines are essential, but in circumstances in which vaccination is not accessible or in individuals with compromised immune systems, drugs can provide additional protection. Targeting host signaling pathways is recommended due to their genomic stability and resistance barriers. Moreover, targeting host factors allows us to develop compounds that are effective against different viral variants as well as against newly emerging virus strains. In recent years, the globe has experienced climate change, which may contribute to the emergence and spread of infectious diseases through a variety of factors. Warmer temperatures and changing precipitation patterns can increase the geographic range of disease-carrying vectors, increasing the risk of diseases spreading to new areas. Climate change may also affect vector behavior, leading to a longer breeding season and more breeding sites for disease vectors. Climate change may also disrupt ecosystems, bringing humans closer to wildlife that transmits zoonotic diseases. All the above factors may accelerate the emergence of new viral epidemics. Plant-derived products, which have been used in traditional medicine for treating pathological conditions, offer structurally novel therapeutic compounds, including those with anti-viral activity. In addition, plant-derived bioactive substances might serve as the ideal basis for developing sustainable/efficient/cost-effective anti-viral alternatives. Interest in herbal antiviral products has increased. More than 50% of approved drugs originate from herbal sources. Plant-derived compounds offer diverse structures and bioactive molecules that are candidates for new drug development. Combining these therapies with conventional drugs could improve patient outcomes. Epigenetics modifications in the genome can affect gene expression without altering DNA sequences. Host cells can use epigenetic gene regulation as a mechanism to silence incoming viral DNA molecules, while viruses recruit cellular epitranscriptomic (covalent modifications of RNAs) modifiers to increase the translational efficiency and transcript stability of viral transcripts to enhance viral gene expression and replication. Moreover, viruses manipulate host cells' epigenetic machinery to ensure productive viral infections. Environmental factors, such as natural products, may influence epigenetic modifications. In this review, we explore the potential of plant-derived substances as epigenetic modifiers for broad-spectrum anti-viral activity, reviewing their modulation processes and anti-viral effects on DNA and RNA viruses, as well as addressing future research objectives in this rapidly emerging field.
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Affiliation(s)
- Rosita Gabbianelli
- Unit of Molecular Biology and Nutrigenomics, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy; (R.G.); (G.d.S.); (L.B.); (G.F.); (F.Z.)
| | - Ehud Shahar
- Department of Nutrition and Natural Products, Migal—Galilee Research Institute, Kiryat Shmona 11016, Israel;
- Department of Biotechnology, Tel-Hai College, Kiryat Shmona 1220800, Israel
| | - Gaia de Simone
- Unit of Molecular Biology and Nutrigenomics, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy; (R.G.); (G.d.S.); (L.B.); (G.F.); (F.Z.)
| | - Chiara Rucci
- Unit of Molecular Biology and Nutrigenomics, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy; (R.G.); (G.d.S.); (L.B.); (G.F.); (F.Z.)
| | - Laura Bordoni
- Unit of Molecular Biology and Nutrigenomics, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy; (R.G.); (G.d.S.); (L.B.); (G.F.); (F.Z.)
| | - Giulia Feliziani
- Unit of Molecular Biology and Nutrigenomics, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy; (R.G.); (G.d.S.); (L.B.); (G.F.); (F.Z.)
| | - Fanrui Zhao
- Unit of Molecular Biology and Nutrigenomics, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy; (R.G.); (G.d.S.); (L.B.); (G.F.); (F.Z.)
| | - Marta Ferrati
- Chemistry Interdisciplinary Project (ChIP) Research Centre, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy; (M.F.); (F.M.); (E.S.)
| | - Filippo Maggi
- Chemistry Interdisciplinary Project (ChIP) Research Centre, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy; (M.F.); (F.M.); (E.S.)
| | - Eleonora Spinozzi
- Chemistry Interdisciplinary Project (ChIP) Research Centre, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy; (M.F.); (F.M.); (E.S.)
| | - Jamal Mahajna
- Department of Nutrition and Natural Products, Migal—Galilee Research Institute, Kiryat Shmona 11016, Israel;
- Department of Biotechnology, Tel-Hai College, Kiryat Shmona 1220800, Israel
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20
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Wang B, Zhou M, Gan XL, Ren YX, Yang YZ, Weng ZJ, Zhang XF, Guan JX, Tang LY, Ren ZF. Combined low levels of H4K16ac and H4K20me3 predicts poor prognosis in breast cancer. Int J Clin Oncol 2023; 28:1147-1157. [PMID: 37428307 DOI: 10.1007/s10147-023-02378-y] [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] [Received: 04/01/2023] [Accepted: 06/27/2023] [Indexed: 07/11/2023]
Abstract
BACKGROUND Results of previous studies about the prognostic roles of histone H4 lysine 16 acetylation (H4K16ac) and histone H4 lysine 20 trimethylation (H4K20me3) in breast cancer were inconsistent. Cellular experiments revealed the interplays between H4K16ac and H4K20me3, but no population study explored the interaction between them on the prognosis. METHODS H4K16ac and H4K20me3 levels in tumors were evaluated by immunohistochemistry for 958 breast cancer patients. Hazard ratios for overall survival (OS) and progression-free survival (PFS) were estimated using Cox regression models. Interaction was assessed on multiplicative scale. Concordance index (C-index) was calculated to verify the predictive performance. RESULTS The prognostic roles of the low level of H4K16ac or H4K20me3 were significant only in patients with the low level of another marker and their interactions were significant. Moreover, compared with joint high levels of both them, only the combined low levels of both them was associated with a poor prognosis but not the low level of single one. The C-index of the clinicopathological model combined the joint expression of H4K16ac and H4K20me3 [0.739 for OS; 0.672 for PFS] was significantly larger than that of the single clinicopathological model [0.699 for OS, P < 0.001; 0.642 for PFS, P = 0.003] or the model combined with the single H4K16ac [0.712 for OS, P < 0.001; 0.646 for PFS, P < 0.001] or H4K20me3 [0.724 for OS, P = 0.031; 0.662 for PFS, P = 0.006]. CONCLUSIONS There was an interaction between H4K16ac and H4K20me3 on the prognosis of breast cancer and the combination of them was a superior prognostic marker compared to the single one.
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Affiliation(s)
- Bo Wang
- Department of Epidemiology and Health Statistics, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Rd, Guangzhou, 510080, Guangdong, China
| | - Meng Zhou
- Department of Epidemiology and Health Statistics, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Rd, Guangzhou, 510080, Guangdong, China
| | - Xing-Li Gan
- Department of Epidemiology and Health Statistics, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Rd, Guangzhou, 510080, Guangdong, China
| | - Yue-Xiang Ren
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Rd, Guangzhou, 510630, Guangdong, China
| | - Yuan-Zhong Yang
- Department of Pathology, The Sun Yat-Sen University Cancer Center, Guangzhou, 510080, Guangdong, China
| | - Zi-Jin Weng
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Rd, Guangzhou, 510630, Guangdong, China
| | - Xiao-Fang Zhang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Rd, Guangzhou, 510630, Guangdong, China
| | - Jie-Xia Guan
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Rd, Guangzhou, 510630, Guangdong, China
| | - Lu-Ying Tang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Rd, Guangzhou, 510630, Guangdong, China.
| | - Ze-Fang Ren
- Department of Epidemiology and Health Statistics, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Rd, Guangzhou, 510080, Guangdong, China.
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21
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Xiao HT, Jin J, Zheng ZG. Emerging role of GCN5 in human diseases and its therapeutic potential. Biomed Pharmacother 2023; 165:114835. [PMID: 37352700 DOI: 10.1016/j.biopha.2023.114835] [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: 02/22/2023] [Revised: 04/18/2023] [Accepted: 05/02/2023] [Indexed: 06/25/2023] Open
Abstract
As the first histone acetyltransferase to be cloned and identified in yeast, general control non-depressible 5 (GCN5) plays a crucial role in epigenetic and chromatin modifications. It has been extensively studied for its essential role in regulating and causing various diseases. There is mounting evidence to suggest that GCN5 plays an emerging role in human diseases and its therapeutic potential is promising. In this paper, we begin by providing an introduction GCN5 including its structure, catalytic mechanism, and regulation, followed by a review of the current research progress on the role of GCN5 in regulating various diseases, such as cancer, diabetes, osteoporosis. Thus, we delve into the various aspects of GCN5 inhibitors, including their types, characteristics, means of discovery, activities, and limitations from a medicinal chemistry perspective. Our analysis highlights the importance of identifying and creating inhibitors that are both highly selective and effective inhibitors, for the future development of novel therapeutic agents aimed at treating GCN5-related diseases.
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Affiliation(s)
- Hai-Tao Xiao
- State Key Laboratory of Natural Medicines, Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China
| | - Jing Jin
- State Key Laboratory of Natural Medicines, Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China
| | - Zu-Guo Zheng
- State Key Laboratory of Natural Medicines, Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China.
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22
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Zhong X, Deng H, Long M, Yin H, Zhong Q, Zheng S, Gong T, He L, Wang G, Sun Q. Discovery of berberine analogs as potent and highly selective p300/CBP HAT inhibitors. Bioorg Chem 2023; 138:106597. [PMID: 37245245 DOI: 10.1016/j.bioorg.2023.106597] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 04/23/2023] [Accepted: 05/04/2023] [Indexed: 05/30/2023]
Abstract
The protein p300 is a positive regulator of cancer progression and is related to many human pathological conditions. To find effective p300/CBP HAT inhibitors, we screened an internal compound library and identified berberine as a lead compound. Next, we designed, synthesized, and screened a series of novel berberine analogs, and discovered that analog 5d was a potent and highly selective p300/CBP HAT inhibitor with IC50 values of 0.070 μM and 1.755 μM for p300 and CBP, respectively. Western blotting further proved that 5d specifically decreased H3K18Ac and interfere with the function of histone acetyltransferase. Although 5d had only a moderate inhibitory effect on the MDA-MB-231 cell line, 5d suppressed the growth of 4T1 tumor growth in mice with a tumor weight inhibition ratio (TWI) of 39.7%. Further, liposomes-encapsulated 5d increased its inhibition of tumor growth to 57.8 % TWI. In addition, 5d has no obvious toxicity to the main organ of mice and the pharmacokinetic study confirmed that 5d has good absorption properties in vivo.
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Affiliation(s)
- Xue Zhong
- Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Huiwen Deng
- Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Min Long
- Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Honglu Yin
- Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiu Zhong
- Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA
| | - Shilong Zheng
- Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA
| | - Tao Gong
- Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ling He
- Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Guangdi Wang
- Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA.
| | - Qiu Sun
- Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; West China Medical Publishers, West China Hospital, Sichuan University, Chengdu 610041, China.
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23
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Brahadeeswaran S, Dasgupta T, Manickam V, Saraswathi V, Tamizhselvi R. NLRP3: a new therapeutic target in alcoholic liver disease. Front Immunol 2023; 14:1215333. [PMID: 37520548 PMCID: PMC10374212 DOI: 10.3389/fimmu.2023.1215333] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/28/2023] [Indexed: 08/01/2023] Open
Abstract
The liver is in charge of a wide range of critical physiological processes and it plays an important role in activating the innate immune system which elicits the inflammatory events. Chronic ethanol exposure disrupts hepatic inflammatory mechanism and leads to the release of proinflammatory mediators such as chemokines, cytokines and activation of inflammasomes. The mechanism of liver fibrosis/cirrhosis involve activation of NLRP3 inflammasome, leading to the destruction of hepatocytes and subsequent metabolic dysregulation in humans. In addition, increasing evidence suggests that alcohol intake significantly modifies liver epigenetics, promoting the development of alcoholic liver disease (ALD). Epigenetic changes including histone modification, microRNA-induced genetic modulation, and DNA methylation are crucial in alcohol-evoked cell signaling that affects gene expression in the hepatic system. Though we are at the beginning stage without having the entire print of epigenetic signature, it is time to focus more on NLRP3 inflammasome and epigenetic modifications. Here we review the novel aspect of ALD pathology linking to inflammation and highlighting the role of epigenetic modification associated with NLRP3 inflammasome and how it could be a therapeutic target in ALD.
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Affiliation(s)
- Subhashini Brahadeeswaran
- Department of Biosciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Tiasha Dasgupta
- Department of Biosciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Venkatraman Manickam
- Department of Biosciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Viswanathan Saraswathi
- Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, Veterans Affairs Medical Center, University of Nebraska Medical Center, Omaha, NE, United States
| | - Ramasamy Tamizhselvi
- Department of Biosciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
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24
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Tauchen J, Frankova A, Manourova A, Valterova I, Lojka B, Leuner O. Garcinia kola: a critical review on chemistry and pharmacology of an important West African medicinal plant. PHYTOCHEMISTRY REVIEWS : PROCEEDINGS OF THE PHYTOCHEMICAL SOCIETY OF EUROPE 2023:1-47. [PMID: 37359709 PMCID: PMC10205037 DOI: 10.1007/s11101-023-09869-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 04/03/2023] [Indexed: 06/28/2023]
Abstract
Garcinia kola Heckel (Clusiaceae) is a tree indigenous to West and Central Africa. All plant parts, but especially the seeds, are of value in local folklore medicine. Garcinia kola is used in treatment of numerous diseases, including gastric disorders, bronchial diseases, fever, malaria and is used to induce a stimulating and aphrodisiac effect. The plant is now attracting considerable interest as a possible source of pharmaceutically important drugs. Several different classes of compounds such as biflavonoids, benzophenones, benzofurans, benzopyran, vitamin E derivatives, xanthones, and phytosterols, have been isolated from G. kola, of which many appears to be found only in this species, such as garcinianin (found in seeds and roots), kolanone (fruit pulp, seeds, roots), gakolanone (stem bark), garcinoic acid, garcinal (both in seeds), garcifuran A and B, and garcipyran (all in roots). They showed a wide range of pharmacological activities (e.g. analgesic, anticancer, antidiabetic, anti-inflammatory, antimalarial, antimicrobial, hepatoprotective and neuroprotective effects), though this has only been confirmed in animal models. Kolaviron is the most studied compound and is perceived by many studies as the active principle of G. kola. However, its research is associated with significant flaws (e.g. too high doses tested, inappropriate positive control). Garcinol has been tested under better conditions and is perhaps showing more promising results and should attract deeper research interest (especially in the area of anticancer, antimicrobial, and neuroprotective activity). Human clinical trials and mechanism-of-action studies must be carried out to verify whether any of the compounds present in G. kola may be used as a lead in the drug development.
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Affiliation(s)
- Jan Tauchen
- Department of Food Science, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences, Prague, Czech Republic
| | - Adela Frankova
- Department of Food Science, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences, Prague, Czech Republic
| | - Anna Manourova
- Department of Crop Sciences and Agroforestry, Faculty of Tropical AgriSciences, Czech University of Life Sciences, Prague, Czech Republic
| | - Irena Valterova
- Department of Crop Sciences and Agroforestry, Faculty of Tropical AgriSciences, Czech University of Life Sciences, Prague, Czech Republic
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Bohdan Lojka
- Department of Crop Sciences and Agroforestry, Faculty of Tropical AgriSciences, Czech University of Life Sciences, Prague, Czech Republic
| | - Olga Leuner
- Department of Crop Sciences and Agroforestry, Faculty of Tropical AgriSciences, Czech University of Life Sciences, Prague, Czech Republic
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25
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Wang X, Wan TC, Kulik KR, Lauth A, Smith BC, Lough JW, Auchampach JA. Pharmacological inhibition of the acetyltransferase Tip60 mitigates myocardial infarction injury. Dis Model Mech 2023; 16:dmm049786. [PMID: 36341679 PMCID: PMC9672930 DOI: 10.1242/dmm.049786] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 09/16/2022] [Indexed: 11/09/2022] Open
Abstract
Pharmacologic strategies that target factors with both pro-apoptotic and anti-proliferative functions in cardiomyocytes (CMs) may be useful for the treatment of ischemic heart disease. One such multifunctional candidate for drug targeting is the acetyltransferase Tip60, which is known to acetylate both histone and non-histone protein targets that have been shown in cancer cells to promote apoptosis and to initiate the DNA damage response, thereby limiting cellular expansion. Using a murine model, we recently published findings demonstrating that CM-specific disruption of the Kat5 gene encoding Tip60 markedly protects against the damaging effects of myocardial infarction (MI). In the experiments described here, in lieu of genetic targeting, we administered TH1834, an experimental drug designed to specifically inhibit the acetyltransferase domain of Tip60. We report that, similar to the effect of disrupting the Kat5 gene, daily systemic administration of TH1834 beginning 3 days after induction of MI and continuing for 2 weeks of a 4-week timeline resulted in improved systolic function, reduced apoptosis and scarring, and increased activation of the CM cell cycle, effects accompanied by reduced expression of genes that promote apoptosis and inhibit the cell cycle and reduced levels of CMs exhibiting phosphorylated Atm. These results support the possibility that drugs that inhibit the acetyltransferase activity of Tip60 may be useful agents for the treatment of ischemic heart disease.
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Affiliation(s)
- Xinrui Wang
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Tina C. Wan
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Katherine R. Kulik
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Amelia Lauth
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Brian C. Smith
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - John W. Lough
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - John A. Auchampach
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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26
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Zhang J, Hu Z, Chung HH, Tian Y, Lau KW, Ser Z, Lim YT, Sobota RM, Leong HF, Chen BJ, Yeo CJ, Tan SYX, Kang J, Tan DEK, Sou IF, McClurg UL, Lakshmanan M, Vaiyapuri TS, Raju A, Wong ESM, Tergaonkar V, Rajarethinam R, Pathak E, Tam WL, Tan EY, Tee WW. Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis. Nat Commun 2023; 14:2439. [PMID: 37117180 PMCID: PMC10147683 DOI: 10.1038/s41467-023-38132-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/17/2023] [Indexed: 04/30/2023] Open
Abstract
Cancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Using cancer cell lines and patient-derived tumor organoids, we demonstrate that loss of the negative elongation factor (NELF) complex inhibits breast cancer development through downregulating epithelial-mesenchymal transition (EMT) and stemness-associated genes. Quantitative multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) further reveals a significant rewiring of NELF-E-associated chromatin partners as a function of EMT and a co-option of NELF-E with the key EMT transcription factor SLUG. Accordingly, loss of NELF-E leads to impaired SLUG binding on chromatin. Through integrative transcriptomic and genomic analyses, we identify the histone acetyltransferase, KAT2B, as a key functional target of NELF-E-SLUG. Genetic and pharmacological inactivation of KAT2B ameliorate the expression of EMT markers, phenocopying NELF ablation. Elevated expression of NELF-E and KAT2B is associated with poorer prognosis in breast cancer patients, highlighting the clinical relevance of our findings. Taken together, we uncover a crucial role of the NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis.
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Affiliation(s)
- Jieqiong Zhang
- Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Republic of Singapore
| | - Zhenhua Hu
- Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Hwa Hwa Chung
- Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Yun Tian
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 210004, Nanjing, People's Republic of China
| | - Kah Weng Lau
- Department of Pathology, National University Hospital, 5 Lower Kent Ridge Road, Singapore, 119074, Republic of Singapore
| | - Zheng Ser
- Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Yan Ting Lim
- Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Radoslaw M Sobota
- Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Hwei Fen Leong
- Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Benjamin Jieming Chen
- Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Clarisse Jingyi Yeo
- Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Shawn Ying Xuan Tan
- Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Jian Kang
- Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Dennis Eng Kiat Tan
- Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Ieng Fong Sou
- Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK
| | - Urszula Lucja McClurg
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK
| | - Manikandan Lakshmanan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Thamil Selvan Vaiyapuri
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Anandhkumar Raju
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Esther Sook Miin Wong
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Vinay Tergaonkar
- Department of Pathology, National University Hospital, 5 Lower Kent Ridge Road, Singapore, 119074, Republic of Singapore
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore, 117597, Republic of Singapore
| | - Ravisankar Rajarethinam
- Advanced Molecular Pathology Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
| | - Elina Pathak
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Drive, Genome, Singapore, 138672, Republic of Singapore
| | - Wai Leong Tam
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore, 117597, Republic of Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Drive, Genome, Singapore, 138672, Republic of Singapore
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore
| | - Ern Yu Tan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore
- Department of General Surgery, Tan Tock Seng Hospital, Singapore, 308433, Republic of Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Republic of Singapore
| | - Wee-Wei Tee
- Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore.
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Republic of Singapore.
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore.
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27
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Jaganathan R, Kumaradhas P. Binding mechanism of anacardic acid, carnosol and garcinol with PCAF: A comprehensive study using molecular docking and molecular dynamics simulations and binding free energy analysis. J Cell Biochem 2023; 124:731-742. [PMID: 36966470 DOI: 10.1002/jcb.30400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/09/2023] [Accepted: 03/12/2023] [Indexed: 03/27/2023]
Abstract
The p300/CBP associated factor bromodomain (PCAF Brd) is emerged as one of the promising target proteins for different types of cancers. PCAF is one among the histone acetyltransferase enzymes which involved in the regulation of transcriptase process by modifying the chromatin structure. Anacardic acid, carnosol, garcinol are the experimentally reported inhibitors of PCAF Brd; however, their detailed binding mechanism these inhibitors are not yet known. The intermolecular interaction, binding energy, and the stability of these inhibitors with the active site of PCAF Brd are playing the key role in the binding of these inhibitors with PCAF. The in silico study incorporates the molecular docking and dynamics simulations; these molecular level simulations allow to understand the binding mechanism. In the present study, the induced fit molecular docking and molecular dynamics of anacardic acid, carnosol and garcinol molecules against the PCAF Brd have been performed. The docking score values of these molecules are -5.112 (anacardic acid), -5.141 (carnosol), -5.199 (garcinol) and -3.641 (L45) kcal/mol, respectively. Further, the molecular dynamics simulation was carried out for these docked complexes to understand their conformational their stability and binding energy from the roots means square deviation (RMSD) and root means square of fluctuation (RMSF), and molecular mechanics with the generalized born and surface area solvation (MM/GBSA) binding free energy calculations. The intermolecular interactions and binding free energy values confirm that garcinol forms key interactions and has high binding affinity towards PCAF Brd on compare with the other two inhibitors. Therefore, garcinol may be considered as a potential inhibitor of PCAF Brd.
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Affiliation(s)
- Ramakrishnan Jaganathan
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
| | - Poomani Kumaradhas
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
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28
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Louwies T, Mohammadi E, Greenwood-Van Meerveld B. Epigenetic mechanisms underlying stress-induced visceral pain: Resilience versus vulnerability in a two-hit model of early life stress and chronic adult stress. Neurogastroenterol Motil 2023; 35:e14558. [PMID: 36893055 DOI: 10.1111/nmo.14558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/16/2022] [Accepted: 02/19/2023] [Indexed: 03/10/2023]
Abstract
BACKGROUND Women with a history of early life stress (ELS) have a higher risk of developing irritable bowel syndrome (IBS). In addition, chronic stress in adulthood can exacerbate IBS symptoms such as abdominal pain due to visceral hypersensitivity. We previously showed that sex and the predictability of ELS determine whether rats develop visceral hypersensitivity in adulthood. In female rats, unpredictable ELS confers vulnerability and results in visceral hypersensitivity, whereas predictable ELS induces resilience and does not induce visceral hypersensitivity in adulthood. However, this resilience is lost after exposure to chronic stress in adulthood leading to an exacerbation of visceral hypersensitivity. Evidence suggests that changes in histone acetylation at the promoter regions of glucocorticoid receptor (GR) and corticotrophin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) underlie stress-induced visceral hypersensitivity. Here, we aimed to investigate the role of histone acetylation in the CeA on visceral hypersensitivity in a two-hit model of ELS followed by chronic stress in adulthood. METHODS Male and female neonatal rats were exposed to unpredictable, predictable ELS, or odor only (no stress control) from postnatal days 8 to 12. In adulthood, rats underwent stereotaxic implantation of indwelling cannulas. Rats were exposed to chronic water avoidance stress (WAS, 1 h/day for 7 days) or SHAM stress and received infusions of vehicle, the histone deacetylase inhibitor trichostatin A (TSA) or the histone acetyltransferase inhibitor garcinol (GAR) after each WAS session. 24 h after the final infusion, visceral sensitivity was assessed and the CeA was removed for molecular experiments. RESULTS In the two-hit model (ELS + WAS), female rats previously exposed to predictable ELS, showed a significant reduction in histone 3 lysine 9 (H3K9) acetylation at the GR promoter and a significant increase in H3K9 acetylation at the CRF promoter. These epigenetic changes were associated with changes in GR and CRF mRNA expression in the CeA and an exacerbation of stress-induced visceral hypersensitivity in female animals. TSA infusions in the CeA attenuated the exacerbated stress-induced visceral hypersensitivity, whereas GAR infusions only partially ameliorated ELS+WAS induced visceral hypersensitivity. CONCLUSION The two-hit model of ELS followed by WAS in adulthood revealed that epigenetic dysregulation occurs after exposure to stress in two important periods of life and contributes to the development of visceral hypersensitivity. These aberrant underlying epigenetic changes may explain the exacerbation of stress-induced abdominal pain in IBS patients.
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Affiliation(s)
- Tijs Louwies
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
| | - Ehsan Mohammadi
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
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Ramakrishnan J, Magudeeswaran S, Suresh S, Poomani K. Investigation of intermolecular interactions and binding mechanism of PU139 and PU141 molecules with p300 HAT enzyme via molecular docking, molecular dynamics simulations and binding free energy analysis. J Biomol Struct Dyn 2023; 41:1351-1365. [PMID: 34974819 DOI: 10.1080/07391102.2021.2020164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The p300 histone acetyltransferase (HAT) enzyme acetylates the lysine residue of histone promotes the transcription reaction. The abnormal function of p300 HAT enzyme causes various diseases such as Cancer, Asthma, Alzheimer, Diabetics, and AIDS. In the recent years, several studies have been conducted to design potential drug to inhibit this enzyme. Recently, an in vitro study has been performed on the synthetic molecules PU139 and PU141 to inhibit the p300 HAT enzyme. The present study aims to understand the binding affinity, intermolecular interactions, conformational stability and binding energy of PU139 and PU141 molecules in the active site of p300 HAT enzyme from the in silico studies. The molecular docking and molecular dynamics (MD) simulations were carried out for both ligands with the p300 HAT enzyme. The molecular docking and MD simulations reveals that both molecules forms expected interactions with the catalytic site key residues of p300 enzyme. The MD simulation shows the maximum RMSD value for the PU141 is 2.3 Å, whereas for PU139 is 3.3 Å; these low RMSD values indicate that both molecules are highly stable in the active site of p300. The calculated binding free energy of PU141 (-20.62 kcal/mol) is higher than the molecule PU139 (-17.67 kcal/mol). Among the results, PU141 shows the high binding affinity with p300 while comparing with PU139. The results of this in-silico study coupled with the findings reported in the in vitro study confirm that PU141 may be suitable for clinical study.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Jaganathan Ramakrishnan
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
| | - Sivanandam Magudeeswaran
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
| | - Suganya Suresh
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
| | - Kumaradhas Poomani
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
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Yao W, Guo B, Jin T, Bao Z, Wang T, Wen S, Huang F. Garcinol Promotes the Formation of Slow-Twitch Muscle Fibers by Inhibiting p300-Dependent Acetylation of PGC-1α. Int J Mol Sci 2023; 24:ijms24032702. [PMID: 36769025 PMCID: PMC9916769 DOI: 10.3390/ijms24032702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 12/31/2022] [Accepted: 01/05/2023] [Indexed: 02/04/2023] Open
Abstract
The conversion of skeletal muscle fiber from fast-twitch to slow-twitch is crucial for sustained contractile and stretchable events, energy homeostasis, and anti-fatigue ability. The purpose of our study was to explore the mechanism and effects of garcinol on the regulation of skeletal muscle fiber type transformation. Forty 21-day-old male C57/BL6J mice (n = 10/diet) were fed a control diet or a control diet plus garcinol at 100 mg/kg (Low Gar), 300 mg/kg (Mid Gar), or 500 mg/kg (High Gar) for 12 weeks. The tibialis anterior (TA) and soleus muscles were collected for protein and immunoprecipitation analyses. Dietary garcinol significantly downregulated (p < 0.05) fast myosin heavy chain (MyHC) expression and upregulated (p < 0.05) slow MyHC expression in the TA and soleus muscles. Garcinol significantly increased (p < 0.05) the activity of peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) and markedly decreased (p < 0.05) the acetylation of PGC-1α. In vitro and in vivo experiments showed that garcinol decreased (p < 0.05) lactate dehydrogenase activity and increased (p < 0.05) the activities of malate dehydrogenase and succinic dehydrogenase. In addition, the results of C2C12 myotubes showed that garcinol treatment increased (p < 0.05) the transformation of glycolytic muscle fiber to oxidative muscle fiber by 45.9%. Garcinol treatment and p300 interference reduced (p < 0.05) the expression of fast MyHC but increased (p < 0.05) the expression of slow MyHC in vitro. Moreover, the acetylation of PGC-1α was significantly decreased (p < 0.05). Garcinol promotes the transformation of skeletal muscle fibers from the fast-glycolytic type to the slow-oxidative type through the p300/PGC-1α signaling pathway in C2C12 myotubes.
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Affiliation(s)
- Weilei Yao
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Baoyin Guo
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Taimin Jin
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Zhengxi Bao
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Tongxin Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Shu Wen
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Feiruo Huang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
- Correspondence: ; Tel.: +86-10-87286912; Fax: +86-10-87280408
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Di Pietrantonio N, Di Tomo P, Mandatori D, Formoso G, Pandolfi A. Diabetes and Its Cardiovascular Complications: Potential Role of the Acetyltransferase p300. Cells 2023; 12:431. [PMID: 36766773 PMCID: PMC9914144 DOI: 10.3390/cells12030431] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/17/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Diabetes has been shown to accelerate vascular senescence, which is associated with chronic inflammation and oxidative stress, both implicated in the development of endothelial dysfunction. This condition represents the initial alteration linking diabetes to related cardiovascular (CV) complications. Recently, it has been hypothesised that the acetyltransferase, p300, may contribute to establishing an early vascular senescent phenotype, playing a relevant role in diabetes-associated inflammation and oxidative stress, which drive endothelial dysfunction. Specifically, p300 can modulate vascular inflammation through epigenetic mechanisms and transcription factors acetylation. Indeed, it regulates the inflammatory pathway by interacting with nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit (NF-κB p65) or by inducing its acetylation, suggesting a crucial role of p300 as a bridge between NF-κB p65 and the transcriptional machinery. Additionally, p300-mediated epigenetic modifications could be upstream of the activation of inflammatory cytokines, and they may induce oxidative stress by affecting the production of reactive oxygen species (ROS). Because several in vitro and in vivo studies shed light on the potential use of acetyltransferase inhibitors, a better understanding of the mechanisms underlying the role of p300 in diabetic vascular dysfunction could help in finding new strategies for the clinical management of CV diseases related to diabetes.
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Affiliation(s)
- Nadia Di Pietrantonio
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Pamela Di Tomo
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Domitilla Mandatori
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Gloria Formoso
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Assunta Pandolfi
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
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Kumar A, Emdad L, Fisher PB, Das SK. Targeting epigenetic regulation for cancer therapy using small molecule inhibitors. Adv Cancer Res 2023; 158:73-161. [PMID: 36990539 DOI: 10.1016/bs.acr.2023.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Cancer cells display pervasive changes in DNA methylation, disrupted patterns of histone posttranslational modification, chromatin composition or organization and regulatory element activities that alter normal programs of gene expression. It is becoming increasingly clear that disturbances in the epigenome are hallmarks of cancer, which are targetable and represent attractive starting points for drug creation. Remarkable progress has been made in the past decades in discovering and developing epigenetic-based small molecule inhibitors. Recently, epigenetic-targeted agents in hematologic malignancies and solid tumors have been identified and these agents are either in current clinical trials or approved for treatment. However, epigenetic drug applications face many challenges, including low selectivity, poor bioavailability, instability and acquired drug resistance. New multidisciplinary approaches are being designed to overcome these limitations, e.g., applications of machine learning, drug repurposing, high throughput virtual screening technologies, to identify selective compounds with improved stability and better bioavailability. We provide an overview of the key proteins that mediate epigenetic regulation that encompass histone and DNA modifications and discuss effector proteins that affect the organization of chromatin structure and function as well as presently available inhibitors as potential drugs. Current anticancer small-molecule inhibitors targeting epigenetic modified enzymes that have been approved by therapeutic regulatory authorities across the world are highlighted. Many of these are in different stages of clinical evaluation. We also assess emerging strategies for combinatorial approaches of epigenetic drugs with immunotherapy, standard chemotherapy or other classes of agents and advances in the design of novel epigenetic therapies.
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Garcia K, Gingras AC, Harvey KF, Tanas MR. TAZ/YAP fusion proteins: mechanistic insights and therapeutic opportunities. Trends Cancer 2022; 8:1033-1045. [PMID: 36096997 PMCID: PMC9671862 DOI: 10.1016/j.trecan.2022.08.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/07/2022] [Accepted: 08/09/2022] [Indexed: 12/24/2022]
Abstract
The Hippo pathway is dysregulated in many different cancers, but point mutations in the pathway are rare. Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) fusion proteins have emerged in almost all major cancer types and represent the most common genetic mechanism by which the two transcriptional co-activators are activated. Given that the N termini of TAZ or YAP are fused to the C terminus of another transcriptional regulator, the resultant fusion proteins hyperactivate a TEAD transcription factor-based transcriptome. Recent advances show that the C-terminal fusion partners confer oncogenic properties to TAZ/YAP fusion proteins by recruiting epigenetic modifiers that promote a hybrid TEAD-based transcriptome. Elucidating these cooperating epigenetic complexes represents a strategy to identify new therapeutic approaches for a pathway that has been recalcitrant to medical therapy.
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Affiliation(s)
- Keith Garcia
- Department of Pathology, University of Iowa, Iowa City, IA, USA; Cancer Biology Graduate Program, University of Iowa, Iowa City, IA, USA
| | - Anne-Claude Gingras
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Kieran F Harvey
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia; Department of Anatomy and Developmental Biology, and Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Munir R Tanas
- Department of Pathology, University of Iowa, Iowa City, IA, USA; Cancer Biology Graduate Program, University of Iowa, Iowa City, IA, USA; Pathology and Laboratory Medicine, Veterans Affairs Medical Center, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
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Pacifico R, Del Gaudio N, Bove G, Altucci L, Siragusa L, Cruciani G, Ruvo M, Bellavita R, Grieco P, Adamo MFA. Discovery of a new class of triazole based inhibitors of acetyl transferase KAT2A. J Enzyme Inhib Med Chem 2022; 37:1987-1994. [PMID: 35880250 PMCID: PMC9331200 DOI: 10.1080/14756366.2022.2097447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
We have recently developed a new synthetic methodology that provided both N-aryl-5-hydroxytriazoles and N-pyridine-4-alkyl triazoles. A selection of these products was carried through virtual screening towards targets that are contemporary and validated for drug discovery and development. This study determined a number of potential structure target dyads of which N-pyridinium-4-carboxylic-5-alkyl triazole displayed the highest score specificity towards KAT2A. Binding affinity tests of abovementioned triazole and related analogs towards KAT2A confirmed the predictions of the in-silico assay. Finally, we have run in vitro inhibition assays of selected triazoles towards KAT2A; the ensemble of binding and inhibition assays delivered pyridyl-triazoles carboxylates as the prototype of a new class of inhibitors of KAT2A.
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Affiliation(s)
- Roberta Pacifico
- Centre for Synthesis and Chemical Biology (CSCB), Department of Chemistry, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Nunzio Del Gaudio
- Department of precision medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Guglielmo Bove
- Department of precision medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Lucia Altucci
- Department of precision medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | | | - Gabriele Cruciani
- Laboratory for Chemometrics and Molecular Modeling, Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy
| | - Menotti Ruvo
- Institute of Biostructures and Bioimaging, Consiglio Nazionale delle Ricerche, Naples, Italy
| | - Rosa Bellavita
- Department of Pharmacy, School of Medicine, University of Naples 'Federico II', Naples, Italy
| | - Paolo Grieco
- Department of Pharmacy, School of Medicine, University of Naples 'Federico II', Naples, Italy
| | - Mauro F A Adamo
- Centre for Synthesis and Chemical Biology (CSCB), Department of Chemistry, Royal College of Surgeons in Ireland, Dublin, Ireland
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Yahaya TO, Bashar DM, Oladele EO, Umar J, Anyebe D, Izuafa A. Epigenetics in the etiology and management of infertility. World J Med Genet 2022; 10:7-21. [DOI: 10.5496/wjmg.v10.i2.7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 06/28/2022] [Accepted: 10/12/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Epigenetic disruptions have been implicated in some cases of infertility and can serve as therapeutic targets. However, the involvement of epigenetics in infertility has not received adequate attention.
AIM This study aimed to determine the epigenetic basis of infertility in order to enhance public knowledge.
METHODS Relevant articles on the subject were collected from PubMed, RCA, Google Scholar, SpringerLink, and Scopus. The articles were pooled together and duplicates were removed using Endnote software.
RESULTS Available information shows that epigenetic mechanisms, mainly DNA methylation, histone modification, and microRNA interference are necessary for normal gametogenesis and embryogenesis. As a result, epigenetic disruptions in genes that control gametogenesis and embryogenesis, such as DDX3X, ADH4, AZF, PLAG1, D1RAS3, CYGB, MEST, JMJD1A, KCNQ1, IGF2, H19, and MTHFR may result in infertility. Aberrant DNA methylation during genomic imprinting and parental epigenetic mark erasures, in particular, may affect the DNA epigenomes of sperm and oocytes, resulting in reproductive abnormalities. Histone epigenetic dysregulation during oocyte development and histone-protamine replacement in the sperm may also cause reproductive abnormalities. Furthermore, overexpression or repression of certain microRNAs embedded in the ovary, testis, embryo, as well as granulosa cells and oocytes may impair reproduction. Male infertility is characterized by spermatogenesis failure, which includes oligozoospermia, asthenozoospermia, and teratozoospermia, while female infertility is characterized by polycystic ovary syndrome. Some epigenetic modifications can be reversed by deactivating the regulatory enzymes, implying that epigenetic reprogramming could help treat infertility in some cases. For some disorders, epigenetic drugs are available, but none have been formulated for infertility.
CONCLUSION Some cases of infertility have an epigenetic etiology and can be treated by reversing the same epigenetic mechanism that caused it. As a result, medical practitioners are urged to come up with epigenetic treatments for infertility that have an epigenetic cause.
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Affiliation(s)
| | - Danlami M Bashar
- Department of Microbiology, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
| | - Esther O Oladele
- Biology Unit, Distance Learning Institute, University of Lagos, Lagos State 23401, Nigeria
| | - Ja'afar Umar
- Department of Biological Sciences, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
| | - Daniel Anyebe
- Department of Biochemistry and Molecular Biology, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
| | - Abdulrazaq Izuafa
- Department of Biological Sciences, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
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36
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Sakamoto Y, Kawamura A, Suzuki T, Segami S, Maeshima M, Polyn S, De Veylder L, Sugimoto K. Transcriptional activation of auxin biosynthesis drives developmental reprogramming of differentiated cells. THE PLANT CELL 2022; 34:4348-4365. [PMID: 35922895 PMCID: PMC9614439 DOI: 10.1093/plcell/koac218] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/19/2022] [Indexed: 05/26/2023]
Abstract
Plant cells exhibit remarkable plasticity of their differentiation states, enabling regeneration of whole plants from differentiated somatic cells. How they revert cell fate and express pluripotency, however, remains unclear. In this study, we demonstrate that transcriptional activation of auxin biosynthesis is crucial for reprogramming differentiated Arabidopsis (Arabidopsis thaliana) leaf cells. Our data show that interfering with the activity of histone acetyltransferases dramatically reduces callus formation from leaf mesophyll protoplasts. Histone acetylation permits transcriptional activation of PLETHORAs, leading to the induction of their downstream YUCCA1 gene encoding an enzyme for auxin biosynthesis. Auxin biosynthesis is in turn required to accomplish initial cell division through the activation of G2/M phase genes mediated by MYB DOMAIN PROTEIN 3-RELATED (MYB3Rs). We further show that the AUXIN RESPONSE FACTOR 7 (ARF7)/ARF19 and INDOLE-3-ACETIC ACID INDUCIBLE 3 (IAA3)/IAA18-mediated auxin signaling pathway is responsible for cell cycle reactivation by transcriptionally upregulating MYB3R4. These findings provide a mechanistic model of how differentiated plant cells revert their fate and reinitiate the cell cycle to become pluripotent.
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Affiliation(s)
- Yuki Sakamoto
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan
- Center for Sustainable Resource Science, RIKEN, Yokohama 230-0045, Japan
| | - Ayako Kawamura
- Center for Sustainable Resource Science, RIKEN, Yokohama 230-0045, Japan
| | - Takamasa Suzuki
- Department of Biological Chemistry, College of Bioscience and Biotechnology, Chubu University, Kasugai 487-8501, Japan
| | - Shoji Segami
- Division of Evolutionary Biology, National Institute for Basic Biology, Okazaki 444-8585, Japan
- Department of Basic Biology, School of Life Science, The Graduate University for Advanced Studies, SOKENDAI, Okazaki 444-8585, Japan
| | - Masayoshi Maeshima
- Department of Biological Chemistry, College of Bioscience and Biotechnology, Chubu University, Kasugai 487-8501, Japan
| | - Stefanie Polyn
- Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent B-9052, Belgium
- VIB Center for Plant Systems Biology, Ghent B-9052, Belgium
| | - Lieven De Veylder
- Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent B-9052, Belgium
- VIB Center for Plant Systems Biology, Ghent B-9052, Belgium
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Feng J, Meng X. Histone modification and histone modification-targeted anti-cancer drugs in breast cancer: Fundamentals and beyond. Front Pharmacol 2022; 13:946811. [PMID: 36188615 PMCID: PMC9522521 DOI: 10.3389/fphar.2022.946811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/15/2022] [Indexed: 12/21/2022] Open
Abstract
Dysregulated epigenetic enzymes and resultant abnormal epigenetic modifications (EMs) have been suggested to be closely related to tumor occurrence and progression. Histone modifications (HMs) can assist in maintaining genome stability, DNA repair, transcription, and chromatin modulation within breast cancer (BC) cells. In addition, HMs are reversible, dynamic processes involving the associations of different enzymes with molecular compounds. Abnormal HMs (e.g. histone methylation and histone acetylation) have been identified to be tightly related to BC occurrence and development, even though their underlying mechanisms remain largely unclear. EMs are reversible, and as a result, epigenetic enzymes have aroused wide attention as anti-tumor therapeutic targets. At present, treatments to restore aberrant EMs within BC cells have entered preclinical or clinical trials. In addition, no existing studies have comprehensively analyzed aberrant HMs within BC cells; in addition, HM-targeting BC treatments remain to be further investigated. Histone and non-histone protein methylation is becoming an attractive anti-tumor epigenetic therapeutic target; such methylation-related enzyme inhibitors are under development at present. Consequently, the present work focuses on summarizing relevant studies on HMs related to BC and the possible mechanisms associated with abnormal HMs. Additionally, we also aim to analyze existing therapeutic agents together with those drugs approved and tested through pre-clinical and clinical trials, to assess their roles in HMs. Moreover, epi-drugs that target HMT inhibitors and HDAC inhibitors should be tested in preclinical and clinical studies for the treatment of BC. Epi-drugs that target histone methylation (HMT inhibitors) and histone acetylation (HDAC inhibitors) have now entered clinical trials or are approved by the US Food and Drug Administration (FDA). Therefore, the review covers the difficulties in applying HM-targeting treatments in clinics and proposes feasible approaches for overcoming such difficulties and promoting their use in treating BC cases.
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Langeh U, Kumar V, Singh C, Singh A. Drug-herb combination therapy in cancer management. Mol Biol Rep 2022; 49:11009-11024. [PMID: 36083521 DOI: 10.1007/s11033-022-07861-9] [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: 04/16/2022] [Accepted: 08/11/2022] [Indexed: 11/26/2022]
Abstract
Cancer is the second leading cause of fatality all over the world. Various unwanted side effects are being reported with the use of conventional chemotherapy. The plant derived bioactive compounds are the prominent alternative medicinal approach for reduction of chemotherapy associated side effects. The data is collected from Pubmed, Sci-hub, Google scholar, and Research gate were systematically searched up to year 2020. Several herbal drugs have been investigated and found with grateful anti-cancer potentials hence, it can be used in combination with chemotherapy for the depletion of associated side-effects. Herbal drugs and their extracts contain a mixture of active ingredients, which show interactions within themselves and along with chemotherapeutic agents to show either synergistic or antagonistic therapeutic effects. Therefore, it is necessary to develop alternative treatment to control chemotherapy associated side-effects. In this review, we discussed some of the significant chemical compounds, which could be efficient against cancer. This review focuses on the different herbal drugs that play an important role in the treatment of cancer and its associated side-effects. This study aimed to evaluate the efficacy of herbal treatment in combination with chemotherapy for cancer treatment.
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Affiliation(s)
- Urvashi Langeh
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India
| | - Vishal Kumar
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India
| | - Charan Singh
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India
| | - Arti Singh
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India.
- IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India.
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Lisi S, Trovato M, Vitaloni O, Fantini M, Chirichella M, Tognini P, Cornuti S, Costa M, Groth M, Cattaneo A. Acetylation-Specific Interference by Anti-Histone H3K9ac Intrabody Results in Precise Modulation of Gene Expression. Int J Mol Sci 2022; 23:ijms23168892. [PMID: 36012156 PMCID: PMC9408029 DOI: 10.3390/ijms23168892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/01/2022] [Accepted: 08/05/2022] [Indexed: 11/29/2022] Open
Abstract
Among Histone post-translational modifications (PTMs), lysine acetylation plays a pivotal role in the epigenetic regulation of gene expression, mediated by chromatin modifying enzymes. Due to their activity in physiology and pathology, several chemical compounds have been developed to inhibit the function of these proteins. However, the pleiotropy of these classes of proteins represents a weakness of epigenetic drugs. Ideally, a new generation of epigenetic drugs should target with molecular precision individual acetylated lysines on the target protein. We exploit a PTM-directed interference, based on an intrabody (scFv-58F) that selectively binds acetylated lysine 9 of histone H3 (H3K9ac), to test the hypothesis that targeting H3K9ac yields more specific effects than inhibiting the corresponding HAT enzyme that installs that PTM. In yeast scFv-58F modulates, gene expression in a more specific way, compared to two well-established HAT inhibitors. This PTM-specific interference modulated expression of genes involved in ribosome biogenesis and function. In mammalian cells, the scFv-58F induces exclusive changes in the H3K9ac-dependent expression of specific genes. These results suggest the H3K9ac-specific intrabody as the founder of a new class of molecules to directly target histone PTMs, inverting the paradigm from inhibiting the writer enzyme to acting on the PTM.
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Affiliation(s)
- Simonetta Lisi
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
| | - Matteo Trovato
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
- European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany
| | | | - Marco Fantini
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
| | | | - Paola Tognini
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Sara Cornuti
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
| | - Mario Costa
- Institute of Neurosciences, Consiglio Nazionale Delle Ricerche, 56124 Pisa, Italy
| | - Marco Groth
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), 07745 Jena, Germany
| | - Antonino Cattaneo
- Bio@SNS Laboratory, Scuola Normale Superiore, 56126 Pisa, Italy
- Correspondence: ; Tel.: +39-050-509320
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Desai S, Sharma P, Kashyap P, Choudhary B, Kaur J. Bioactive compounds, bio‐functional properties, and food applications of
Garcinia indica
: A review. J Food Biochem 2022; 46:e14344. [DOI: 10.1111/jfbc.14344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/06/2022] [Accepted: 07/09/2022] [Indexed: 11/27/2022]
Affiliation(s)
- Sahil Desai
- Department of Food Technology and Nutrition School of Agriculture, Lovely Professional University Phagwara India
| | - Poorva Sharma
- Department of Food Technology and Nutrition School of Agriculture, Lovely Professional University Phagwara India
| | - Piyush Kashyap
- Department of Food Technology and Nutrition School of Agriculture, Lovely Professional University Phagwara India
| | | | - Jasleen Kaur
- Department of Food Technology and Nutrition School of Agriculture, Lovely Professional University Phagwara India
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van Dijk A, Anten J, Bakker A, Evers N, Hoekstra AT, Chang JC, Scheenstra MR, Veldhuizen EJA, Netea MG, Berkers CR, Haagsman HP. Innate Immune Training of Human Macrophages by Cathelicidin Analogs. Front Immunol 2022; 13:777530. [PMID: 35958593 PMCID: PMC9360325 DOI: 10.3389/fimmu.2022.777530] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/15/2022] [Indexed: 11/21/2022] Open
Abstract
Trained innate immunity can be induced in human macrophages by microbial ligands, but it is unknown if exposure to endogenous alarmins such as cathelicidins can have similar effects. Previously, we demonstrated sustained protection against infection by the chicken cathelicidin-2 analog DCATH-2. Thus, we assessed the capacity of cathelicidins to induce trained immunity. PMA-differentiated THP-1 (dTHP1) cells were trained with cathelicidin analogs for 24 hours and restimulated after a 3-day rest period. DCATH-2 training of dTHP-1 cells amplified their proinflammatory cytokine response when restimulated with TLR2/4 agonists. Trained cells displayed a biased cellular metabolism towards mTOR-dependent aerobic glycolysis and long-chain fatty acid accumulation and augmented microbicidal activity. DCATH-2-induced trained immunity was inhibited by histone acetylase inhibitors, suggesting epigenetic regulation, and depended on caveolae/lipid raft-mediated uptake, MAPK p38 and purinergic signaling. To our knowledge, this is the first report of trained immunity by host defense peptides.
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Affiliation(s)
- Albert van Dijk
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
- *Correspondence: Albert van Dijk,
| | - Jennifer Anten
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Anne Bakker
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Noah Evers
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Anna T. Hoekstra
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands
| | - Jung-Chin Chang
- Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Maaike R. Scheenstra
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Edwin J. A. Veldhuizen
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Mihai G. Netea
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
| | - Celia R. Berkers
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands
- Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Henk P. Haagsman
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
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Chen Q, Yang B, Liu X, Zhang XD, Zhang L, Liu T. Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents. Am J Cancer Res 2022; 12:4935-4948. [PMID: 35836809 PMCID: PMC9274749 DOI: 10.7150/thno.73223] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/23/2022] [Indexed: 01/12/2023] Open
Abstract
The histone acetyltransferases CBP and p300, often referred to as CBP/p300 due to their sequence homology and functional overlap and co-operation, are emerging as critical drivers of oncogenesis in the past several years. CBP/p300 induces histone H3 lysine 27 acetylation (H3K27ac) at target gene promoters, enhancers and super-enhancers, thereby activating gene transcription. While earlier studies indicate that CBP/p300 deletion/loss can promote tumorigenesis, CBP/p300 have more recently been shown to be over-expressed in cancer cells and drug-resistant cancer cells, activate oncogene transcription and induce cancer cell proliferation, survival, tumorigenesis, metastasis, immune evasion and drug-resistance. Small molecule CBP/p300 histone acetyltransferase inhibitors, bromodomain inhibitors, CBP/p300 and BET bromodomain dual inhibitors and p300 protein degraders have recently been discovered. The CBP/p300 inhibitors and degraders reduce H3K27ac, down-regulate oncogene transcription, induce cancer cell growth inhibition and cell death, activate immune response, overcome drug resistance and suppress tumor progression in vivo. In addition, CBP/p300 inhibitors enhance the anticancer efficacy of chemotherapy, radiotherapy and epigenetic anticancer agents, including BET bromodomain inhibitors; and the combination therapies exert substantial anticancer effects in mouse models of human cancers including drug-resistant cancers. Currently, two CBP/p300 inhibitors are under clinical evaluation in patients with advanced and drug-resistant solid tumors or hematological malignancies. In summary, CBP/p300 have recently been identified as critical tumorigenic drivers, and CBP/p300 inhibitors and protein degraders are emerging as promising novel anticancer agents for clinical translation.
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Affiliation(s)
- Qingjuan Chen
- Department of Oncology, 3201 Hospital of Xi'an Jiaotong University Health Science Center, Hanzhong, Shaanxi 723000, China
| | - Binhui Yang
- Department of Oncology, 3201 Hospital of Xi'an Jiaotong University Health Science Center, Hanzhong, Shaanxi 723000, China
| | - Xiaochen Liu
- Department of Oncology, 3201 Hospital of Xi'an Jiaotong University Health Science Center, Hanzhong, Shaanxi 723000, China
| | - Xu D. Zhang
- School of Medicine and Public Health, Priority Research Centre for Cancer Research, University of Newcastle, Callaghan, Newcastle, NSW 2308, Australia.,Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.,✉ Corresponding authors: E-mail: (Xu D. Zhang), (Lirong Zhang); (Tao Liu)
| | - Lirong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.,✉ Corresponding authors: E-mail: (Xu D. Zhang), (Lirong Zhang); (Tao Liu)
| | - Tao Liu
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.,Children's Cancer Institute Australia, Randwick, Sydney, NSW 2031, Australia.,School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.,✉ Corresponding authors: E-mail: (Xu D. Zhang), (Lirong Zhang); (Tao Liu)
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Shang Y, Zhang Z, Tian J, Li X. Anti-Inflammatory Effects of Natural Products on Cerebral Ischemia. Front Pharmacol 2022; 13:914630. [PMID: 35795571 PMCID: PMC9251309 DOI: 10.3389/fphar.2022.914630] [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: 04/07/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Cerebral ischemia with high mortality and morbidity still requires the effectiveness of medical treatments. A growing number of investigations have shown strong links between inflammation and cerebral ischemia. Natural medicine’s treatment methods of cerebral ischemic illness have amassed a wealth of treatment experience and theoretical knowledge. This review summarized recent progress on the disease inflammatory pathways as well as 26 representative natural products that have been routinely utilized to treat cerebral ischemic injury. These natural products have exerted anti-inflammatory effects in cerebral ischemia based on their inflammatory mechanisms, including their inflammatory gene expression patterns and their related different cell types, and the roles of inflammatory mediators in ischemic injury. Overall, the combination of the potential therapeutic interventions of natural products with the inflammatory mechanisms will make them be applicable for cerebral ischemic patients in the future.
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Barrero MJ, Cejas P, Long HW, Ramirez de Molina A. Nutritional Epigenetics in Cancer. Adv Nutr 2022; 13:1748-1761. [PMID: 35421212 PMCID: PMC9526851 DOI: 10.1093/advances/nmac039] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 03/11/2022] [Accepted: 04/09/2022] [Indexed: 01/28/2023] Open
Abstract
Alterations in the epigenome are well known to affect cancer development and progression. Epigenetics is highly influenced by the environment, including diet, which is a source of metabolic substrates that influence the synthesis of cofactors or substrates for chromatin and RNA modifying enzymes. In addition, plants are a common source of bioactives that can directly modify the activity of these enzymes. Here, we review and discuss the impact of diet on epigenetic mechanisms, including chromatin and RNA regulation, and its potential implications for cancer prevention and treatment.
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Affiliation(s)
| | - Paloma Cejas
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA,Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA,Translational Oncology Laboratory, Hospital La Paz Institute for Health Research, Madrid, Spain
| | - Henry W Long
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA,Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
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The Polyunsaturated Fatty Acids, EPA and DHA, Ameliorate Myocardial Infarction-induced Heart Failure by Inhibiting p300-HAT Activity in Rats. J Nutr Biochem 2022; 106:109031. [DOI: 10.1016/j.jnutbio.2022.109031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 11/24/2021] [Accepted: 03/18/2022] [Indexed: 12/25/2022]
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Pathak K, Pathak MP, Saikia R, Gogoi U, Sahariah JJ, Zothantluanga JH, Samanta A, Das A. Cancer Chemotherapy via Natural Bioactive Compounds. Curr Drug Discov Technol 2022; 19:e310322202888. [PMID: 35362385 DOI: 10.2174/1570163819666220331095744] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/29/2021] [Accepted: 12/17/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Cancer-induced mortality is increasingly prevalent globally which skyrocketed the necessity to discover new/novel safe and effective anticancer drugs. Cancer is characterized by the continuous multiplication of cells in the human which is unable to control. Scientific research is drawing its attention towards naturally-derived bioactive compounds as they have fewer side effects compared to the current synthetic drugs used for chemotherapy. OBJECTIVE Drugs isolated from natural sources and their role in the manipulation of epigenetic markers in cancer are discussed briefly in this review article. METHODS With advancing medicinal plant biotechnology and microbiology in the past century, several anticancer phytomedicines were developed. Modern pharmacopeia contains at least 25% herbal-based remedy including clinically used anticancer drugs. These drugs mainly include the podophyllotoxin derivatives vinca alkaloids, curcumin, mistletoe plant extracts, taxanes, camptothecin, combretastatin, and others including colchicine, artesunate, homoharringtonine, ellipticine, roscovitine, maytanasin, tapsigargin,andbruceantin. RESULTS Compounds (psammaplin, didemnin, dolastin, ecteinascidin,and halichondrin) isolated from marine sources and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates. They have been evaluated for their anticancer activity on cells and experimental animal models and used chemotherapy.Drug induced manipulation of epigenetic markers plays an important role in the treatment of cancer. CONCLUSION The development of a new drug from isolated bioactive compounds of plant sources has been a feasible way to lower the toxicity and increase their effectiveness against cancer. Potential anticancer therapeutic leads obtained from various ethnomedicinal plants, foods, marine, and microorganisms are showing effective yet realistically safe pharmacological activity. This review will highlight important plant-based bioactive compounds like curcumin, stilbenes, terpenes, other polyphenolic phyto-compounds, and structurally related families that are used to prevent/ ameliorate cancer. However, a contribution from all possible fields of science is still a prerequisite for discovering safe and effective anticancer drugs.
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Affiliation(s)
- Kalyani Pathak
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh - 786004, Assam, India
| | - Manash Pratim Pathak
- Faculty of Pharmaceutical Sciences, Assam down town University, Panikhaiti, Guwahati-781026, Assam, India
| | - Riya Saikia
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh - 786004, Assam, India
| | - Urvashee Gogoi
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh - 786004, Assam, India
| | - Jon Jyoti Sahariah
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh - 786004, Assam, India
| | - James H Zothantluanga
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh - 786004, Assam, India
| | - Abhishek Samanta
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh - 786004, Assam, India
| | - Aparoop Das
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh - 786004, Assam, India
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Paul B, Gaonkar RH, Dutta D, Dasi R, Mukherjee B, Ganguly S, Das SK. Inhibitory potential of iRGD peptide-conjugated garcinol-loaded biodegradable nanoparticles in rat colorectal carcinoma. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2022; 134:112714. [DOI: 10.1016/j.msec.2022.112714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 01/18/2022] [Accepted: 02/09/2022] [Indexed: 10/19/2022]
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Jaiswal B, Agarwal A, Gupta A. Lysine Acetyltransferases and Their Role in AR Signaling and Prostate Cancer. Front Endocrinol (Lausanne) 2022; 13:886594. [PMID: 36060957 PMCID: PMC9428678 DOI: 10.3389/fendo.2022.886594] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 06/17/2022] [Indexed: 11/18/2022] Open
Abstract
The development and growth of a normal prostate gland, as well as its physiological functions, are regulated by the actions of androgens through androgen receptor (AR) signaling which drives multiple cellular processes including transcription, cellular proliferation, and apoptosis in prostate cells. Post-translational regulation of AR plays a vital role in directing its cellular activities via modulating its stability, nuclear localization, and transcriptional activity. Among various post-translational modifications (PTMs), acetylation is an essential PTM recognized in AR and is governed by the regulated actions of acetyltransferases and deacetyltransferases. Acetylation of AR has been identified as a critical step for its activation and depending on the site of acetylation, the intracellular dynamics and activity of the AR can be modulated. Various acetyltransferases such as CBP, p300, PCAF, TIP60, and ARD1 that are known to acetylate AR, may directly coactivate the AR transcriptional function or help to recruit additional coactivators to functionally regulate the transcriptional activity of the AR. Aberrant expression of acetyltransferases and their deregulated activities have been found to interfere with AR signaling and play a key role in development and progression of prostatic diseases, including prostate cancer (PCa). In this review, we summarized recent research advances aimed at understanding the role of various lysine acetyltransferases (KATs) in the regulation of AR activity at the level of post-translational modifications in normal prostate physiology, as well as in development and progression of PCa. Considering the critical importance of KATs in modulating AR activity in physiological and patho-physiological context, we further discussed the potential of targeting these enzymes as a therapeutic option to treat AR-related pathology in combination with hormonal therapy.
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Affiliation(s)
- Bharti Jaiswal
- Integrative Chemical Biology (ICB), Institute for Stem Cell Science and Regenerative Medicine (inStem), Bengaluru, India
- *Correspondence: Ashish Gupta, ; Bharti Jaiswal,
| | - Akanksha Agarwal
- Epigenetics and Human Disease Laboratory, Centre of Excellence in Epigenetics (CoEE) Department of Life Sciences, Shiv Nadar University, Delhi, UP, India
| | - Ashish Gupta
- Epigenetics and Human Disease Laboratory, Centre of Excellence in Epigenetics (CoEE) Department of Life Sciences, Shiv Nadar University, Delhi, UP, India
- *Correspondence: Ashish Gupta, ; Bharti Jaiswal,
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Quaas CE, Long DT. Targeting (de)acetylation: A Diversity of Mechanism and Disease. COMPREHENSIVE PHARMACOLOGY 2022:469-492. [DOI: 10.1016/b978-0-12-820472-6.00076-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Lim SH, Lee HS, Lee CH, Choi CI. Pharmacological Activity of Garcinia indica (Kokum): An Updated Review. Pharmaceuticals (Basel) 2021; 14:ph14121338. [PMID: 34959738 PMCID: PMC8708457 DOI: 10.3390/ph14121338] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 01/02/2023] Open
Abstract
Garcinia indica (commonly known as kokum), belonging to the Clusiaceae family (mangosteen family), is a tropical evergreen tree distributed in certain regions of India. It has been used in culinary and industrial applications for a variety of purposes, including acidulant in curries, pickles, health drinks, wine, and butter. In particular, G. indica has been used in traditional medicine to treat inflammation, dermatitis, and diarrhea, and to promote digestion. According to several studies, various phytochemicals such as garcinol, hydroxycitric acid (HCA), cyanidin-3-sambubioside, and cyanidin-3-glucoside were isolated from G. indica, and their pharmacological activities were published. This review highlights recent updates on the various pharmacological activities of G. indica. These studies reported that G. indica has antioxidant, anti-obesity, anti-arthritic, anti-inflammatory, antibacterial, hepatoprotective, cardioprotective, antidepressant and anxiolytic effects both in vitro and in vivo. These findings, together with previously published reports of pharmacological activity of various components isolated from G. indica, suggest its potential as a promising therapeutic agent to prevent various diseases.
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Affiliation(s)
- Sung Ho Lim
- Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea; (S.H.L.); (H.S.L.)
| | - Ho Seon Lee
- Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea; (S.H.L.); (H.S.L.)
| | - Chang Hoon Lee
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea;
| | - Chang-Ik Choi
- Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea; (S.H.L.); (H.S.L.)
- Correspondence: ; Tel.: +82-31-961-5230
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