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Utpal BK, Bouenni H, Zehravi M, Sweilam SH, Mortuza MR, Arjun UVNV, Shanmugarajan TS, Mahesh PG, Roja P, Dodda RK, Thilagam E, Almahjari MS, Rab SO, Koula D, Emran TB. Exploring natural products as apoptosis modulators in cancers: insights into natural product-based therapeutic strategies. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03876-8. [PMID: 40014131 DOI: 10.1007/s00210-025-03876-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 02/02/2025] [Indexed: 02/28/2025]
Abstract
Cancer remains a leading cause of mortality globally, necessitating ongoing research and development of innovative therapeutic strategies. Natural products from plants, herbs, and marine species have shown great promise as anti-cancer therapies due to their bioactive components that alter cellular pathways, particularly apoptosis. This review explores the mechanism by which natural chemicals trigger the apoptosis of cancerous cells, which is crucial for eliminating them and halting tumor growth. These can affect the mitochondrial process by controlling the Bcl-2 protein family, increasing cytochrome c release, and activating caspases. They also activate death receptors like Fas and TRAIL to enhance the extrinsic apoptotic pathway. We focus on the main signaling channels involved, such as the endoplasmic reticulum (ER) stress-mediated apoptosis, extrinsic death receptor, and intrinsic mitochondrial pathways. The review explores the role of natural substances such as polyphenols, terpenoids, alkaloids, and flavonoids in promoting apoptotic cell death and increasing cancer cell susceptibility, potentially aiding in cancer treatments and the potential of combining natural products with traditional chemotherapeutic medicines to combat medication resistance and enhance therapeutic efficacy. Understanding cancer development involves inhibiting cell proliferation, regulating it, targeting apoptosis pathways, and using plant and marine extracts as apoptotic inducers.
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Affiliation(s)
- Biswajit Kumar Utpal
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka, 1216, Bangladesh.
| | - Hasna Bouenni
- Laboratory of Agrobiotechnology and Nutrition in Semi-Arid Zones, Faculty of Nature and Life Sciences, University of Ibn Khaldoun, Tiaret, Algeria
| | - Mehrukh Zehravi
- Department of Clinical Pharmacy, College of Dentistry & Pharmacy, Buraydah Private Colleges, 51418, Buraydah, Saudi Arabia.
| | - Sherouk Hussein Sweilam
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al-Kharj, Saudi Arabia
- Department of Pharmacognosy, Faculty of Pharmacy, Egyptian Russian University, Cairo-Suez Road, Badr City, 11829, Cairo, Egypt
| | | | - Uppuluri Varuna Naga Venkata Arjun
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies (VISTAS), PV Vaithiyalingam Rd, Velan Nagar, Krishna Puram, Pallavaram, Chennai, 600117, Tamil Nadu, India
| | - Thukani Sathanantham Shanmugarajan
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies (VISTAS), PV Vaithiyalingam Rd, Velan Nagar, Krishna Puram, Pallavaram, Chennai, 600117, Tamil Nadu, India
| | - Ponnammal Ganesan Mahesh
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies (VISTAS), PV Vaithiyalingam Rd, Velan Nagar, Krishna Puram, Pallavaram, Chennai, 600117, Tamil Nadu, India
| | - Pathakota Roja
- Department of Pharmacology, Sree Dattha Institute of Pharmacy, Sheriguda, Ibrahimpatnam, Hyderabad, Telangana, 501510, India
| | - Ravi Kalyan Dodda
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies (VISTAS), PV Vaithiyalingam Rd, Velan Nagar, Krishna Puram, Pallavaram, Chennai, 600117, Tamil Nadu, India
| | - E Thilagam
- Department of Pharmacognosy, JKKMMRF'S-ANNAI JKK Sampooorani Ammal College of Pharmacy, Ethirmedu, Komarapalayam (Affiliated to The Tamil Nadu Dr. M.G.R. Medical University, Chennai), India
| | - Mohammed Saeed Almahjari
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Doukani Koula
- Laboratory of Agrobiotechnology and Nutrition in Semi-Arid Zones, Faculty of Nature and Life Sciences, University of Ibn Khaldoun, Tiaret, Algeria
- Laboratory of Animal Production Sciences and Techniques, University of Abdelhamid Ibn Badis, Mostaganem, Algeria
| | - Talha Bin Emran
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka, 1216, Bangladesh
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Li Z, Fei X, Pan Z, Liang Y, Yang Q, Cheng D. Mometasone furoate inhibits tumor progression and promotes apoptosis through activation of the AMPK/mTOR signaling pathway in osteosarcoma. J Bone Oncol 2024; 47:100618. [PMID: 39050186 PMCID: PMC11267072 DOI: 10.1016/j.jbo.2024.100618] [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: 02/27/2024] [Revised: 06/03/2024] [Accepted: 06/20/2024] [Indexed: 07/27/2024] Open
Abstract
Osteosarcoma is the most common primary malignant bone tumor in adolescents. While treatments for osteosarcoma have improved, the overall survival has not changed for three decades, and thus, new targets for therapeutic development are needed. Recently, glucocorticoids have been reported to have antitumor effects. Mometasone furoate (MF), a synthetic glucocorticoid, is of great value in clinical application, but there are few reports on its antitumor effect. Here, we verified the effect of MF on osteosarcoma in vitro and in vivo. In vitro, cell proliferation, cell cycle progression, apoptosis and cell metastasis were detected using Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, wound-healing and transwell assays, respectively. In vivo, we generated a xenograft mouse model. To examine the potential role of the AMPK pathway, an AMPK-specific inhibitor (dorsomorphin) was used. The expression levels of factors related to the cell cycle, apoptosis and activation of the AMPK/mTOR pathway were assessed by immunohistochemistry and Western blotting. MF inhibited proliferation and metastasis and induced S phase arrest and apoptosis in osteosarcoma cells in a dose-dependent manner. In vivo, MF effectively inhibited osteosarcoma cell growth and pulmonary metastasis; however, it had no negative effect on the internal organs. Additionally, MF could activate the AMPK/mTOR pathway in osteosarcoma. Dorsomorphin significantly attenuated MF-induced antitumor activities. In summary, MF can inhibit osteosarcoma proliferation and metastasis and promote osteosarcoma cell apoptosis through the AMPK/mTOR signaling pathway in vitro and in vivo, which can provide a new rationale for subsequent academic and clinical research on osteosarcoma treatment.
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Affiliation(s)
- Zhaohui Li
- Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Xiang Fei
- Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Zhen Pan
- Department of Orthopedics, Tong Ren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Yonghui Liang
- Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Qingcheng Yang
- Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Dongdong Cheng
- Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
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Abulaizi A, Wang R, Xiong Z, Zhang S, Li Y, Ge H, Guo Z. Secondary Metabolites with Agricultural Antagonistic Potential from Aspergillus sp. ITBBc1, a Coral-Associated Marine Fungus. Mar Drugs 2024; 22:270. [PMID: 38921581 PMCID: PMC11205182 DOI: 10.3390/md22060270] [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: 05/16/2024] [Revised: 06/07/2024] [Accepted: 06/09/2024] [Indexed: 06/27/2024] Open
Abstract
A marine-derived fungal strain, Aspergillus sp. ITBBc1, was isolated from coral collected from the South China Sea in Hainan province. Intensive chemical investigation of the fermentation extract of this strain afforded four new secondary metabolites (1-4), named megastigmanones A-C and prenylterphenyllin H, along with four known compounds (5-8). Their structures were elucidated by extensive spectroscopic analysis including one-and two-dimensional (1D and 2D) NMR spectroscopy and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). The modified Mosher's method was undertaken to determine the absolute configurations of new compounds. The phytotoxic activity test showed that compounds 6-8 exhibited significant antagonistic activity against the germination of Triticum aestivum L. and Oryza sativa L. seeds with a dose-dependent relationship.
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Affiliation(s)
- Ailiman Abulaizi
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences, Nanjing University, Nanjing 210023, China;
| | - Rong Wang
- Hainan Key Laboratory of Tropical Microbe Resources, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences & Key Laboratory for Biology and Genetic Resources of Tropical Crops of Hainan Province, Hainan Institute for Tropical Agricultural Resources, Haikou 571101, China; (R.W.); (Z.X.); (S.Z.)
- Hainan Provincial Key Laboratory of Tropical Maricultural Technologies, Hainan Academy of Ocean and Fisheries Sciences, Haikou 571126, China
| | - Zijun Xiong
- Hainan Key Laboratory of Tropical Microbe Resources, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences & Key Laboratory for Biology and Genetic Resources of Tropical Crops of Hainan Province, Hainan Institute for Tropical Agricultural Resources, Haikou 571101, China; (R.W.); (Z.X.); (S.Z.)
| | - Shiqing Zhang
- Hainan Key Laboratory of Tropical Microbe Resources, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences & Key Laboratory for Biology and Genetic Resources of Tropical Crops of Hainan Province, Hainan Institute for Tropical Agricultural Resources, Haikou 571101, China; (R.W.); (Z.X.); (S.Z.)
| | - Yuanchao Li
- Hainan Provincial Key Laboratory of Tropical Maricultural Technologies, Hainan Academy of Ocean and Fisheries Sciences, Haikou 571126, China
| | - Huiming Ge
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences, Nanjing University, Nanjing 210023, China;
| | - Zhikai Guo
- Hainan Key Laboratory of Tropical Microbe Resources, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences & Key Laboratory for Biology and Genetic Resources of Tropical Crops of Hainan Province, Hainan Institute for Tropical Agricultural Resources, Haikou 571101, China; (R.W.); (Z.X.); (S.Z.)
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Sarkar A, Paul A, Banerjee T, Maji A, Saha S, Bishayee A, Maity TK. Therapeutic advancements in targeting BCL-2 family proteins by epigenetic regulators, natural, and synthetic agents in cancer. Eur J Pharmacol 2023; 944:175588. [PMID: 36791843 DOI: 10.1016/j.ejphar.2023.175588] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 01/21/2023] [Accepted: 02/08/2023] [Indexed: 02/17/2023]
Abstract
Cancer is amongst the deadliest and most disruptive disorders, having a much higher death rate than other diseases worldwide. Human cancer rates continue to rise, thereby posing the most significant concerns for medical health professionals. In the last two decades, researchers have gone past several milestones in tackling cancer while gaining insight into the role of apoptosis in cancer or targeting various biomarker tools for prognosis and diagnosis. Apoptosis which is still a topic full of complexities, can be controlled considerably by B-cell lymphoma 2 (BCL-2) and its family members. Therefore, targeting proteins of this family to prevent tumorigenesis, is essential to focus on the pharmacological features of the anti-apoptotic and pro-apoptotic members, which will help to develop and manage this disorder. This review deals with the advancements of various epigenetic regulators to target BCL-2 family proteins, including the mechanism of several microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Similarly, a rise in natural and synthetic molecules' research over the last two decades has allowed us to acquire insights into understanding and managing the transcriptional alterations that have led to apoptosis and treating various neoplastic diseases. Furthermore, several inhibitors targeting anti-apoptotic proteins and inducers or activators targeting pro-apoptotic proteins in preclinical and clinical stages have been summarized. Overall, agonistic and antagonistic mechanisms of BCL-2 family proteins conciliated by epigenetic regulators, natural and synthetic agents have proven to be an excellent choice in developing cancer therapeutics.
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Affiliation(s)
- Arnab Sarkar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Abhik Paul
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Tanmoy Banerjee
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Avik Maji
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Sanjukta Saha
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
| | - Tapan Kumar Maity
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
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Fungus-Derived 3-Hydroxyterphenyllin and Candidusin A Ameliorate Palmitic Acid-Induced Human Podocyte Injury via Anti-Oxidative and Anti-Apoptotic Mechanisms. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27072109. [PMID: 35408508 PMCID: PMC9000303 DOI: 10.3390/molecules27072109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/14/2022] [Accepted: 03/18/2022] [Indexed: 11/16/2022]
Abstract
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. An elevated fatty acid plasma concentration leads to podocyte injury and DN progression. This study aimed to identify and characterize cellular mechanisms of natural compounds that inhibit palmitic acid (PA)-induced human podocyte injury. By screening 355 natural compounds using a cell viability assay, 3-hydroxyterphenyllin (3-HT) and candidusin A (CDA), isolated from the marine-derived fungus Aspergillus candidus PSU-AMF169, were found to protect against PA-induced podocyte injury, with half-maximal inhibitory concentrations (IC50) of ~16 and ~18 µM, respectively. Flow cytometry revealed that 3-HT and CDA suppressed PA-induced podocyte apoptosis. Importantly, CDA significantly prevented PA-induced podocyte barrier impairment as determined by 70 kDa dextran flux. Reactive oxygen species (ROS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) direct scavenging assays indicated that both compounds exerted an anti-oxidative effect via direct free radical-scavenging activity. Moreover, 3-HT and CDA upregulated the anti-apoptotic Bcl2 protein. In conclusion, 3-HT and CDA represent fungus-derived bioactive compounds that have a novel protective effect on PA-induced human podocyte apoptosis via mechanisms involving free radical scavenging and Bcl2 upregulation.
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Miao Y, Wan W, Zhu K, Pan M, Zhao X, Ma B, Wei Q. Effects of 4-vinylcyclohexene diepoxide on the cell cycle, apoptosis, and steroid hormone secretion of goat ovarian granulosa cells. In Vitro Cell Dev Biol Anim 2022; 58:220-231. [PMID: 35386089 DOI: 10.1007/s11626-022-00663-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/24/2022] [Indexed: 12/19/2022]
Abstract
4-Vinylcyclohexene diepoxide (VCD) is a potentially hazardous industrial chemical that may enter a goat's body in various ways during industrial breeding. Ovarian granulosa cells (GCs) play a critical role in supporting follicle development and hormone synthesis. However, there are few studies on the effect of VCD on goat ovarian GCs. In this study, goat ovarian GCs were isolated and treated with VCD. The results showed that treatment with VCD increased the proportion of S phase and G2/M cells, but decreased the proportion of G1 phase. VCD treatment significantly inhibited the expression of cyclin A and cyclin-dependent kinase 2 (CDK2). But the expression levels of p21 and p27 were increased. VCD could induce an apparent increase in the proportion of apoptosis and the level of cleaved caspase 3. Treatment with VCD significantly reduced the progesterone and estrogen concentration in the medium in which goat ovarian GCs were cultured. Correspondingly, the expression level of steroidogenic acute regulatory protein (STAR) was significantly downregulated. Treatment with 0.25 and 0.5 mM VCD, the protein expression level of insulin-like growth factor 1 receptor (IGF1R) and Akt were significantly decreased. Moreover, treatment with 0.25 mM VCD significantly inhibited the phosphorylation of Akt. In conclusion, VCD exposure had cytotoxic effects such as decreased cell viability, disordered cell cycle, increased apoptosis, and interference with steroid hormone synthesis on goat GCs. These cytotoxic effects of VCD on goat GCs may be due to the downregulation of IGF1R and the inhibition of IGF1R/Akt signaling pathway.
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Affiliation(s)
- Yuyang Miao
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, Yangling, China
| | - Wenjing Wan
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, Yangling, China
| | - Kunyuan Zhu
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, Yangling, China
| | - Menghao Pan
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, Yangling, China
| | - Xiaoe Zhao
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, Yangling, China
| | - Baohua Ma
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, Yangling, China.
| | - Qiang Wei
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
- College of Veterinary Medicine, Northwest A&F University, Shaanxi, 712100, Yangling, China.
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Al-Obaidi JR, Jambari NN, Ahmad-Kamil EI. Mycopharmaceuticals and Nutraceuticals: Promising Agents to Improve Human Well-Being and Life Quality. J Fungi (Basel) 2021; 7:jof7070503. [PMID: 34202552 PMCID: PMC8304235 DOI: 10.3390/jof7070503] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 01/19/2023] Open
Abstract
Fungi, especially edible mushrooms, are considered as high-quality food with nutritive and functional values. They are of considerable interest and have been used in the synthesis of nutraceutical supplements due to their medicinal properties and economic significance. Specific fungal groups, including predominantly filamentous endophytic fungi from Ascomycete phylum and several Basidiomycetes, produce secondary metabolites (SMs) with bioactive properties that are involved in the antimicrobial and antioxidant activities. These beneficial fungi, while high in protein and important fat contents, are also a great source of several minerals and vitamins, in particular B vitamins that play important roles in carbohydrate and fat metabolism and the maintenance of the nervous system. This review article will summarize and discuss the abilities of fungi to produce antioxidant, anticancer, antiobesity, and antidiabetic molecules while also reviewing the evidence from the last decade on the importance of research in fungi related products with direct and indirect impact on human health.
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Affiliation(s)
- Jameel R. Al-Obaidi
- Department of Biology, Faculty of Science and Mathematics, Universiti Pendidikan Sultan Idris, Tanjong Malim 35900, Perak, Malaysia
- Correspondence: (J.R.A.-O.); (N.N.J.)
| | - Nuzul Noorahya Jambari
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
- Laboratory of Food Safety and Food Integrity, Institute of Tropical Agriculture and Food Security, Universti Putra Malaysia, Serdang 43400, Selangor, Malaysia
- Correspondence: (J.R.A.-O.); (N.N.J.)
| | - E. I. Ahmad-Kamil
- Malaysian Nature Society (MNS), JKR 641, Jalan Kelantan, Bukit Persekutuan, Kuala Lumpur 50480, Malaysia;
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Wang HX, Qin XH, Shen J, Liu QH, Shi YB, Xue L. Proteomic Analysis Reveals That Placenta-Specific Protein 9 Inhibits Proliferation and Stimulates Motility of Human Bronchial Epithelial Cells. Front Oncol 2021; 11:628480. [PMID: 34123785 PMCID: PMC8194706 DOI: 10.3389/fonc.2021.628480] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 04/14/2021] [Indexed: 11/13/2022] Open
Abstract
Placenta-specific protein 9 (PLAC9) is a putative secretory protein that was initially identified in the placenta and is involved in cell proliferation and motility. Bioinformatics analyses revealed that PLAC9 is repressed in lung cancers (LCs), especially lung adenocarcinomas, compared to that in the paired adjacent normal tissues, indicating that PLAC9 might be involved in the pathogenesis of pulmonary diseases. To investigate the potential role of PLAC9 in the abnormal reprogramming of airway epithelial cells (AECs), a key cause of pulmonary diseases, we constructed a stable PLAC9-overexpressing human bronchial epithelial cell line (16HBE-GFP-Plac9). We utilized the proteomic approach isobaric tag for relative and absolute quantification (iTRAQ) to analyze the effect of PLAC9 on cellular protein composition. Gene ontology (GO) and pathway analyses revealed that GO terms and pathways associated with cell proliferation, cell cycle progression, and cell motility and migration were significantly enriched among the proteins regulated by PLAC9. Our in vitro results showed that PLAC9 overexpression reduced cell proliferation, altered cell cycle progression, and increased cell motility, including migration and invasion. Our findings suggest that PLAC9 inhibits cell proliferation through S phase arrest by altering the expression levels of cyclin/cyclin-dependent kinases (CDKs) and promotes cell motility, likely via the concerted actions of cyclins, E-cadherin, and vimentin. Since these mechanisms may underlie PLAC9-mediated abnormal human bronchial pathogenesis, our study provides a basis for the development of molecular targeted treatments for LCs.
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Affiliation(s)
- Hai-Xia Wang
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Xu-Hui Qin
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Jinhua Shen
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Qing-Hua Liu
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Yun-Bo Shi
- Section on Molecular Morphogenesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Lu Xue
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China.,Section on Molecular Morphogenesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
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Huang H, Chen AY, Ye X, Guan R, Rankin GO, Chen YC. Galangin, a Flavonoid from Lesser Galangal, Induced Apoptosis via p53-Dependent Pathway in Ovarian Cancer Cells. Molecules 2020; 25:molecules25071579. [PMID: 32235536 PMCID: PMC7180956 DOI: 10.3390/molecules25071579] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/23/2020] [Accepted: 03/27/2020] [Indexed: 12/12/2022] Open
Abstract
Among women worldwide, ovarian cancer is one of the most dangerous cancers. Patients undergoing platinum-based chemotherapy might get adverse side effects and develop resistance to drugs. In recent years, natural compounds have aroused growing attention in cancer treatment. Galangin inhibited the growth of two cell lines, A2780/CP70 and OVCAR-3, more strongly than the growth of a normal ovarian cell line, IOSE 364. The IC50 values of galangin on proliferation of A2780/CP70, OVCAR-3 and IOSE 364 cells were 42.3, 34.5, and 131.3 μM, respectively. Flow cytometry analysis indicated that galangin preferentially induced apoptosis in both ovarian cancer cells with respect to normal ovarian cells. Galangin treatment increased the level of cleaved caspase-3 and -7 via the p53-dependent intrinsic apoptotic pathway by up-regulating Bax protein and via the p53-dependent extrinsic apoptotic pathway by up-regulating DR5 protein. By down-regulating the level of p53 with 20 μM pifithrin-α (PFT-α), the apoptotic rates of OVCAR-3 cells induced by galangin treatment (40 μM) were significantly decreased from 18.2% to 10.2%, indicating that p53 is a key regulatory protein in galangin-induced apoptosis in ovarian cancer cells. Although galangin up-regulated the expression of p21, it had little effect on the cell cycle of the two ovarian cancer cell lines. Furthermore, the levels of phosphorylated Akt and phosphorylated p70S6K were decreased through galangin treatment, suggesting that the Akt/p70S6K pathways might be involved in the apoptosis. Our results suggested that galangin is selective against cancer cells and can be used for the treatment of platinum-resistant ovarian cancers in humans.
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Affiliation(s)
- Haizhi Huang
- College of Life Sciences, China Jiliang University, Hangzhou 310018, China;
- College of Science, Technology & Mathematics, Alderson Broaddus University, Philippi, WV 26416, USA
| | - Allen Y. Chen
- Department of Pharmacy Informatics, Seattle Children’s Hospital, Seattle, WA 98101, USA;
| | - Xingqian Ye
- College of Biosystems Engineering and Food Science, National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou 310058, China;
| | - Rongfa Guan
- College of Food Science and Engineering, Zhejiang University of Technology, Hangzhou 310014, China;
| | - Gary O. Rankin
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA;
| | - Yi Charlie Chen
- College of Science, Technology & Mathematics, Alderson Broaddus University, Philippi, WV 26416, USA
- Correspondence: ; Tel.: +1-304-457-6277; Fax: +1-304-457-6239
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A novel function of calcium sensing receptor in chronic hypoxia-induced pulmonary venous smooth muscle cells proliferation. Hypertens Res 2019; 43:271-280. [PMID: 31853041 DOI: 10.1038/s41440-019-0373-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/27/2019] [Accepted: 11/02/2019] [Indexed: 11/08/2022]
Abstract
Chronic hypoxia (CH) causes remodeling not only in pulmonary arteries but also in pulmonary veins. Pulmonary vascular remodeling stems from increased pulmonary vascular myocyte proliferation. However, the pathogenesis of CH-induced proliferation of pulmonary venous smooth muscle cells (PVSMCs) remains unknown. The present study aimed to explore the mechanisms by which CH affects PVSMCs proliferation. PVSMCs were isolated from rat distal pulmonary veins and exposed to CH (4% O2 for 60 h). The expression of calcium sensing receptor (CaSR) was determined by immunofluorescence, real-time quantitative PCR and Western blotting. Cell proliferation was assessed by cell counting, CCK-8 assay, and BrdU incorporation. Apoptosis analysis was examined by flow cytometry. In rat distal PVSMCs, CH increased the cell number and cell viability and enhanced DNA synthesis, which is accompanied by upregulated mRNA and protein expression levels of CaSR. Two negative CaSR modulators (NPS2143, NPS2390) not only attenuated CH-induced CaSR upregulation but also inhibited CH-induced increases in cell number, cell viability and the proliferation index of PVSMCs, whereas two positive modulators (spermine, R568) not only amplified CH-induced CaSR upregulation but also intensified CH-induced increases in cell number, cell viability and the proliferation index of PVSMCs. Silencing CaSR with siRNA similarly attenuated the CH-induced enhancement of cell number, cell viability and DNA synthesis in PVSMCs. Neither CH nor downregulation of CaSR with siRNA had an effect on apoptosis in PVSMCs. These results suggest that CaSR mediating excessive proliferation is a new pathogenic mechanism involved in the initiation and progression of distal PVSMCs proliferation under CH conditions.
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11
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Yang D, Jiang T, Liu J, Zhang B, Lin P, Chen H, Zhou D, Tang K, Wang A, Jin Y. CREB3 regulatory factor -mTOR-autophagy regulates goat endometrial function during early pregnancy. Biol Reprod 2019; 98:713-721. [PMID: 29447354 DOI: 10.1093/biolre/ioy044] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 02/12/2018] [Indexed: 02/06/2023] Open
Abstract
In domestic ruminants, a receptive endometrium is crucial for successful pregnancy. Although many essential molecular modulators and pathways have been identified during early pregnancy, the precise mechanisms regulating goat endometrial function remains largely unknown. Here, we describe a novel regulator during early pregnancy, whereby hormones increased CREB3 regulatory factor (CREBRF) expression and act as a potential activator of autophagy in endometrial epithelial cells (EECs) via the mTOR pathway. Our results showed that knockdown of CREBRF via shCREBRF hampered EECs proliferation by S-phase cell cycle arrest and significantly inhibited endometrial function. We also reported that CREBRF-mTOR-autophagy pathway plays a vital role in regulating endometrial function, with a blockade of the mTOR by rapamycin demonstrating the regulatory function on prostaglandin (PGs) secretion and cell attachment in EECs. Moreover, chloroquine pretreatment also proved the above conclusion. Collectively, our findings provide new insight into the molecular mechanisms of goat endometrial function and indicate that the CREBRF-mTOR-autophagy pathway plays a central role in PGs secretion and cell attachment.
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Affiliation(s)
- Diqi Yang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Tingting Jiang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Jianguo Liu
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Beibei Zhang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Pengfei Lin
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.,Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Huatao Chen
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.,Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Dong Zhou
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.,Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Keqiong Tang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.,Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Aihua Wang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.,Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
| | - Yaping Jin
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.,Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
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12
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Jiang Y, Lyu T, Che X, Jia N, Li Q, Feng W. Overexpression of SMYD3 in Ovarian Cancer is Associated with Ovarian Cancer Proliferation and Apoptosis via Methylating H3K4 and H4K20. J Cancer 2019; 10:4072-4084. [PMID: 31417652 PMCID: PMC6692630 DOI: 10.7150/jca.29861] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 05/05/2019] [Indexed: 12/13/2022] Open
Abstract
Background: Epigenetic regulation has been verified as a key mechanism in tumorigenesis. SET and MYND domain-containing protein 3 (SMYD3), a histone methyltransferase, is a promising epigenetic therapeutic target and is overexpressed in numerous human tumors. SMYD3 can promote oncogenic progression by methylating lysines to integrate cytoplasmic kinase signaling cascades or by methylating histone lysines to regulate specific gene transcription. However, the exact role of SMYD3 in the progression of ovarian cancer is still unknown. Methods: Immunohistochemistry was employed to test SMYD3 expression in ovarian cancer tissues from clinical patients. CCK-8 assay, Real-time cell analysis (RTCA), colony formation assay, cell cycle and apoptosis tested by Flow cytometer were employed to test the effects of SMYD3 on cell proliferation and apoptosis in ovarian cancer cell lines. A PCR array was used to identify the downstream targets of SMYD3. And, PCR and Western blot were used to verify their expression. The binding of SMYD3 on the promoter of target genes were tested by ChIP assays. We also use nude mice subcutaneous tumor model and patient-derived xenograft (PDX) model to investigate the tumor promotive function of SMYD3 in vivo. Results: SMYD3 expression was higher in ovarian cancer tissues and cell lines than in normal ovarian epithelial tissue and human ovarian surface epithelial cells (HOSEpiC). After silencing SMYD3, the proliferation of ovarian cancer cells was significantly inhibited in vitro. In addition, the SMYD3-specific small-molecule inhibitor BCI-121 suppressed ovarian cancer cell proliferation. Downregulation of SMYD3 led to S phase arrest and increased the cell apoptosis rate. Furthermore, a PCR array revealed that SMYD3 knockdown caused the upregulation of the cyclin-dependent kinase (CDK) inhibitors CDKN2A (p16INK4), CDKN2B (p15INK4B), CDKN3 and CDC25A, which may be responsible for the S phase arrest. In addition, the upregulation of CD40LG and downregulation of BIRC3 may explain the increased cell apoptosis rate after silencing SMYD3. We also discovered that SMYD3 bound on the promoter of CDKN2A and down-regulated its expression by triple-methylating H4K20. In addition, SMYD3 bound on the promoter of BIRC3 and up-regulated its expression by triple-methylating H3K4. Finally, knocking down SMYD3 could inhibit ovarian cancer growth in nude mice subcutaneous tumor model and PDX model. Conclusion: Our results demonstrated that SMYD3 was overexpressed in ovarian cancer and contributes to the regulation of tumor proliferation and apoptosis via SMYD3-H4K20me3-CDKN2A pathway and SMYD3-H3K4me3-BIRC3 pathway. Thus, SMYD3 is a promising epigenetic therapeutic target for ovarian cancer.
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Affiliation(s)
- Yahui Jiang
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai, 200011. China.,Shanghai Key Laboratory of Female Reproductive Endocrine - Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai, 200011. China
| | - Tianjiao Lyu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai, 200011. China.,Shanghai Key Laboratory of Female Reproductive Endocrine - Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai, 200011. China.,Department of Gynecology and Obstetrics, Ruijin Hospital,Shanghai Jiaotong University , School of Medicine, 197 Ruijin Road, Shanghai, 200025, China
| | - Xiaoxia Che
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai, 200011. China.,Shanghai Key Laboratory of Female Reproductive Endocrine - Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai, 200011. China
| | - Nan Jia
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai, 200011. China.,Shanghai Key Laboratory of Female Reproductive Endocrine - Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai, 200011. China
| | - Qin Li
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai, 200011. China.,Shanghai Key Laboratory of Female Reproductive Endocrine - Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai, 200011. China
| | - Weiwei Feng
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fang Xie Road, Shanghai, 200011. China.,Department of Gynecology and Obstetrics, Ruijin Hospital,Shanghai Jiaotong University , School of Medicine, 197 Ruijin Road, Shanghai, 200025, China
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13
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The synergistic effect of PFK15 with metformin exerts anti-myeloma activity via PFKFB3. Biochem Biophys Res Commun 2019; 515:332-338. [DOI: 10.1016/j.bbrc.2019.05.136] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 05/21/2019] [Indexed: 02/08/2023]
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14
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Li H, Wang C, Li L, Bu W, Zhang M, Wei J, Tao L, Qian K, Ma P. Adapalene suppressed the proliferation of melanoma cells by S-phase arrest and subsequent apoptosis via induction of DNA damage. Eur J Pharmacol 2019; 851:174-185. [DOI: 10.1016/j.ejphar.2019.03.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 02/08/2019] [Accepted: 03/01/2019] [Indexed: 02/03/2023]
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15
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An J, He H, Wang L, Jin Y, Kong J, Zhong Y, Liu M, Shang Y. Fresh and ozonized black carbon promoted DNA damage and repair responses in A549 cells. Toxicol Res (Camb) 2019; 8:180-187. [PMID: 30931099 PMCID: PMC6404160 DOI: 10.1039/c8tx00281a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 11/15/2018] [Indexed: 01/16/2023] Open
Abstract
Nano-sized ambient black carbon (BC) is hypothesized to pose a serious threat to human health. After emission into the air, the atmospheric oxidation process can modify its physiochemical properties and change its biological responses. In this study, we aimed to compare different DNA damage and repair responses promoted by fresh BC (FBC) and ozone oxidized-BC (OBC). The cell apoptosis, cell arrest, DNA damage and repair were investigated in A549 cells after treatment with FBC and OBC. Associated gene expressions were measured with the reverse transcription quantitative polymerase chain reaction (RT-qPCR) method. Both FBC and OBC could induce cell apoptosis in A549 cells with up-regulated gene of promyelocytic leukemia protein (pml) and down-regulated gene of anti-apoptotic B-cell lymphoma-2 (bcl-2). FBC caused cell cycle arrest at S and G2/M phases, which was associated with up-regulated ataxia telangiectasia mutated (atm), checkpoint kinase 2 (chk2), structural maintenance of chromosomes 1 (smc1) and cell division cycle 25 homolog A (cdc25a) genes. OBC promoted cell cycle arrest at the S phase with up-regulated genes of atm, chk2 and smc1. Both FBC and OBC induced oxidative DNA damage and time-dependent DNA repair responses with increased gene expressions of breast cancer susceptibility protein 1 (brca1), recombination protein A paralog B (rad51b), methyl methanesulfonate-sensitivity protein 22-like and tonsoku-like (mms22l). Compared to FBC, OBC could cause more sufficient DNA damage repair responses through cell cycle arrest at the S phase, resulting in relatively weaker DNA damages.
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Affiliation(s)
- Jing An
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
| | - Huixin He
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
| | - Lu Wang
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
| | - Yingying Jin
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
| | - Jiexing Kong
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
| | - Yufang Zhong
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
| | - Mingyuan Liu
- Department of Neurology , Yueyang Hospital of Integrated Chinese and Western Medicine , Shanghai University of Traditional Chinese Medicine , Shanghai 200437 , China . ; Tel: +86 21 65161782
| | - Yu Shang
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
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16
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Yuan XL, Mao XX, Du YM, Yan PZ, Hou XD, Zhang ZF. Anti-Tumor Activity of Cembranoid-Type Diterpenes Isolated from Nicotiana tabacum L. Biomolecules 2019; 9:E45. [PMID: 30696084 PMCID: PMC6406568 DOI: 10.3390/biom9020045] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 01/17/2019] [Accepted: 01/17/2019] [Indexed: 12/16/2022] Open
Abstract
Recently, the incidence of hepatocellular carcinoma has increased worldwide. Cembranoid-type diterpenes (CBDs) from tobacco exhibit good antimicrobial, antitumor, and neuroprotective activities. Therefore, in this study, we isolated CBDs from Nicotiana tabacum L. and evaluated their antitumor activity against hepatoma cell lines. Particularly, the anti-tumor activity of α-2,7,11-cyprotermine-4,6-diol (α-CBD) was investigated against HepG2, SMMC-7721, and HL-7702 cells. The MTT assay revealed that α-CBD reduced the formation of cell clones and inhibited the proliferation of hepatocellular carcinoma cells. Morphological observations showed that α-CBD altered cell morphology and membrane permeability before inducing apoptosis. To further explore the antitumor mechanism of α-CBD, flow cytometry and transcriptome analysis were performed using HepG2 cells. The results showed that the number of HepG2 cells increased from 10.4% to 29.8%, indicating that α-CBD inhibits the proliferation of hepatocellular carcinoma cells in the S phase. The gene expression analysis of HepG2 cells treated with α-CBD showed 3068 genes with altered expression, among which 1289 were upregulated and 1779 were downregulated. Apoptosis induced by these differentially expressed genes might be mediated by the p53-PUMA, PI3K-Akt, and IL-1-NF-κB-IAP pathways. Comprehensively, our study shows that α-CBD isolated from N. tabacum L. can be potentially used as a natural antitumor agent.
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Affiliation(s)
| | | | | | | | - Xiao-Dong Hou
- Tobacco Research Institute of Chinese Academy of Agricultural Sciences, Qingdao 266101, China; (X.-L.Y.); (X.-X.M.); (Y.-M.D.); (P.-Z.Y.)
| | - Zhong-Feng Zhang
- Tobacco Research Institute of Chinese Academy of Agricultural Sciences, Qingdao 266101, China; (X.-L.Y.); (X.-X.M.); (Y.-M.D.); (P.-Z.Y.)
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17
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Wang L, Mao B, He H, Shang Y, Zhong Y, Yu Z, Yang Y, Li H, An J. Comparison of hepatotoxicity and mechanisms induced by triclosan (TCS) and methyl-triclosan (MTCS) in human liver hepatocellular HepG2 cells. Toxicol Res (Camb) 2018; 8:38-45. [PMID: 30713659 DOI: 10.1039/c8tx00199e] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 10/10/2018] [Indexed: 12/23/2022] Open
Abstract
Triclosan (TCS) is used as an antimicrobial agent and has been widely dispersed and detected in the environment and organisms including human samples. Methyl-triclosan (MTCS) is the predominant bacterial TCS metabolite. At present, the toxicological effects and mechanism of TCS and MTCS are still not fully understood. In this study, the cytotoxic effects of TCS and MTCS in HepG2 cells were investigated in terms of cell proliferation, comet assay, cell cycle, and apoptosis. In addition, the expressions of related proteins were detected with western blotting analysis. The results showed that TCS could significantly inhibit cell proliferation, while MTCS had no obvious effect on cell growth. Both TCS and MTCS caused oxidative injury associated with HO-1 induction and increased DNA strand breaks, which consequently initiated the damage repair process via up-regulation of DNA-PKcs. In addition, TCS blocked the HepG2 cells in S and G2/M phases of cell cycle through down-regulation of cyclin A2 and CDK; while MTCS induced cell cycle arrest at the S phase through up-regulation of cyclin A2 and CDK. Furthermore, TCS activated p53 mediated apoptosis in HepG2 cells in a caspase-independent manner, while MTCS induced apoptosis was dependent on caspase. Moreover, TCS exposure exhibited more severe toxicity in HepG2 cells as compared with MTCS exposure, indicating that the replacement of the ionizable proton in TCS by the methyl group in MTCS is correlated with the cellular toxicity and the molecular mechanism.
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Affiliation(s)
- Lu Wang
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
| | - Boyu Mao
- Implant Dentistry Department , Jiangbei Dental Hospital , Ningbo 315000 , China
| | - Huixin He
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
| | - Yu Shang
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
| | - Yufang Zhong
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
| | - Zhiqiang Yu
- State Key Laboratory of Organic Geochemistry , Guangzhou Institute of Geochemistry , Chinese Academy of Sciences , Guangzhou 510640 , China
| | - Yiting Yang
- Department of Neurology , Changhai Hospital , Second Military Medical University , Shanghai 200433 , China .
| | - Hui Li
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
| | - Jing An
- School of Environmental and Chemical Engineering , Shanghai University , Shanghai 200444 , China . ; Tel: +86 21 66137736
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18
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Park S, Lim W, Jeong W, Bazer FW, Lee D, Song G. Sideroxylin (Callistemon lanceolatus) suppressed cell proliferation and increased apoptosis in ovarian cancer cells accompanied by mitochondrial dysfunction, the generation of reactive oxygen species, and an increase of lipid peroxidation. J Cell Physiol 2018; 233:8597-8604. [PMID: 29904922 DOI: 10.1002/jcp.26540] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 02/12/2018] [Indexed: 02/06/2023]
Abstract
Sideroxylin is a C-methylated flavone isolated from Callistemon lanceolatus and exerts antimicrobial activity against Staphylococcus aureus. However, the anticancer effects of sideroxylin and its intracellular signaling mechanisms have not yet been identified. Results of our study showed that sideroxylin decreased cell proliferation and increased apoptosis, causing DNA fragmentation, depolarization of the mitochondrial membrane, the generation of reactive oxygen species, and an increase of lipid peroxidation in ovarian cancer cells (ES2 and OV90 cells). Additionally, sideroxylin activated the phosphorylation of ERK1/2, JNK, P38, and MAPK proteins and the use of LY294002, U0126, SB203580, and SP600125 to block their phosphorylation, respectively, in ES2 and OV90 cells. Collectively, the results of present study indicated that sideroxylin was a novel therapeutic agent to combat the proliferation of ovarian cancer cells through the induction of mitochondrial dysfunction and the activation of PI3 K and MAPK signal transduction.
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Affiliation(s)
- Sunwoo Park
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Whasun Lim
- Department of Biomedical Sciences, Catholic Kwandong University, Gangneung, Republic of Korea
| | - Wonsik Jeong
- Bio-Center, Gyeonggido Business and Science Accelerator, Suwon, Republic of Korea
| | - Fuller W Bazer
- Center for Animal Biotechnology and Genomics and Department of Animal Science, Texas A&M University, College Station, Texas
| | - Dongho Lee
- Department of Biosystems and Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Gwonhwa Song
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
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19
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Hubka V, Nováková A, Jurjević Ž, Sklenář F, Frisvad JC, Houbraken J, Arendrup MC, Jørgensen KM, Siqueira JPZ, Gené J, Kolařík M. Polyphasic data support the splitting of Aspergillus candidus into two species; proposal of Aspergillus dobrogensis sp. nov. Int J Syst Evol Microbiol 2018; 68:995-1011. [PMID: 29458472 DOI: 10.1099/ijsem.0.002583] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Aspergillus candidus is a species frequently isolated from stored grain, food, indoor environments, soil and occasionally also from clinical material. Recent bioprospecting studies highlighted the potential of using A. candidus and its relatives in various industrial sectors as a result of their significant production of enzymes and bioactive compounds. A high genetic variability was observed among A. candidus isolates originating from various European countries and the USA, that were mostly isolated from indoor environments, caves and clinical material. The A. candidus sensu lato isolates were characterized by DNA sequencing of four genetic loci, and agreement between molecular species delimitation results, morphological characters and exometabolite spectra were studied. Classical phylogenetic methods (maximum likelihood, Bayesian inference) and species delimitation methods based on the multispecies coalescent model supported recognition of up to three species in A. candidus sensu lato. After evaluation of phenotypic data, a broader species concept was adopted, and only one new species, Aspergillus dobrogensis, was proposed. This species is represented by 22 strains originating from seven countries (ex-type strain CCF 4651T=NRRL 62821T=IBT 32697T=CBS 143370T) and its differentiation from A. candidus is relevant for bioprospecting studies because these species have different exometabolite profiles. Evaluation of the antifungal susceptibility of section Candidi members to six antifungals using the reference EUCAST method showed that all species have low minimum inhibitory concentrations for all tested antifungals. These results suggest applicability of a wide spectrum of antifungal agents for treatment of infections caused by species from section Candidi.
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Affiliation(s)
- Vit Hubka
- Laboratory of Fungal Genetics and Metabolism, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic.,Department of Botany, Faculty of Science, Charles University, Prague, Czech Republic
| | - Alena Nováková
- Laboratory of Fungal Genetics and Metabolism, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | | | - František Sklenář
- Department of Botany, Faculty of Science, Charles University, Prague, Czech Republic.,Laboratory of Fungal Genetics and Metabolism, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jens C Frisvad
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Jos Houbraken
- Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands
| | - Maiken C Arendrup
- Unit of Mycology, Statens Serum Institut, Copenhagen, Denmark.,Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | | | - João P Z Siqueira
- Unitat de Micologia, Facultat de Medicina i Ciències de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Spain.,Laboratório de Microbiologia, Faculdade de Medicina de SãoJosé do Rio Preto, São José do Rio Preto, Brazil
| | - Josepa Gené
- Unitat de Micologia, Facultat de Medicina i Ciències de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Spain
| | - Miroslav Kolařík
- Department of Botany, Faculty of Science, Charles University, Prague, Czech Republic.,Laboratory of Fungal Genetics and Metabolism, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
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20
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Flavonoids from Chinese bayberry leaves induced apoptosis and G1 cell cycle arrest via Erk pathway in ovarian cancer cells. Eur J Med Chem 2018; 147:218-226. [PMID: 29438890 DOI: 10.1016/j.ejmech.2018.01.084] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 01/25/2018] [Accepted: 01/26/2018] [Indexed: 01/15/2023]
Abstract
Ovarian cancer is one of the leading causes of death related to the female reproductive system in western countries. Adverse side effects and resistance to platinum based chemotherapy have become the major obstacles for ovarian cancer treatment. Natural products have gained great attention in cancer treatment in recent years. Chinese bayberry leaves flavonoids (BLF) containing rich content of myricitrin (myricetin 3-O-rhamnoside) and a part of quercetrin (quercetin 3-rhamnoside) inhibited the growth of an ovarian cancer cell line A2780/CP70. Such inhibitory effects might be due to the induction of apoptosis and G1 cell cycle arrest. BLF treatment increased the expression of cleaved caspase-3 and -7 and induced apoptosis via a Erk-dependent caspase-9 activation intrinsic apoptotic pathway by up-regulating the pro-apoptotic proteins (Bad and Bax) and down-regulating the anti-apoptotic proteins (Bcl-xL and Bcl-2), which were also in consistency with the results from Hoechst 33342 staining and flow cytometry analysis. Furthermore, by reducing the expression of cyclin D1 and CDK4 and p-Erk, BLF elevated the distribution of G1 phase in cell cycle and thus caused G1 cell cycle arrest. Overall, these results indicated that BLPs could be a valuable resource of natural compound for ovarian cancer treatment.
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21
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Pistollato F, Calderón Iglesias R, Ruiz R, Aparicio S, Crespo J, Dzul Lopez L, Giampieri F, Battino M. The use of natural compounds for the targeting and chemoprevention of ovarian cancer. Cancer Lett 2017; 411:191-200. [PMID: 29017913 DOI: 10.1016/j.canlet.2017.09.050] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 09/25/2017] [Accepted: 09/25/2017] [Indexed: 12/21/2022]
Abstract
Among gynaecological cancers, ovarian cancer represents the leading cause of death in women. Current treatment for ovarian cancer entails surgery followed by combined chemotherapy with platinum and taxane, which are associated, particularly cisplatin, with severe side effects. While this treatment approach appears to be initially effective in a high number of patients, nearly 70% of them suffer a relapse within a few months after initial treatment. Therefore, more effective and better-tolerated treatment options are clearly needed. In recent years, several natural compounds (such as curcumin, epigallocatechin 3-gallate (EGCG), resveratrol, sulforaphane and Withaferin-A), characterized by long-term safety and negligible and/or inexistent side effects, have been proposed as possible adjuvants of traditional chemotherapy. Indeed, several in vitro and in vivo studies have shown that phytocompounds can effectively inhibit tumor cell proliferation, stimulate autophagy, induce apoptosis, and specifically target ovarian cancer stem cells (CSCs), which are generally considered to be responsible for tumor recurrence in several types of cancer. Here we review current literature on the role of natural products in ovarian cancer chemoprevention, highlighting their effects particularly on the regulation of inflammation, autophagy, proliferation and apoptosis, chemotherapy resistance, and ovarian CSC growth.
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Affiliation(s)
- Francesca Pistollato
- Centre for Nutrition and Health, Universidad Europea Del Atlántico (UEA), Santander, Spain
| | | | - Roberto Ruiz
- Centre for Nutrition and Health, Universidad Europea Del Atlántico (UEA), Santander, Spain
| | - Silvia Aparicio
- Centre for Nutrition and Health, Universidad Europea Del Atlántico (UEA), Santander, Spain
| | - Jorge Crespo
- Centre for Nutrition and Health, Universidad Europea Del Atlántico (UEA), Santander, Spain
| | - Luis Dzul Lopez
- Universidad Internacional Iberoamericana (UNINI), Campeche, Mexico
| | - Francesca Giampieri
- Dipartimento di Scienze Cliniche Specialistiche Ed Odontostomatologiche, Sez. Biochimica, Università Politecnica Delle Marche, Ancona, Italy.
| | - Maurizio Battino
- Centre for Nutrition and Health, Universidad Europea Del Atlántico (UEA), Santander, Spain; Dipartimento di Scienze Cliniche Specialistiche Ed Odontostomatologiche, Sez. Biochimica, Università Politecnica Delle Marche, Ancona, Italy.
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