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Luján-Méndez F, Roldán-Padrón O, Castro-Ruíz JE, López-Martínez J, García-Gasca T. Capsaicinoids and Their Effects on Cancer: The "Double-Edged Sword" Postulate from the Molecular Scale. Cells 2023; 12:2573. [PMID: 37947651 PMCID: PMC10650825 DOI: 10.3390/cells12212573] [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: 09/18/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023] Open
Abstract
Capsaicinoids are a unique chemical species resulting from a particular biosynthesis pathway of hot chilies (Capsicum spp.) that gives rise to 22 analogous compounds, all of which are TRPV1 agonists and, therefore, responsible for the pungency of Capsicum fruits. In addition to their human consumption, numerous ethnopharmacological uses of chili have emerged throughout history. Today, more than 25 years of basic research accredit a multifaceted bioactivity mainly to capsaicin, highlighting its antitumor properties mediated by cytotoxicity and immunological adjuvancy against at least 74 varieties of cancer, while non-cancer cells tend to have greater tolerance. However, despite the progress regarding the understanding of its mechanisms of action, the benefit and safety of capsaicinoids' pharmacological use remain subjects of discussion, since CAP also promotes epithelial-mesenchymal transition, in an ambivalence that has been referred to as "the double-edge sword". Here, we update the comparative discussion of relevant reports about capsaicinoids' bioactivity in a plethora of experimental models of cancer in terms of selectivity, efficacy, and safety. Through an integration of the underlying mechanisms, as well as inherent aspects of cancer biology, we propose mechanistic models regarding the dichotomy of their effects. Finally, we discuss a selection of in vivo evidence concerning capsaicinoids' immunomodulatory properties against cancer.
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Affiliation(s)
- Francisco Luján-Méndez
- Laboratorio de Biología Celular y Molecular, Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Av. De las Ciencias s/n, Juriquilla, Querétaro 76230, Querétaro, Mexico; (F.L.-M.); (O.R.-P.); (J.L.-M.)
| | - Octavio Roldán-Padrón
- Laboratorio de Biología Celular y Molecular, Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Av. De las Ciencias s/n, Juriquilla, Querétaro 76230, Querétaro, Mexico; (F.L.-M.); (O.R.-P.); (J.L.-M.)
| | - J. Eduardo Castro-Ruíz
- Escuela de Odontología, Facultad de Medicina, Universidad Autónoma de Querétaro, Querétaro 76176, Querétaro, Mexico;
| | - Josué López-Martínez
- Laboratorio de Biología Celular y Molecular, Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Av. De las Ciencias s/n, Juriquilla, Querétaro 76230, Querétaro, Mexico; (F.L.-M.); (O.R.-P.); (J.L.-M.)
| | - Teresa García-Gasca
- Laboratorio de Biología Celular y Molecular, Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Av. De las Ciencias s/n, Juriquilla, Querétaro 76230, Querétaro, Mexico; (F.L.-M.); (O.R.-P.); (J.L.-M.)
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Patwardhan CA, Kommalapati VK, Llbiyi T, Singh D, Alfa E, Horuzsko A, Korkaya H, Panda S, Reilly CA, Popik V, Chadli A. Capsaicin binds the N-terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti-tumor effects of 17-AAG (Tanespimycin). Sci Rep 2023; 13:13790. [PMID: 37612326 PMCID: PMC10447550 DOI: 10.1038/s41598-023-40933-9] [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: 06/26/2023] [Accepted: 08/18/2023] [Indexed: 08/25/2023] Open
Abstract
Heat shock protein 90 (Hsp90) and its co-chaperones promote cancer, and targeting Hsp90 holds promise for cancer treatment. Most of the efforts to harness this potential have focused on targeting the Hsp90 N-terminus ATP binding site. Although newer-generation inhibitors have shown improved efficacy in aggressive cancers, induction of the cellular heat shock response (HSR) by these inhibitors is thought to limit their clinical efficacy. Therefore, Hsp90 inhibitors with novel mechanisms of action and that do not trigger the HSR would be advantageous. Here, we investigated the mechanism by which capsaicin inhibits Hsp90. Through mutagenesis, chemical modifications, and proteomic studies, we show that capsaicin binds to the N-terminus of Hsp90 and inhibits its ATPase activity. Consequently, capsaicin and its analogs inhibit Hsp90 ATPase-dependent progesterone receptor reconstitution in vitro. Capsaicin did not induce the HSR, instead, it promoted the degradation of Hsp70 through the lysosome-autophagy pathway. Remarkably, capsaicin did not induce degradation of the constitutively expressed cognate Hsc70, indicating selectivity for Hsp70. Combined treatments of capsaicin and the Hsp90 inhibitor 17-AAG improved the anti-tumor efficacy of 17-AAG in cell culture and tridimensional tumor spheroid growth assays using breast and prostate cancer models. Consistent with this, in silico docking studies revealed that capsaicin binding to the ATP binding site of Hsp90 was distinct from classical N-terminus Hsp90 inhibitors, indicating a novel mechanism of action. Collectively, these findings support the use of capsaicin as a chemical scaffold to develop novel Hsp90 N-terminus inhibitors as well as its ability to be a potential cancer co-therapeutic.
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Affiliation(s)
- Chaitanya A Patwardhan
- Georgia Cancer Center at Augusta University (Formerly Medical College of Georgia), 1410 Laney Walker Blvd, CN-3313, Augusta, GA, 30912, USA
| | - Vamsi Krishna Kommalapati
- Georgia Cancer Center at Augusta University (Formerly Medical College of Georgia), 1410 Laney Walker Blvd, CN-3313, Augusta, GA, 30912, USA
| | - Taoufik Llbiyi
- Georgia Cancer Center at Augusta University (Formerly Medical College of Georgia), 1410 Laney Walker Blvd, CN-3313, Augusta, GA, 30912, USA
| | - Digvijay Singh
- Georgia Cancer Center at Augusta University (Formerly Medical College of Georgia), 1410 Laney Walker Blvd, CN-3313, Augusta, GA, 30912, USA
| | - Eyad Alfa
- Georgia Cancer Center at Augusta University (Formerly Medical College of Georgia), 1410 Laney Walker Blvd, CN-3313, Augusta, GA, 30912, USA
| | - Anatolij Horuzsko
- Georgia Cancer Center at Augusta University (Formerly Medical College of Georgia), 1410 Laney Walker Blvd, CN-3313, Augusta, GA, 30912, USA
| | - Hasan Korkaya
- Georgia Cancer Center at Augusta University (Formerly Medical College of Georgia), 1410 Laney Walker Blvd, CN-3313, Augusta, GA, 30912, USA
| | - Siva Panda
- Department of Chemistry and Biochemistry, Augusta University, Augusta, GA, 30912, USA
| | - Christopher A Reilly
- Department of Pharmacology and Toxicology, Center for Human Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, 84112, USA
| | - Vladimir Popik
- Department of Chemistry, University of Georgia, Athens, GA, 30602, USA
| | - Ahmed Chadli
- Georgia Cancer Center at Augusta University (Formerly Medical College of Georgia), 1410 Laney Walker Blvd, CN-3313, Augusta, GA, 30912, USA.
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Jia XY, Jiang DL, Jia XT, Fu LY, Tian H, Liu KL, Qi J, Kang YM, Yu XJ. Capsaicin improves hypertension and cardiac hypertrophy via SIRT1/NF-κB/MAPKs pathway in the hypothalamic paraventricular nucleus. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 118:154951. [PMID: 37453193 DOI: 10.1016/j.phymed.2023.154951] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/09/2023] [Accepted: 07/04/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND Hypertension has seriously affected a large part of the adult and elderly population. The complications caused by hypertension are important risk factors for cardiovascular disease accidents. Capsaicin, a pungent component of chili pepper has been revealed to improve hypertension. However, its potential mechanism in improving hypertension remains to be explored. PURPOSE In the present study, we aimed to investigate whether capsaicin could attenuate the SIRT1/NF-κB/MAPKs pathway in the paraventricular nucleus of hypothalamus (PVN). METHODS We used spontaneous hypertensive rats (SHRs) as animal model rats. Micro osmotic pump was used to give capsaicin through PVN for 28 days, starting from age12-week-old. RESULTS The results showed that capsaicin significantly reduced blood pressure from the 16th day of infusion onward. At the end of the experimental period, we measured cardiac hypertrophy index and the heart rate (HR), and the results showed that the cardiac hypertrophy and heart rate of rats was significantly improved upon capsaicin chronic infusion. Norepinephrine (NE) and epinephrine (EPI) in plasma of SHRs treated with capsaicin were also decreased. Additionally, capsaicin increased the protein expression and number of positive cells of SIRT1 and the 67-kDa isoform of glutamate decarboxylase (GAD67), decreased the production of reactive oxygen species (ROS), number of positive cells of NOX2, those of Angiotensin Converting Enzyme (ACE) and p-IKKβ, tyrosine hydroxylase (TH), the gene expression levels of NOX4 and pro-inflammatory cytokines. Capsaicin also decreased the relative protein expressions of protein in MAPKs pathway. CONCLUSION Current data indicated that capsaicin within the PVN improves hypertension and cardiac hypertrophy via SIRT1/NF-κB/MAPKs pathway in the PVN of SHRs, supporting its potential as candidate drug for preventing and improving hypertension.
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Affiliation(s)
- Xiu-Yue Jia
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an 710061, China; Department of Physiology, Basic Medical College, Jiamusi University, Jiamusi, Heilongjiang 154007, China
| | - Da-Li Jiang
- Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xiao-Tao Jia
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an 710061, China
| | - Li-Yan Fu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an 710061, China
| | - Hua Tian
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an 710061, China
| | - Kai-Li Liu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an 710061, China
| | - Jie Qi
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an 710061, China
| | - Yu-Ming Kang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an 710061, China
| | - Xiao-Jing Yu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an 710061, China.
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Barnard SJ, Haunschild J, Heiser L, Dieterlen MT, Klaeske K, Borger MA, Etz CD. Apoptotic Cell Death in Bicuspid-Aortic-Valve-Associated Aortopathy. Int J Mol Sci 2023; 24:ijms24087429. [PMID: 37108591 PMCID: PMC10138609 DOI: 10.3390/ijms24087429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/12/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
The bicuspid aortic valve (BAV) is the most common cardiovascular congenital abnormality and is frequently associated with proximal aortopathy. We analyzed the tissues of patients with bicuspid and tricuspid aortic valve (TAV) regarding the protein expression of the receptor for advanced glycation products (RAGE) and its ligands, the advanced glycation end products (AGE), as well as the S100 calcium-binding protein A6 (S100A6). Since S100A6 overexpression attenuates cardiomyocyte apoptosis, we investigated the diverse pathways of apoptosis and autophagic cell death in the human ascending aortic specimen of 57 and 49 patients with BAV and TAV morphology, respectively, to identify differences and explanations for the higher risk of patients with BAV for severe cardiovascular diseases. We found significantly increased levels of RAGE, AGE and S100A6 in the aortic tissue of bicuspid patients which may promote apoptosis via the upregulation of caspase-3 activity. Although increased caspase-3 activity was not detected in BAV patients, increased protein expression of the 48 kDa fragment of vimentin was detected. mTOR as a downstream protein of Akt was significantly higher in patients with BAV, whereas Bcl-2 was increased in patients with TAV, assuming a better protection against apoptosis. The autophagy-related proteins p62 and ERK1/2 were increased in patients with BAV, assuming that cells in bicuspid tissue are more likely to undergo apoptotic cell death leading to changes in the wall and finally to aortopathies. We provide first-hand evidence of increased apoptotic cell death in the aortic tissue of BAV patients which may thus provide an explanation for the increased risk of structural aortic wall deficiency possibly underlying aortic aneurysm formation or acute dissection.
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Affiliation(s)
- Sarah J Barnard
- Heisenberg Working Group, Saxonian Incubator for Clinical Translation, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany
| | - Josephina Haunschild
- Heisenberg Working Group, Saxonian Incubator for Clinical Translation, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
| | - Linda Heiser
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
| | - Maja T Dieterlen
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
| | - Kristin Klaeske
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
| | - Michael A Borger
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
| | - Christian D Etz
- Heisenberg Working Group, Saxonian Incubator for Clinical Translation, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany
- University Department for Cardiac Surgery, Heart Center Leipzig, 04289 Leipzig, Germany
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Li T, Liu N, Zhang G, Chen M. CASP4 and CASP8 as newly defined autophagy-pyroptosis-related genes associated with clinical and prognostic features of renal cell carcinoma. J Cancer Res Ther 2022; 18:1952-1960. [PMID: 36647955 DOI: 10.4103/jcrt.jcrt_126_22] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Objective The rapid discoveries of autophagy and pyroptosis have opened new avenues for treating renal cell carcinoma (RCC). The objective was to identify potential autophagy-pyroptosis-related drug targets and plausible prognostic biomarkers crucial for disease detection. Materials and Methods Gene expression data were downloaded from Gene Expression Omnibus (GSE168845), and autophagy-pyroptosis-related differentially expressed genes (DEGs) were identified. The prognostic values of DEGs were assessed using differential expression analysis and Kaplan-Meier curves, a prognostic nomogram was constructed using the DEG data, and the correlation between DEGs and infiltrating immune cells was evaluated. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were carried out to verify the expression levels of DEGs. Results CASP4 and CASP8 were identified as RCC-associated autophagy-pyroptosis-related genes, and CASP4 and CASP8 were found to be highly expressed in RCC tumor tissues. High expression of CASP4 and CASP8 was associated with higher pathological staging and poorer prognosis, whereas a prognostic nomogram constructed based on CASP4 and CASP8 could better predict RCC patient survival rates. Additionally, increased expression of CASP4 and CASP8 was highly correlated with the expression levels of multiple infiltrating immune cell types. Moreover, qRT-PCR and IHC validated the increased expression of CASP4 and CASP8 in RCC. Conclusion CASP4 and CASP8 were autophagy-pyroptosis-related genes associated with immunotherapy in RCC. CASP4 and CASP8 were identified as potential targets and effective prognostic biomarkers for RCC.
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Affiliation(s)
- Tao Li
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Ning Liu
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Guangyuan Zhang
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Ming Chen
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
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Sun Y, Zboril EK, De La Chapa JJ, Chai X, Da Conceicao VN, Valdez MC, McHardy SF, Gonzales CB, Singh BB. Inhibition of Ca 2+ entry by capsazepine analog CIDD-99 prevents oral squamous carcinoma cell proliferation. Front Physiol 2022; 13:969000. [PMID: 36187775 PMCID: PMC9521718 DOI: 10.3389/fphys.2022.969000] [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: 06/15/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Oral cancer patients have a poor prognosis, with approximately 66% of patients surviving 5-years after diagnosis. Treatments for oral cancer are limited and have many adverse side effects; thus, further studies are needed to develop drugs that are more efficacious. To achieve this objective, we developed CIDD-99, which produces cytotoxic effects in multiple oral squamous cell carcinoma (OSCC) cell lines. While we demonstrated that CIDD-99 induces ER stress and apoptosis in OSCC, the mechanism was unclear. Investigation of the Bcl-family of proteins showed that OSCC cells treated with CIDD-99 undergo downregulation of Bcl-XL and Bcl-2 anti-apoptotic proteins and upregulation of Bax (pro-apoptotic). Importantly, OSCC cells treated with CIDD-99 displayed decreased calcium signaling in a dose and time-dependent manner, suggesting that blockage of calcium signaling is the key mechanism that induces cell death in OSCC. Indeed, CIDD-99 anti-proliferative effects were reversed by the addition of exogenous calcium. Moreover, electrophysiological properties further established that calcium entry was via the non-selective TRPC1 channel and prolonged CIDD-99 incubation inhibited STIM1 expression. CIDD-99 inhibition of calcium signaling also led to ER stress and inhibited mitochondrial complexes II and V in vitro. Taken together, these findings suggest that inhibition of TRPC mediates induction of ER stress and mitochondrial dysfunction as a part of the cellular response to CIDD-99 in OSCC.
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Affiliation(s)
- Yuyang Sun
- Department of Periodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Emily K. Zboril
- Department of Periodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Jorge J. De La Chapa
- Department of Comprehensive Dentistry, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Xiufang Chai
- Department of Periodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX, United States
| | | | - Matthew C. Valdez
- Department of Chemistry and the Center for Innovative Drug Discovery, University of Texas at San Antonio, San Antonio, TX, United States
| | - Stanton F. McHardy
- Department of Chemistry and the Center for Innovative Drug Discovery, University of Texas at San Antonio, San Antonio, TX, United States
| | - Cara B. Gonzales
- Department of Comprehensive Dentistry, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Brij B. Singh
- Department of Periodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX, United States
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Adetunji TL, Olawale F, Olisah C, Adetunji AE, Aremu AO. Capsaicin: A Two-Decade Systematic Review of Global Research Output and Recent Advances Against Human Cancer. Front Oncol 2022; 12:908487. [PMID: 35912207 PMCID: PMC9326111 DOI: 10.3389/fonc.2022.908487] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/30/2022] [Indexed: 12/23/2022] Open
Abstract
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is one of the most important natural products in the genus Capsicum. Due to its numerous biological effects, there has been extensive and increasing research interest in capsaicin, resulting in increased scientific publications in recent years. Therefore, an in-depth bibliometric analysis of published literature on capsaicin from 2001 to 2021 was performed to assess the global research status, thematic and emerging areas, and potential insights into future research. Furthermore, recent research advances of capsaicin and its combination therapy on human cancer as well as their potential mechanisms of action were described. In the last two decades, research outputs on capsaicin have increased by an estimated 18% per year and were dominated by research articles at 93% of the 3753 assessed literature. In addition, anti-cancer/pharmacokinetics, cytotoxicity, in vivo neurological and pain research studies were the keyword clusters generated and designated as thematic domains for capsaicin research. It was evident that the United States, China, and Japan accounted for about 42% of 3753 publications that met the inclusion criteria. Also, visibly dominant collaboration nodes and networks with most of the other identified countries were established. Assessment of the eligible literature revealed that the potential of capsaicin for mitigating cancer mainly entailed its chemo-preventive effects, which were often linked to its ability to exert multi-biological effects such as anti-mutagenic, antioxidant and anti-inflammatory activities. However, clinical studies were limited, which may be related to some of the inherent challenges associated with capsaicin in the limited clinical trials. This review presents a novel approach to visualizing information about capsaicin research and a comprehensive perspective on the therapeutic significance and applications of capsaicin in the treatment of human cancer.
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Affiliation(s)
- Tomi Lois Adetunji
- Unit for Environmental Sciences and Management, North-West University, Potchefstroom, South Africa
| | - Femi Olawale
- Nano-Gene and Drug Delivery Group, Discipline of Biochemistry, School of Life Sciences, College of Agriculture, Engineering and Science, University of KwaZulu-Natal, Durban, South Africa
| | - Chijioke Olisah
- Department of Botany and Institute for Coastal and Marine Research, Nelson Mandela University, Port Elizabeth, South Africa
| | | | - Adeyemi Oladapo Aremu
- Indigenous Knowledge Systems Centre, Faculty of Natural and Agricultural Sciences, North-West University, Mmabatho, South Africa
- School of Life Sciences, College of Agriculture, Engineering and Science, University of KwaZulu-Natal, Durban, South Africa
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Aldehyde Dehydrogenase 2 (ALDH2) Elicits Protection against Pulmonary Hypertension via Inhibition of ERK1/2-Mediated Autophagy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2555476. [PMID: 35770049 PMCID: PMC9236760 DOI: 10.1155/2022/2555476] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/06/2022] [Accepted: 05/30/2022] [Indexed: 11/18/2022]
Abstract
Pulmonary hypertension (PH) is caused by chronic hypoxia that induces the migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs), eventually resulting in right heart failure. PH has been related to aberrant autophagy; however, the hidden mechanisms are still unclear. Approximately 40% East Asians, equivalent to 8% of the universal population, carry a mutation in Aldehyde dehydrogenase 2 (ALDH2), which leads to the aggregation of noxious reactive aldehydes and increases the propensity of several diseases. Therefore, we explored the potential aspect of ALDH2 in autophagy associated with PH. In vitro mechanistic studies were conducted in human PASMCs (HPASMCs) after lentiviral ALDH2 knockdown and treatment with platelet-derived growth factor-BB (PDGF-BB). PH was induced in wild-type (WT) and ALDH2-knockout (ALDH2−/−) mice using vascular endothelial growth factor receptor inhibitor SU5416 under hypoxic conditions (HySU). Right ventricular function was assessed using echocardiography and invasive hemodynamic monitoring. Histological and immunohistochemical analyses were performed to evaluate pulmonary vascular remodeling. EdU, transwell, and wound healing assays were used to evaluate HPASMC migration and proliferation, and electron microscopy and immunohistochemical and immunoblot assays were performed to assess autophagy. The findings demonstrated that ALDH2 deficiency exacerbated right ventricular pressure, hypertrophy, fibrosis, and right heart failure resulting from HySU-induced PH. ALDH2−/− mice exhibited increased pulmonary artery muscularization and 4-hydroxynonenal (4-HNE) levels in lung tissues. ALDH2 knockdown increased PDGF-BB-induced PASMC migration and proliferation and 4-HNE accumulation in vitro. Additionally, ALDH2 deficiency increased the number of autophagosomes and autophagic lysosomes together with autophagic flux and ERK1/2-Beclin-1 activity in lung tissues and PASMCs, indicating enhanced autophagy. In conclusion, the study shows that ALDH2 has a protective role against the migration and proliferation of PASMCs and PH, possibly by regulating autophagy through the ERK1/2-Beclin-1 pathway.
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Pang Y, Lin W, Zhan L, Zhang J, Zhang S, Jin H, Zhang H, Wang X, Li X. Inhibiting Autophagy Pathway of PI3K/AKT/mTOR Promotes Apoptosis in SK-N-SH Cell Model of Alzheimer's Disease. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:6069682. [PMID: 35178230 PMCID: PMC8846974 DOI: 10.1155/2022/6069682] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 12/22/2021] [Accepted: 12/31/2021] [Indexed: 01/31/2023]
Abstract
Alzheimer's disease is the most common dementia disease characterized by chronic progressive neurodegeneration. The incidence of Alzheimer's disease is on the rise as the population ages at an accelerating pace. According to epidemiological data, by 2050, the number of Alzheimer's patients in the United States will be three times higher than that in 2010, and a similar trend is occurring in China. To explore the effect and mechanism of let-7b by detecting the expression level of let-7b in Alzheimer's disease, fifty patients with Alzheimer's disease and thirty healthy controls were selected. The expression levels of let-7 families (let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, and let-7i) were detected by qPCR. Human neuroblastoma cell SK-N-SH were divided into control group (untreated), model group (treated with Aβ1-40), Aβ1-40+let-7b mimic group (treated with Aβ1-40 and transfected with let-7b mimic), and Aβ1-40+miR-NC group (treated with aβ1-40 and transfected with miR-NC). let-7b expression and cell survival rate were detected by qPCR and CCK-8, and the levels of caspase 3, LC3, beclin-1, PI3K, p-AKT, and p-mTOR were detected by Western blot. let-7b was significantly different between the case group and the control group (p < 0.001). CCK-8 showed a significant decrease in cell viability in Aβ1-40 treatment group compared with that in the control group (p < 0.01). Overexpression of let-7b significantly reduced the survival rate of the cells, and the expression of LC3II/LC3I and beclin-1 in the cells was significantly reduced by aβ1-40 treatment (p < 0.001). let-7b overexpression also inhibited autophagy via reducing the level of LC3II/LC3I and beclin-1 (p < 0.001). Aβ1-40 treatment and let-7b overexpression promoted apoptosis by increasing the expression of cleavage caspase 3. Western blot indicated that Aβ1-40 treatment and let-7b overexpression could increase the expression of PI3K, p-AKT, and p-mTOR. let-7b overexpression could inhibit autophagy and promote apoptosis in Alzheimer's cells by promoting PI3K/AKT/mTOR signaling pathway. PI3K/AKT/mTOR signaling pathway is involved in the imbalance between autophagy and apoptosis.
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Affiliation(s)
- Yu Pang
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Wennan Lin
- General Department, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Lan Zhan
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Jiawen Zhang
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Shicun Zhang
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Hongwei Jin
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - He Zhang
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Xiaoli Wang
- School of Pharmacy, Qiqihar Medical University, Qiqihar 161000, China
| | - Xiaoming Li
- The Institute of Medicine, Qiqihar Medical University, Qiqihar 161000, China
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10
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Li M, Zhao X, Yong H, Shang B, Lou W, Wang Y, Bai J. FBXO22 Promotes Growth and Metastasis and Inhibits Autophagy in Epithelial Ovarian Cancers via the MAPK/ERK Pathway. Front Pharmacol 2021; 12:778698. [PMID: 34950036 PMCID: PMC8688818 DOI: 10.3389/fphar.2021.778698] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
E3 ubiquitin ligase F-box only protein 22 (FBXO22), which targets the key regulators of cellular activities for ubiquitylation and degradation, plays an important role in tumorigenesis and metastasis. However, the function of FBXO22 in epithelial ovarian cancers has not been reported. This study aims to explore the biological function of FBXO22 in epithelial ovarian cancers progression and metastasis and its specific regulation mechanism. Immunohistochemistry analysis of tissue microarray was performed to evaluate the expression of FBXO22 in epithelial ovarian cancers patients. The proliferative ability of epithelial ovarian cancers cells was examined by the CCK8. The metastasis ability was detected by the wound healing assay, migration and invasion assays. Western blot was used to verify the relationship between FBXO22 expression and mitogen-activated protein kinase related proteins. Autophagic flux was detected by electron microscopy, mRFP-GFP-LC3 adenovirus, lysosomal tracker and western blot. For in vivo experiments, the effect of FBXO22 on epithelial ovarian cancers resistance was observed in a xenograft tumor model and a metastatic mice model. We found that FBXO22 expression was significantly increased in epithelial ovarian cancers tissues and was closely correlated with clinical pathological factors. As a result, we found that FBXO22 promoted the growth and metastasis, as well as inhibited the autophagy flux. In addition, we identified that FBXO22 performed these functions via the MAPK/ERK pathway. Our results first reported the function of FBXO22 in epithelial ovarian cancer and the correlation between FBXO22 and autophagy, suggesting FBXO22 as a novel target of epithelial ovarian cancers assessment and treatment.
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Affiliation(s)
- Minle Li
- Cancer Institute, Xuzhou Medical University, Xuzhou, China
| | - Xue Zhao
- Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Hongmei Yong
- Department of Oncology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, China
| | - Bingqing Shang
- Cancer Institute, Xuzhou Medical University, Xuzhou, China
| | - Weihua Lou
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - You Wang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jin Bai
- Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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11
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De K, Jayabalan AK, Mariappan R, Ramasamy VS, Ohn T. Dihydrocapsaicin induces translational repression and stress granule through HRI-eIF2α phosphorylation axis. Biochem Biophys Res Commun 2021; 588:125-132. [PMID: 34953209 DOI: 10.1016/j.bbrc.2021.12.049] [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: 10/25/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 11/02/2022]
Abstract
Stress granules (SGs) are cytoplasmic biomolecular condensates that are formed against a variety of stress conditions when translation initiation is perturbed. SGs form through the weak protein-protein, protein-RNA, and RNA-RNA interactions, as well as through the intrinsically disordered domains and post-translation modifications within RNA binding proteins (RBPs). SGs are known to contribute to cell survivability by minimizing the stress-induced damage to the cells by delaying the activation of apoptosis. Here, we find that dihydrocapsaicin (DHC), an analogue of capsaicin, is a SG inducer that promotes polysome disassembly and reduces global protein translation via phosphorylation of eIF2α. DHC-mediated SG assembly is controlled by the phosphorylation of eIF2α at serine 51 position and is controlled by all four eIF2α stress kinases (i.e., HRI, PKR, PERK, and GCN2) with HRI showing maximal effect. We demonstrate that DHC is a bonafide compound that induces SG assembly, disassembles polysome, phosphorylates eIF2α in an HRI dependent manner, and thereby arrest global translation. Together, our results suggest that DHC is a novel SG inducer and an alternate to sodium arsenite to study SG dynamics.
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Affiliation(s)
- Koushitak De
- Department of Cellular & Molecular Medicine, College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea
| | - Aravinth Kumar Jayabalan
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Ramesh Mariappan
- Department of Cellular & Molecular Medicine, College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea
| | - Vijay Sankar Ramasamy
- Department of Cellular & Molecular Medicine, College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea
| | - Takbum Ohn
- Department of Cellular & Molecular Medicine, College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea.
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12
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Zhao Q, Peng C, Zheng C, He XH, Huang W, Han B. Recent Advances in Characterizing Natural Products that Regulate Autophagy. Anticancer Agents Med Chem 2020; 19:2177-2196. [PMID: 31749434 DOI: 10.2174/1871520619666191015104458] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 11/16/2018] [Accepted: 08/26/2019] [Indexed: 02/07/2023]
Abstract
Autophagy, an intricate response to nutrient deprivation, pathogen infection, Endoplasmic Reticulum (ER)-stress and drugs, is crucial for the homeostatic maintenance in living cells. This highly regulated, multistep process has been involved in several diseases including cardiovascular and neurodegenerative diseases, especially in cancer. It can function as either a promoter or a suppressor in cancer, which underlines the potential utility as a therapeutic target. In recent years, increasing evidence has suggested that many natural products could modulate autophagy through diverse signaling pathways, either inducing or inhibiting. In this review, we briefly introduce autophagy and systematically describe several classes of natural products that implicated autophagy modulation. These compounds are of great interest for their potential activity against many types of cancer, such as ovarian, breast, cervical, pancreatic, and so on, hoping to provide valuable information for the development of cancer treatments based on autophagy.
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Affiliation(s)
- Qian Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Chuan Zheng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Xiang-Hong He
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China.,The RNA Institute, University at Albany, State University of New York, Albany, NY 12222, United States
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13
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Yao RQ, Ren C, Xia ZF, Yao YM. Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles. Autophagy 2020; 17:385-401. [PMID: 32048886 PMCID: PMC8007140 DOI: 10.1080/15548627.2020.1725377] [Citation(s) in RCA: 272] [Impact Index Per Article: 54.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The structural integrity and functional stability of organelles are prerequisites for the viability and responsiveness of cells. Dysfunction of multiple organelles is critically involved in the pathogenesis and progression of various diseases, such as chronic obstructive pulmonary disease, cardiovascular diseases, infection, and neurodegenerative diseases. In fact, those organelles synchronously present with evident structural derangement and aberrant function under exposure to different stimuli, which might accelerate the corruption of cells. Therefore, the quality control of multiple organelles is of great importance in maintaining the survival and function of cells and could be a potential therapeutic target for human diseases. Organelle-specific autophagy is one of the major subtypes of autophagy, selectively targeting different organelles for quality control. This type of autophagy includes mitophagy, pexophagy, reticulophagy (endoplasmic reticulum), ribophagy, lysophagy, and nucleophagy. These kinds of organelle-specific autophagy are reported to be beneficial for inflammatory disorders by eliminating damaged organelles and maintaining homeostasis. In this review, we summarized the recent findings and mechanisms covering different kinds of organelle-specific autophagy, as well as their involvement in various diseases, aiming to arouse concern about the significance of the quality control of multiple organelles in the treatment of inflammatory diseases.Abbreviations: ABCD3: ATP binding cassette subfamily D member 3; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ARIH1: ariadne RBR E3 ubiquitin protein ligase 1; ATF: activating transcription factor; ATG: autophagy related; ATM: ATM serine/threonine kinase; BCL2: BCL2 apoptosis regulator; BCL2L11/BIM: BCL2 like 11; BCL2L13: BCL2 like 13; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CANX: calnexin; CAT: catalase; CCPG1: cell cycle progression 1; CHDH: choline dehydrogenase; COPD: chronic obstructive pulmonary disease; CSE: cigarette smoke exposure; CTSD: cathepsin D; DDIT3/CHOP: DNA-damage inducible transcript 3; DISC1: DISC1 scaffold protein; DNM1L/DRP1: dynamin 1 like; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EIF2S1/eIF2α: eukaryotic translation initiation factor 2 alpha kinase 3; EMD: emerin; EPAS1/HIF-2α: endothelial PAS domain protein 1; ER: endoplasmic reticulum; ERAD: ER-associated degradation; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FBXO27: F-box protein 27; FKBP8: FKBP prolyl isomerase 8; FTD: frontotemporal dementia; FUNDC1: FUN14 domain containing 1; G3BP1: G3BP stress granule assembly factor 1; GBA: glucocerebrosidase beta; HIF1A/HIF1: hypoxia inducible factor 1 subunit alpha; IMM: inner mitochondrial membrane; LCLAT1/ALCAT1: lysocardiolipin acyltransferase 1; LGALS3/Gal3: galectin 3; LIR: LC3-interacting region; LMNA: lamin A/C; LMNB1: lamin B1; LPS: lipopolysaccharide; MAPK8/JNK: mitogen-activated protein kinase 8; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFN1: mitofusin 1; MOD: multiple organelles dysfunction; MTPAP: mitochondrial poly(A) polymerase; MUL1: mitochondrial E3 ubiquitin protein ligase 1; NBR1: NBR1 autophagy cargo receptor; NLRP3: NLR family pyrin domain containing 3; NUFIP1: nuclear FMR1 interacting protein 1; OMM: outer mitochondrial membrane; OPTN: optineurin; PD: Parkinson disease; PARL: presenilin associated rhomboid like; PEX3: peroxisomal biogenesis factor 3; PGAM5: PGAM family member 5; PHB2: prohibitin 2; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RETREG1/FAM134B: reticulophagy regulator 1; RHOT1/MIRO1: ras homolog family member T1; RIPK3/RIP3: receptor interacting serine/threonine kinase 3; ROS: reactive oxygen species; RTN3: reticulon 3; SEC62: SEC62 homolog, preprotein translocation factor; SESN2: sestrin2; SIAH1: siah E3 ubiquitin protein ligase 1; SNCA: synuclein alpha; SNCAIP: synuclein alpha interacting protein; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TICAM1/TRIF: toll-like receptor adaptor molecule 1; TIMM23: translocase of inner mitochondrial membrane 23; TNKS: tankyrase; TOMM: translocase of the outer mitochondrial membrane; TRIM: tripartite motif containing; UCP2: uncoupling protein 2; ULK1: unc-51 like autophagy activating kinase; UPR: unfolded protein response; USP10: ubiquitin specific peptidase 10; VCP/p97: valosin containing protein; VDAC: voltage dependent anion channels; XIAP: X-linked inhibitor of apoptosis; ZNHIT3: zinc finger HIT-type containing 3.
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Affiliation(s)
- Ren-Qi Yao
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing, People's Republic of China.,Department of Burn Surgery, Changhai Hospital, Navy Medical University, Shanghai, People's Republic of China
| | - Chao Ren
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Zhao-Fan Xia
- Department of Burn Surgery, Changhai Hospital, Navy Medical University, Shanghai, People's Republic of China
| | - Yong-Ming Yao
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing, People's Republic of China
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14
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Joshi V, Upadhyay A, Prajapati VK, Mishra A. How autophagy can restore proteostasis defects in multiple diseases? Med Res Rev 2020; 40:1385-1439. [PMID: 32043639 DOI: 10.1002/med.21662] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 01/03/2020] [Accepted: 01/28/2020] [Indexed: 12/12/2022]
Abstract
Cellular evolution develops several conserved mechanisms by which cells can tolerate various difficult conditions and overall maintain homeostasis. Autophagy is a well-developed and evolutionarily conserved mechanism of catabolism, which endorses the degradation of foreign and endogenous materials via autolysosome. To decrease the burden of the ubiquitin-proteasome system (UPS), autophagy also promotes the selective degradation of proteins in a tightly regulated way to improve the physiological balance of cellular proteostasis that may get perturbed due to the accumulation of misfolded proteins. However, the diverse as well as selective clearance of unwanted materials and regulations of several cellular mechanisms via autophagy is still a critical mystery. Also, the failure of autophagy causes an increase in the accumulation of harmful protein aggregates that may lead to neurodegeneration. Therefore, it is necessary to address this multifactorial threat for in-depth research and develop more effective therapeutic strategies against lethal autophagy alterations. In this paper, we discuss the most relevant and recent reports on autophagy modulations and their impact on neurodegeneration and other complex disorders. We have summarized various pharmacological findings linked with the induction and suppression of autophagy mechanism and their promising preclinical and clinical applications to provide therapeutic solutions against neurodegeneration. The conclusion, key questions, and future prospectives sections summarize fundamental challenges and their possible feasible solutions linked with autophagy mechanism to potentially design an impactful therapeutic niche to treat neurodegenerative diseases and imperfect aging.
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Affiliation(s)
- Vibhuti Joshi
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Karwar, India
| | - Arun Upadhyay
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Karwar, India
| | - Vijay K Prajapati
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Karwar, India
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15
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Maeyashiki C, Melhem H, Hering L, Baebler K, Cosin-Roger J, Schefer F, Weder B, Hausmann M, Scharl M, Rogler G, de Vallière C, Ruiz PA. Activation of pH-Sensing Receptor OGR1 (GPR68) Induces ER Stress Via the IRE1α/JNK Pathway in an Intestinal Epithelial Cell Model. Sci Rep 2020; 10:1438. [PMID: 31996710 PMCID: PMC6989664 DOI: 10.1038/s41598-020-57657-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 12/31/2019] [Indexed: 12/15/2022] Open
Abstract
Proton-sensing ovarian cancer G-protein coupled receptor (OGR1) plays an important role in pH homeostasis. Acidosis occurs at sites of intestinal inflammation and can induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), an evolutionary mechanism that enables cells to cope with stressful conditions. ER stress activates autophagy, and both play important roles in gut homeostasis and contribute to the pathogenesis of inflammatory bowel disease (IBD). Using a human intestinal epithelial cell model, we investigated whether our previously observed protective effects of OGR1 deficiency in experimental colitis are associated with a differential regulation of ER stress, the UPR and autophagy. Caco-2 cells stably overexpressing OGR1 were subjected to an acidic pH shift. pH-dependent OGR1-mediated signalling led to a significant upregulation in the ER stress markers, binding immunoglobulin protein (BiP) and phospho-inositol required 1α (IRE1α), which was reversed by a novel OGR1 inhibitor and a c-Jun N-terminal kinase (JNK) inhibitor. Proton-activated OGR1-mediated signalling failed to induce apoptosis, but triggered accumulation of total microtubule-associated protein 1 A/1B-light chain 3, suggesting blockage of late stage autophagy. Our results show novel functions for OGR1 in the regulation of ER stress through the IRE1α-JNK signalling pathway, as well as blockage of autophagosomal degradation. OGR1 inhibition might represent a novel therapeutic approach in IBD.
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Affiliation(s)
- Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Hassan Melhem
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Larissa Hering
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Katharina Baebler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Jesus Cosin-Roger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Fabian Schefer
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Bruce Weder
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, Zurich, Switzerland
| | - Cheryl de Vallière
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
| | - Pedro A Ruiz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
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16
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Yu S, Mu Y, Zhang X, Li J, Lee C, Wang H. Molecular mechanisms underlying titanium dioxide nanoparticles (TiO 2NP) induced autophagy in mesenchymal stem cells (MSC). JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2019; 82:997-1008. [PMID: 31718501 DOI: 10.1080/15287394.2019.1688482] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The bone marrow is one of the target tissues for titanium dioxide nanoparticles (TiO2NP) following environmental exposure. At present, the consequences of TiO2NP exposure in bone are not well known. The aim of this study was to investigate the effects of TiO2NP on mesenchymal stem cells (MSCs) and potential underlying mechanisms. Mesenchymal bone marrow-derived cells were cultured and treated with various concentrations of TiO2NP. Results showed that TiO2NP incubation produced cytotoxicity as evidenced by reduced cell viability. Using Western blotting TiO2NP was found to increase autophagy as determined by elevation in ratio of LC3-II from LC3-I without evidence of necrotic cell death as estimated by lactic dehydrogenase (LDH) level. TiO2NP produced a rise in intracellular reactive oxygen species (ROS) levels. The observed alterations in autophagy and oxidant stress were associated with upregulation of protein expression of p38, JNK, and ERK. Data indicate that TiO2NP-mediated decrease in MSC survival involves a complex series of events associated stimulation of mitogen-activated protein kinase (MAPK) pathway and consequent autophagy and oxidative damage.
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Affiliation(s)
- Shunbang Yu
- School of Health Sciences, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia
| | - Yongping Mu
- Tumor Molecular Diagnostic Laboratory, Department of Clinical Laboratory Centre, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Xudong Zhang
- School of Health Sciences, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia
| | - Jian Li
- Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, US
| | - Charles Lee
- School of Health Sciences, Faculty of Health and Medicine, University of Newcastle, Singapore
| | - He Wang
- School of Health Sciences, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia
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17
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Hao P, Cui X, Liu J, Li M, Fu Y, Liu Q. Identification and characterization of stearoyl-CoA desaturase in Toxoplasma gondii. Acta Biochim Biophys Sin (Shanghai) 2019; 51:615-626. [PMID: 31139819 DOI: 10.1093/abbs/gmz040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Indexed: 12/29/2022] Open
Abstract
Few information of the function of stearoyl-coenzyme A (CoA) desaturase (SCD) in apicomplaxan parasite has been obtained. In this study, we retrieved a putative fatty acyl-CoA desaturase (TGGT1_238950) by a protein alignment with Plasmodium falciparum SCD in ToxoDB. A typical Δ9-desaturase domain was revealed in this protein. The putative desaturase was tagged with HA endogenously in Toxoplasma gondii, and the endoplasmic reticulum localization of the putative desaturase was revealed, which was consistent with the fatty acid desaturases in other organisms. Therefore, the TGGT1_238950 was designated T. gondii SCD. Based on CRISPR/Cas9 gene editing technology, SCD conditional knockout mutants in the T. gondii TATi strain were obtained. The growth in vitro and pathogenicity in mice of the mutants suggested that SCD might be dispensable for tachyzoite growth and proliferation. The SCD-overexpressing line was constructed to further explore SCD function. The portion of palmitoleic acid and oleic acid were increased in SCD-overexpressing parasites, compared with the RH parental strain, indicating that T. gondii indeed is competent for unsaturated fatty acid synthesis. The SCD-overexpressing tachyzoites propagated slower than the parental strain, with a decreased invasion capability and weaker pathogenicity in mice. The TgIF2α phosphorylation and the expression changes of several genes demonstrated that ER stress was triggered in the SCD-overexpressing parasites, which were more apt toward autophagy and apoptosis. The function of unsaturated fatty acid synthesis of TgSCD was consistent with our hypothesis. On the other hand, SCD might also be involved in tachyzoite autophagy and apoptosis.
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Affiliation(s)
- Pan Hao
- National Animal Protozoa Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
- Patent Examination Cooperation Sichuan Center of the Patent Office, CNIPA, Chengdu, China
| | - Xia Cui
- Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Research Centre for Preventive Medicine, Beijing, China
| | - Jing Liu
- National Animal Protozoa Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Muzi Li
- National Animal Protozoa Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yong Fu
- National Animal Protozoa Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Qun Liu
- National Animal Protozoa Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
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18
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Fink EE, Moparthy S, Bagati A, Bianchi-Smiraglia A, Lipchick BC, Wolff DW, Roll MV, Wang J, Liu S, Bakin AV, Kandel ES, Lee AH, Nikiforov MA. XBP1-KLF9 Axis Acts as a Molecular Rheostat to Control the Transition from Adaptive to Cytotoxic Unfolded Protein Response. Cell Rep 2018; 25:212-223.e4. [PMID: 30282030 PMCID: PMC6251307 DOI: 10.1016/j.celrep.2018.09.013] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 07/13/2018] [Accepted: 09/07/2018] [Indexed: 02/06/2023] Open
Abstract
Transcription factor XBP1s, activated by endoplasmic reticulum (ER) stress in a dose-dependent manner, plays a central role in adaptive unfolded protein response (UPR) via direct activation of multiple genes controlling protein refolding. Here, we report that elevation of ER stress above a critical threshold causes accumulation of XBP1s protein sufficient for binding to the promoter and activation of a gene encoding a transcription factor KLF9. In comparison to other XBP1s targets, KLF9 promoter contains an evolutionary conserved lower-affinity binding site that requires higher amounts of XBP1s for activation. In turn, KLF9 induces expression of two regulators of ER calcium storage, TMEM38B and ITPR1, facilitating additional calcium release from ER, exacerbation of ER stress, and cell death. Accordingly, Klf9 deficiency attenuates tunicamycin-induced ER stress in mouse liver. These data reveal a role for XBP1s in cytotoxic UPR and provide insights into mechanisms of life-or-death decisions in cells under ER stress.
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Affiliation(s)
- Emily E Fink
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Sudha Moparthy
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA
| | - Archis Bagati
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Anna Bianchi-Smiraglia
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Brittany C Lipchick
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA
| | - David W Wolff
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA
| | - Matthew V Roll
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA
| | - Jianmin Wang
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Andrei V Bakin
- Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Eugene S Kandel
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Ann-Hwee Lee
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Mikhail A Nikiforov
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA.
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Rekha KR, Inmozhi Sivakamasundari R. Geraniol Protects Against the Protein and Oxidative Stress Induced by Rotenone in an In Vitro Model of Parkinson's Disease. Neurochem Res 2018; 43:1947-1962. [PMID: 30141137 DOI: 10.1007/s11064-018-2617-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 07/21/2018] [Accepted: 08/17/2018] [Indexed: 12/27/2022]
Abstract
Dysfunction of autophagy, mitochondrial dynamics and endoplasmic reticulum (ER) stress are currently considered as major contributing factors in the pathogenesis of Parkinson's disease (PD). Accumulation of oxidatively damaged cytoplasmic organelles and unfolded proteins in the lumen of the ER causes ER stress and it is associated with dopaminergic cell death in PD. Rotenone is a pesticide that selectively kills dopaminergic neurons by a variety of mechanism, has been implicated in PD. Geraniol (GE; 3,7-dimethylocta-trans-2,6-dien-1-ol) is an acyclic monoterpene alcohol occurring in the essential oils of several aromatic plants. In this study, we investigated the protective effect of GE on rotenone-induced mitochondrial dysfunction dependent oxidative stress leads to cell death in SK-N-SH cells. In addition, we assessed the involvement of GE on rotenone-induced dysfunction in autophagy machinery via α-synuclein accumulation induced ER stress. We found that pre-treatment of GE enhanced cell viability, ameliorated intracellular redox, preserved mitochondrial membrane potential and improves the level of mitochondrial complex-1 in rotenone treated SK-N-SH cells. Furthermore, GE diminishes autophagy flux by reduced autophagy markers, and decreases ER stress by reducing α-synuclein expression in SK-N-SH cells. Our results demonstrate that GE possess its neuroprotective effect via reduced rotenone-induced oxidative stress by enhanced antioxidant status and maintain mitochondrial function. Furthermore, GE reduced ER stress and improved autophagy flux in the neuroblastomal SK-N-SH cells. The present study could suggest that GE a novel therapeutic avenue for clinical intervention in neurodegenerative diseases especially for PD.
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Affiliation(s)
- Karamkolly R Rekha
- Division of Biochemistry, Faculty of Medicine, Raja Muthaiah Medical College, Annamalai University, Annamalai Nagar, Tamilnadu, 608 002, India
| | - Ramu Inmozhi Sivakamasundari
- Division of Biochemistry, Faculty of Medicine, Raja Muthaiah Medical College, Annamalai University, Annamalai Nagar, Tamilnadu, 608 002, India.
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20
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Oh SH, Yoon MH, Lim KJ, Yu BS, Jee IG, Jung KT. Nefopam downregulates autophagy and c-Jun N-terminal kinase activity in the regulation of neuropathic pain development following spinal nerve ligation. BMC Anesthesiol 2018; 18:97. [PMID: 30053799 PMCID: PMC6064146 DOI: 10.1186/s12871-018-0559-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 07/13/2018] [Indexed: 02/03/2023] Open
Abstract
Background Neurodegeneration is associated with changes in basal cellular function due to the dysregulation of autophagy. A recent study introduced the involvement of autophagy during spinal nerve ligation (SNL). Nefopam has shown potential for reducing neuropathic pain, but the underlying mechanisms are unknown. Here, we investigated the effects of nefopam on neuropathic pain development following SNL, focusing on the involvement of autophagy. Methods The functional role of nefopam in capsaicin-induced autophagy was assessed by human glioblastoma M059 K cells. The neuropathic pain model was used to determine whether the effect of nefopam on pain control was mediated through autophagy control. Neuropathic pain was induced by L5 and L6 SNL in male rats randomized into three groups: Group S (sham-operated), Group C (received normal saline), and Group E (received nefopam). A behavioral test using a von Frey was examined. Expression changes of autophagy in response to nefopam was analyzed in spinal cord tissues (L4-L6) by immunoblotting and immunohistochemistry. Results The paw withdrawal threshold examined on days 3, 5, 7, and 14 post-SNL was significantly higher in Group E than in Group C. SNL increased the levels of microtubule-associated protein 1 light chain 3B (LC3B-1), with concomitant reduction of sequestosome 1 (SQTSM1/p62), compared with Group S, indicating that SNL induced autophagy. These effects were reversed by nefopam injection, and the results were confirmed by immunohistochemistry for LC3-I/II. Furthermore, SNL-mediated JNK activation was markedly decreased following nefopam injection. Hematoxylin and eosin staining on Day 14 post-SNL revealed that SNL caused lymphocyte infiltration and oligodendrocyte localization in the substantia gelatinosa of the dorsal gray horn, which were reduced by nefopam injection. Conclusion Collectively, the mode of action of nefopam on neuropathic pain appears to be associated with downregulation of phospho-JNK and autophagy, as well as modulation of the immune response.
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Affiliation(s)
- Seon-Hee Oh
- School of Medicine, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju, 501-759, South Korea
| | - Myung Ha Yoon
- Department of Anesthesiology and Pain Medicine, Medical School, Chonnam National University, 42 Jebongro, Donggu, Gwangju, 501-757, South Korea
| | - Kyung Joon Lim
- Department of Anesthesiology and Pain Medicine, School of Medicine, Chosun University, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju, 61453, South Korea
| | - Byung Sik Yu
- Department of Anesthesiology and Pain Medicine, School of Medicine, Chosun University, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju, 61453, South Korea
| | - In Gook Jee
- Department of Anesthesiology and Pain Medicine, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju, 61453, South Korea
| | - Ki Tae Jung
- Department of Anesthesiology and Pain Medicine, School of Medicine, Chosun University, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju, 61453, South Korea.
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21
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Weidner J, Jarenbäck L, Åberg I, Westergren‐Thorsson G, Ankerst J, Bjermer L, Tufvesson E. Endoplasmic reticulum, Golgi, and lysosomes are disorganized in lung fibroblasts from chronic obstructive pulmonary disease patients. Physiol Rep 2018; 6:e13584. [PMID: 29484832 PMCID: PMC5827558 DOI: 10.14814/phy2.13584] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 12/18/2017] [Accepted: 12/26/2017] [Indexed: 12/23/2022] Open
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is often caused by smoking and other stressors. This causes oxidative stress, which induces numerous changes on both the transcriptome and proteome of the cell. We aimed to examine if the endomembrane pathway, including the endoplasmic reticulum (ER), Golgi, and lysosomes, was disrupted in fibroblasts from COPD patients as opposed to healthy ever-smokers or never-smokers, and if the response to stress differed. Different cellular compartments involved in the endomembrane pathway, as well as mRNA expression and apoptosis, were examined before and after the addition of stress in lung fibroblasts from never-smokers, ever-smokers, and patients with COPD. We found that the ER, Golgi, and lysosomes were disorganized in fibroblasts from COPD patients under baseline conditions. After a time course with ER stress inducing chemicals, changes to the phenotypes of cellular compartments in COPD patient fibroblasts were observed, and the expression of the ER stress-induced gene ERP72 was upregulated more in the COPD patient's cells compared to ever-smokers or never-smokers. Lastly, a tendency of increased active Caspase-3 was observed in COPD fibroblasts. Our results show that COPD patients have phenotypic changes in the lung fibroblasts endomembrane pathway, and respond differently to stress. Furthermore, these fibroblasts were cultured for several weeks outside the body, but they were not able to regain proper ER structure, indicating that the internal changes to the endomembrane system are permanent in smokers. This vulnerability to cellular stress might be a cause as to why some smokers develop COPD.
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Affiliation(s)
- Julie Weidner
- Department of Clinical Sciences Lund, Respiratory Medicine and AllergologyLund UniversityLundSweden
| | - Linnea Jarenbäck
- Department of Clinical Sciences Lund, Respiratory Medicine and AllergologyLund UniversityLundSweden
| | - Ida Åberg
- Department of Clinical Sciences Lund, Respiratory Medicine and AllergologyLund UniversityLundSweden
| | | | - Jaro Ankerst
- Department of Clinical Sciences Lund, Respiratory Medicine and AllergologyLund UniversityLundSweden
| | - Leif Bjermer
- Department of Clinical Sciences Lund, Respiratory Medicine and AllergologyLund UniversityLundSweden
| | - Ellen Tufvesson
- Department of Clinical Sciences Lund, Respiratory Medicine and AllergologyLund UniversityLundSweden
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22
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Friedman JR, Nolan NA, Brown KC, Miles SL, Akers AT, Colclough KW, Seidler JM, Rimoldi JM, Valentovic MA, Dasgupta P. Anticancer Activity of Natural and Synthetic Capsaicin Analogs. J Pharmacol Exp Ther 2018; 364:462-473. [PMID: 29246887 PMCID: PMC5803642 DOI: 10.1124/jpet.117.243691] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 12/13/2017] [Indexed: 12/28/2022] Open
Abstract
The nutritional compound capsaicin is the major spicy ingredient of chili peppers. Although traditionally associated with analgesic activity, recent studies have shown that capsaicin has profound antineoplastic effects in several types of human cancers. However, the applications of capsaicin as a clinically viable drug are limited by its unpleasant side effects, such as gastric irritation, stomach cramps, and burning sensation. This has led to extensive research focused on the identification and rational design of second-generation capsaicin analogs, which possess greater bioactivity than capsaicin. A majority of these natural capsaicinoids and synthetic capsaicin analogs have been studied for their pain-relieving activity. Only a few of these capsaicin analogs have been investigated for their anticancer activity in cell culture and animal models. The present review summarizes the current knowledge of the growth-inhibitory activity of natural capsaicinoids and synthetic capsaicin analogs. Future studies that examine the anticancer activity of a greater number of capsaicin analogs represent novel strategies in the treatment of human cancers.
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Affiliation(s)
- Jamie R Friedman
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Nicholas A Nolan
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Kathleen C Brown
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Sarah L Miles
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Austin T Akers
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Kate W Colclough
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Jessica M Seidler
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - John M Rimoldi
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Monica A Valentovic
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
| | - Piyali Dasgupta
- Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (J.R.F., N.A.N., S.L.M., K.C.B., A.T.A., K.W.C., J.M.S., M.A.V., P.D.); and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (J.M.R.)
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Inhibiting autophagy overcomes docetaxel resistance in castration-resistant prostate cancer cells. Int Urol Nephrol 2018; 50:675-686. [PMID: 29460131 PMCID: PMC5878207 DOI: 10.1007/s11255-018-1801-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 01/17/2018] [Indexed: 12/25/2022]
Abstract
Background This study investigates the docetaxel-resistant mechanism and explores the effect of tea polyphenols (TP) on autophagy and its related mechanism in human castration-resistant prostate cancer (CRPC) cell lines PC3 and DU145. Methods Immunofluorescence assay and annexin V-FITC/PI double staining flow cytometry were used to analyze the apoptosis and autophagy of PC3 and DU145 cells. The expression of autophagy-related proteins was detected by western bolt. Results Docetaxel could induce autophagy and apoptosis, together with the expression increase in p-JNK, p-Bcl-2 and Beclin1. The level of autophagy was remarkably decreased, but apoptosis was increased after combining with TP. In addition, the expression of p-mTOR was increased after combining with TP. Conclusion Docetaxel induces protective autophagy in CRPC cells by JNK pathway activation and then Bcl-2 phosphorylation and Beclin1 dissociation. TP activates mTOR pathway, which ultimately inhibits docetaxel-induced autophagy and improves therapeutic efficacy of docetaxel in CRPC cells.
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24
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Shubin AV, Demidyuk IV, Komissarov AA, Rafieva LM, Kostrov SV. Cytoplasmic vacuolization in cell death and survival. Oncotarget 2018; 7:55863-55889. [PMID: 27331412 PMCID: PMC5342458 DOI: 10.18632/oncotarget.10150] [Citation(s) in RCA: 248] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 06/06/2016] [Indexed: 12/15/2022] Open
Abstract
Cytoplasmic vacuolization (also called cytoplasmic vacuolation) is a well-known morphological phenomenon observed in mammalian cells after exposure to bacterial or viral pathogens as well as to various natural and artificial low-molecular-weight compounds. Vacuolization often accompanies cell death; however, its role in cell death processes remains unclear. This can be attributed to studying vacuolization at the level of morphology for many years. At the same time, new data on the molecular mechanisms of the vacuole formation and structure have become available. In addition, numerous examples of the association between vacuolization and previously unknown cell death types have been reported. Here, we review these data to make a deeper insight into the role of cytoplasmic vacuolization in cell death and survival.
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Affiliation(s)
- Andrey V Shubin
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia.,Laboratory of Chemical Carcinogenesis, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.,Laboratory of Biologically Active Nanostructures, N.F. Gamaleya Institute of Epidemiology and Microbiology, Moscow, Russia
| | - Ilya V Demidyuk
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
| | - Alexey A Komissarov
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
| | - Lola M Rafieva
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
| | - Sergey V Kostrov
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
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25
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Zhao H, Li Q, Pang J, Jin H, Li H, Yang X. Blocking autophagy enhances the pro-apoptotic effect of bufalin on human gastric cancer cells through endoplasmic reticulum stress. Biol Open 2017; 6:1416-1422. [PMID: 28838965 PMCID: PMC5665466 DOI: 10.1242/bio.026344] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Bufalin has been used to treat cancer for several years. However, the molecular mechanisms for its anti-tumor function are not fully understood. This work aimed to investigate the effect of bufalin on the proliferation and apoptosis of human gastric cancer (HGC) cells and the roles of endoplasmic reticulum (ER) stress and autophagy in bufalin-induced apoptosis. HGC cell lines, SGC7901 and BGC823, were treated with different concentrations of bufalin or 80 nmol/l bufalin for 1, 2, 3 and 4 days. Cell counting kit-8 (CCK-8) assay and direct cell counting method were used to detect proliferation. Cell cycle arrest and apoptosis was detected using flow cytometry. Protein levels of caspase-3, -8, Bax/Bcl-2, Beclin-1, LC3, inositol-requiring enzyme 1 (IRE1) and C/EBP homologous protein (CHOP) were determined using western blotting. Autophagy was blocked using 3-methyladenine (3MA) or Atg5 siRNA to evaluate the effect of autophagy on bufalin-induced apoptosis. The IRE1 and CHOP were knocked down using specific siRNA to determine the pathway involved in bufalin-induced autophagy. It was found that bufalin significantly suppressed proliferation of SGC7901 and BGC823 cells and induced apoptosis in a time- and dose-dependent manner. The mechanism responsible for bufalin-induced apoptosis was the formation of ER stress via the IRE1-JNK pathway. Moreover, autophagy was activated during ER stress, and blocking autophagy significantly exacerbated bufalin-induced apoptosis. Summary: Bufalin suppressed human gastric cancer cells and induced apoptosis. The mechanism was related to ER stress formation via the IRE1-JNK pathway. Blocking autophagy exacerbated bufalin-induced apoptosis.
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Affiliation(s)
- Hongyan Zhao
- Department of Gastroenterology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China .,Department of Gastroenterology, the Fourth Hospital of Harbin, Harbin 150026, China
| | - Qinghua Li
- Department of Hepatology and Pancreatology, Shanghai East Hospital, Tongji University, Shanghai 200120, China
| | - Jie Pang
- Pharmacy, the Fifth Hospital of Harbin, Harbin 150000, China
| | - Huilin Jin
- Department of Gastroenterology, the Fourth Hospital of Harbin, Harbin 150026, China
| | - Hongwei Li
- Department of Gastroenterology, the Fourth Hospital of Harbin, Harbin 150026, China
| | - Xiaoying Yang
- Department of Gastroenterology, the Fourth Hospital of Harbin, Harbin 150026, China
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26
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Kaufman DR, Papillon J, Larose L, Iwawaki T, Cybulsky AV. Deletion of inositol-requiring enzyme-1α in podocytes disrupts glomerular capillary integrity and autophagy. Mol Biol Cell 2017; 28:1636-1651. [PMID: 28428258 PMCID: PMC5469607 DOI: 10.1091/mbc.e16-12-0828] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 04/10/2017] [Accepted: 04/14/2017] [Indexed: 12/02/2022] Open
Abstract
Inositol-requiring enzyme-1α (IRE1α) is an endoplasmic reticulum (ER)-transmembrane endoribonuclease kinase that plays an essential function in extraembryonic tissues during normal development and is activated during ER stress. To address the functional role of IRE1α in glomerular podocytes, we produced podocyte-specific IRE1α-deletion mice. In male mice, deletion of IRE1α in podocytes resulted in albuminuria beginning at 5 mo of age and worsening with time. Electron microscopy revealed focal podocyte foot-process effacement in 9-mo-old male IRE1α-deletion mice, as well as microvillous transformation of podocyte plasma membranes. Compared with control, glomerular cross-sectional and capillary lumenal areas were greater in deletion mice, and there was relative podocyte depletion. Levels of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II expression and c-Jun N-terminal kinase-1 phosphorylation were decreased in IRE1α-deletion glomeruli, in keeping with reduced autophagy. Deletion of IRE1α exacerbated glomerular injury in anti-glomerular basement membrane nephritis. In cell culture, IRE1α dominant-negative mutants reduced the physiological (basal) accumulation of LC3B-II and the size of autophagic vacuoles but did not affect ER-associated degradation. Thus IRE1α is essential for maintaining podocyte and glomerular integrity as mice age and in glomerulonephritis. The mechanism is related, at least in part, to the maintenance of autophagy in podocytes.
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Affiliation(s)
- Daniel Robert Kaufman
- Department of Physiology, McGill University, and McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, Canada
| | - Joan Papillon
- Department of Medicine, McGill University, and McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, Canada
| | - Louise Larose
- Department of Medicine, McGill University, and McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, Canada
| | - Takao Iwawaki
- Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan
| | - Andrey V Cybulsky
- Department of Physiology, McGill University, and McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, Canada
- Department of Medicine, McGill University, and McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, Canada
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Hughes A, Oxford AE, Tawara K, Jorcyk CL, Oxford JT. Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis. Int J Mol Sci 2017; 18:ijms18030665. [PMID: 28335520 PMCID: PMC5372677 DOI: 10.3390/ijms18030665] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Revised: 03/15/2017] [Accepted: 03/16/2017] [Indexed: 12/11/2022] Open
Abstract
Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have catastrophic results, as exemplified by several chondrodystrophies which are frequently accompanied by early onset osteoarthritis. Understanding the mechanisms that underlie chondrocyte apoptosis during endochondral ossification in the growth plate has the potential to impact the development of therapeutic applications for chondrodystrophies and associated early onset osteoarthritis. In recent years, several chondrodysplasias and collagenopathies have been recognized as protein-folding diseases that lead to endoplasmic reticulum stress, endoplasmic reticulum associated degradation, and the unfolded protein response. Under conditions of prolonged endoplasmic reticulum stress in which the protein folding load outweighs the folding capacity of the endoplasmic reticulum, cellular dysfunction and death often occur. However, unfolded protein response (UPR) signaling is also required for the normal maturation of chondrocytes and osteoblasts. Understanding how UPR signaling may contribute to cartilage pathophysiology is an essential step toward therapeutic modulation of skeletal disorders that lead to osteoarthritis.
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Affiliation(s)
- Alexandria Hughes
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA.
- Biomolecular Research Center, Boise State University, Boise, ID 83725, USA.
| | - Alexandra E Oxford
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA.
- Biomolecular Research Center, Boise State University, Boise, ID 83725, USA.
| | - Ken Tawara
- Biomolecular Sciences Graduate Program, Boise State University, Boise, ID 83725, USA.
- Biomolecular Research Center, Boise State University, Boise, ID 83725, USA.
| | - Cheryl L Jorcyk
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA.
- Biomolecular Sciences Graduate Program, Boise State University, Boise, ID 83725, USA.
- Biomolecular Research Center, Boise State University, Boise, ID 83725, USA.
| | - Julia Thom Oxford
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA.
- Biomolecular Sciences Graduate Program, Boise State University, Boise, ID 83725, USA.
- Biomolecular Research Center, Boise State University, Boise, ID 83725, USA.
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28
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Pampaloni F, Mayer B, Kabat Vel-Job K, Ansari N, Hötte K, Kögel D, Stelzer EHK. A Novel Cellular Spheroid-Based Autophagy Screen Applying Live Fluorescence Microscopy Identifies Nonactin as a Strong Inducer of Autophagosomal Turnover. SLAS DISCOVERY 2017; 22:558-570. [PMID: 28297606 DOI: 10.1177/2472555217696798] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Dysregulation of the basal autophagic flux has been linked to several pathological conditions, including neurodegenerative diseases and cancer. In addition, autophagy has profound effects on the response of tumor cells to therapy. Hence, the search for pharmacological modulators of autophagy is of great clinical relevance. We established a drug screening assay in which the autophagic flux is measured by recording the fluorescence emission of the tandem fusion protein mRFP-GFP-LC3 by dynamic live-cell imaging. We optimized the assay for the identification of autophagy modulators in three dimensions with U343 glioma cell spheroids, which represent a more realistic cancer model than conventional 2D cell cultures. We validated the assay by screening a library of known autophagy modulators. As the first application, a small library of 94 natural compounds was screened for its impact on autophagy. We discovered the cyclic ionophore nonactin as a new and potent autophagy inducer. This novel autophagy screening assay based on 3D tumor spheroids is robust, reproducible, and scalable. It provides a valuable tool for both basic research and drug screening campaigns.
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Affiliation(s)
- Francesco Pampaloni
- 1 Physical Biology Group, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe Universität Frankfurt am Main, Frankfurt am Main, Germany
| | - Benjamin Mayer
- 1 Physical Biology Group, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe Universität Frankfurt am Main, Frankfurt am Main, Germany
| | - Konstantin Kabat Vel-Job
- 1 Physical Biology Group, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe Universität Frankfurt am Main, Frankfurt am Main, Germany
| | - Nariman Ansari
- 1 Physical Biology Group, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe Universität Frankfurt am Main, Frankfurt am Main, Germany
| | - Katharina Hötte
- 1 Physical Biology Group, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe Universität Frankfurt am Main, Frankfurt am Main, Germany
| | - Donat Kögel
- 2 Experimental Neurosurgery, Department of Neurosurgery, Goethe Universität Frankfurt am MainFrankfurt am Main, Hessen, Germany
| | - Ernst H K Stelzer
- 1 Physical Biology Group, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe Universität Frankfurt am Main, Frankfurt am Main, Germany
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Friedman JR, Perry HE, Brown KC, Gao Y, Lin J, Stevenson CD, Hurley JD, Nolan NA, Akers AT, Chen YC, Denning KL, Brown LG, Dasgupta P. Capsaicin synergizes with camptothecin to induce increased apoptosis in human small cell lung cancers via the calpain pathway. Biochem Pharmacol 2017; 129:54-66. [PMID: 28104436 DOI: 10.1016/j.bcp.2017.01.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 01/11/2017] [Indexed: 12/20/2022]
Abstract
Small cell lung cancer (SCLC) is characterized by excellent initial response to chemotherapy and radiation therapy with a majority of the patients showing tumor shrinkage and even remission. However, the challenge with SCLC therapy is that patients inevitably relapse and subsequently do not respond to the first line treatment. Recent clinical studies have investigated the possibility of camptothecin-based combination therapy as first line treatment for SCLC patients. Conventionally, camptothecin is used for recurrent SCLC and has poor survival outcomes. Therefore, drugs which can improve the therapeutic index of camptothecin should be valuable for SCLC therapy. Extensive evidence shows that nutritional compounds like capsaicin (the spicy compound of chili peppers) can improve the anti-cancer activity of chemotherapeutic drugs in both cell lines and animal models. Statistical analysis shows that capsaicin synergizes with camptothecin to enhance apoptosis of human SCLC cells. The synergistic activity of camptothecin and capsaicin is observed in both classical and variant SCLC cell lines and, in vivo, in human SCLC tumors xenotransplanted on chicken chorioallantoic membrane (CAM) models. The synergistic activity of capsaicin and camptothecin are mediated by elevation of intracellular calcium and the calpain pathway. Our data foster hope for novel nutrition based combination therapies in SCLC.
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Affiliation(s)
- Jamie R Friedman
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Haley E Perry
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Kathleen C Brown
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Ying Gao
- Department of Biology, Alderson Broaddus University, Philippi, WV 26416, United States
| | - Ju Lin
- Department of Biology, Alderson Broaddus University, Philippi, WV 26416, United States
| | - Cathyrn D Stevenson
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - John D Hurley
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Nicholas A Nolan
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Austin T Akers
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Yi Charlie Chen
- Department of Biology, Alderson Broaddus University, Philippi, WV 26416, United States
| | - Krista L Denning
- Department of Pathology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Linda G Brown
- Department of Pathology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Piyali Dasgupta
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States.
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Tian J, Liu R, Qu Q. Role of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma. Oncol Lett 2017; 13:1437-1443. [PMID: 28454274 DOI: 10.3892/ol.2017.5580] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 10/14/2016] [Indexed: 12/16/2022] Open
Abstract
Endoplasmic reticulum (ER) is an essential site of cellular homeostasis regulation. ER stress (ERS) may induce autophagy in tumor cells that escape from apoptosis. The present study examined the effects and mechanism of ERS on cisplatin (DDP) sensitivity in ovarian carcinoma. SKOV3 tumor cells treated with Saquinavir were subjected to western blot and reverse transcription-quantitative polymerase chain reaction analysis to determine protein and messenger RNA (mRNA) expression levels of mechanistic target of rapamycin (mTOR) and Beclin 1. MTT assay was used to analyze the influence of Saquinavir on DDP resistance in SKOV3 cells. Saquinavir induced glucose-regulated protein 78 expression, which is a marker of ERS. Following treatment with various doses of Saquinavir, the sensitivity of ovarian cancer cells to DDP decreased significantly. Protein and mRNA expression levels of mTOR and Beclin 1 in SKOV3 cells were increased when the cells were exposed to Saquinavir or DDP for 24 h. Moreover, mTOR and Beclin 1 expression levels were highest in the Saquinavir + DDP group (0.684±0.072 and 0.6467±0.0468, respectively). SKOV3 tumor cells were also exposed to the autophagy inhibitor, 3-methyladenine (3-MA), and different concentrations of Saquinavir. Analysis of half maximal inhibitory concentration (IC50) values of DDP after this treatment demonstrated that IC50 values were significantly decreased compared with Saquinavir alone (P<0.001), suggesting that the sensitivity to DDP was improved in ovarian cancer cells after 3-MA exposure. These findings demonstrated that Saquinavir is able to induce ERS in SKOV3 cells effectively, and ER-induced stress may decrease the sensitivity of DDP in SKOV3 cells. Furthermore, ERS may regulate cell autophagy through the mTOR and Beclin 1 pathways, leading to a reduction in the sensitivity of DDP in SKOV3 cells. ERS in tumor cells and autophagy may be a potential target to improve the therapeutic effect of chemotherapy and reduce drug resistance in tumors.
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Affiliation(s)
- Jing Tian
- Department of Gynaecology, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Rong Liu
- Department of Gynaecology, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Quanxin Qu
- Department of Gynaecology, Tianjin First Central Hospital, Tianjin 300192, P.R. China
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31
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Ramos-Torres Á, Bort A, Morell C, Rodríguez-Henche N, Díaz-Laviada I. The pepper's natural ingredient capsaicin induces autophagy blockage in prostate cancer cells. Oncotarget 2016; 7:1569-83. [PMID: 26625315 PMCID: PMC4811481 DOI: 10.18632/oncotarget.6415] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 11/16/2015] [Indexed: 12/22/2022] Open
Abstract
Capsaicin, the pungent ingredient of red hot chili peepers, has been shown to have anti-cancer activities in several cancer cells, including prostate cancer. Several molecular mechanisms have been proposed on its chemopreventive action, including ceramide accumulation, endoplasmic reticulum stress induction and NFκB inhibition. However, the precise mechanisms by which capsaicin exerts its anti-proliferative effect in prostate cancer cells remain questionable. Herein, we have tested the involvement of autophagy on the capsaicin mechanism of action on prostate cancer LNCaP and PC-3 cells. The results showed that capsaicin induced prostate cancer cell death in a time- and concentration-dependent manner, increased the levels of microtubule-associated protein light chain 3-II (LC3-II, a marker of autophagy) and the accumulation of the cargo protein p62 suggesting an autophagy blockage. Moreover, confocal microscopy revealed that capsaicin treatment increased lysosomes which co-localized with LC3 positive vesicles in a similar extent to that produced by the lysosomal protease inhibitors E64 and pepstatin pointing to an autophagolysosomes breakdown inhibition. Furthermore, we found that capsaicin triggered ROS generation in cells, while the levels of ROS decreased with N-acetyl-cysteine (NAC), a ROS scavenger. Co-treatment of cells with NAC and capsaicin abrogated the effects of capsaicin on autophagy and cell death. Normal prostate PNT2 and RWPE-1 cells were more resistant to capsaicin-induced cytotoxicity and did not accumulate p62 protein. Taken together, these results suggest that ROS-mediated capsaicin-induced autophagy blockage contributes to antiproliferation in prostate cancer cells, which provides new insights into the anticancer molecular mechanism of capsaicin.
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Affiliation(s)
- Ágata Ramos-Torres
- Department of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine, Alcala University, Alcala de Henares 28871, Madrid, Spain
| | - Alicia Bort
- Department of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine, Alcala University, Alcala de Henares 28871, Madrid, Spain
| | - Cecilia Morell
- Department of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine, Alcala University, Alcala de Henares 28871, Madrid, Spain
| | - Nieves Rodríguez-Henche
- Department of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine, Alcala University, Alcala de Henares 28871, Madrid, Spain
| | - Inés Díaz-Laviada
- Department of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine, Alcala University, Alcala de Henares 28871, Madrid, Spain
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Tang ZH, Zhang LL, Li T, Lu JH, Ma DL, Leung CH, Chen XP, Jiang HL, Wang YT, Lu JJ. Glycyrrhetinic acid induces cytoprotective autophagy via the inositol-requiring enzyme 1α-c-Jun N-terminal kinase cascade in non-small cell lung cancer cells. Oncotarget 2016; 6:43911-26. [PMID: 26549806 PMCID: PMC4791276 DOI: 10.18632/oncotarget.6084] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 10/23/2015] [Indexed: 01/07/2023] Open
Abstract
Glycerrhetinic acid (GA), one of the main bioactive constituents of Glycyrrhiza uralensis Fisch, exerts anti-cancer effects on various cancer cells. We confirmed that GA inhibited cell proliferation and induced apoptosis in non-small cell lung cancer A549 and NCI-H1299 cells. GA also induced expression of autophagy marker phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II) and punta formation of green fluorescent protein microtubule-associated protein light-chain 3. We further proved that expression of GA-increased autophagy marker was attributed to activation instead of suppression of autophagic flux. The c-jun N-terminal kinase (JNK) pathway was activated after incubation with GA. Pretreatment with the JNK inhibitor SP600125 or silencing of the JNK pathway by siRNA of JNK or c-jun decreased GA-induced autophagy. The endoplasmic reticulum (ER) stress responses were also apparently stimulated by GA by triggering the inositol-requiring enzyme 1α (IRE1α) pathway. The GA-induced JNK pathway activation and autophagy were decreased by IRE1α knockdown, and inhibition of autophagy or the JNK cascade increased GA-stimulated IRE1α expression. In addition, GA-induced cell proliferative inhibition and apoptosis were increased by inhibition of autophagy or the JNK pathway. Our study was the first to demonstrate that GA induces cytoprotective autophagy in non-small cell lung cancer cells by activating the IRE1α-JNK/c-jun pathway. The combined treatment of autophagy inhibitors markedly enhances the anti-neoplasmic activity of GA. Such combination shows potential as a strategy for GA or GA-contained prescriptions in cancer therapy.
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Affiliation(s)
- Zheng-Hai Tang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Le-Le Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Ting Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Jia-Hong Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Dik-Lung Ma
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Chung-Hang Leung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Xiu-Ping Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China
| | - Yi-Tao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Jin-Jian Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
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Fu D, Yu JY, Yang S, Wu M, Hammad SM, Connell AR, Du M, Chen J, Lyons TJ. Survival or death: a dual role for autophagy in stress-induced pericyte loss in diabetic retinopathy. Diabetologia 2016; 59:2251-61. [PMID: 27475954 PMCID: PMC5016562 DOI: 10.1007/s00125-016-4058-5] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 06/27/2016] [Indexed: 12/22/2022]
Abstract
AIMS/HYPOTHESIS Intra-retinal extravasation and modification of LDL have been implicated in diabetic retinopathy: autophagy may mediate these effects. METHODS Immunohistochemistry was used to detect autophagy marker LC3B in human and murine diabetic and non-diabetic retinas. Cultured human retinal capillary pericytes (HRCPs) were treated with in vitro-modified heavily-oxidised glycated LDL (HOG-LDL) vs native LDL (N-LDL) with or without autophagy modulators: green fluorescent protein-LC3 transfection; small interfering RNAs against Beclin-1, c-Jun NH(2)-terminal kinase (JNK) and C/EBP-homologous protein (CHOP); autophagy inhibitor 3-MA (5 mmol/l) and/or caspase inhibitor Z-VAD-fmk (100 μmol/l). Autophagy, cell viability, oxidative stress, endoplasmic reticulum stress, JNK activation, apoptosis and CHOP expression were assessed by western blots, CCK-8 assay and TUNEL assay. Finally, HOG-LDL vs N-LDL were injected intravitreally to STZ-induced diabetic vs control rats (yielding 50 and 200 mg protein/l intravitreal concentration) and, after 7 days, retinas were analysed for ER stress, autophagy and apoptosis. RESULTS Intra-retinal autophagy (LC3B staining) was increased in diabetic vs non-diabetic humans and mice. In HRCPs, 50 mg/l HOG-LDL elicited autophagy without altering cell viability, and inhibition of autophagy decreased survival. At 100-200 mg/l, HOG-LDL caused significant cell death, and inhibition of either autophagy or apoptosis improved survival. Further, 25-200 mg/l HOG-LDL dose-dependently induced oxidative and ER stress. JNK activation was implicated in autophagy but not in apoptosis. In diabetic rat retina, 50 mg/l intravitreal HOG-LDL elicited autophagy and ER stress but not apoptosis; 200 mg/l elicited greater ER stress and apoptosis. CONCLUSIONS Autophagy has a dual role in diabetic retinopathy: under mild stress (50 mg/l HOG-LDL) it is protective; under more severe stress (200 mg/l HOG-LDL) it promotes cell death.
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Affiliation(s)
- Dongxu Fu
- Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
- Department of Immunology, Harbin Medical University, Harbin, People's Republic of China
| | - Jeremy Y Yu
- Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Shihe Yang
- Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Mingyuan Wu
- Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Samar M Hammad
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Anna R Connell
- Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Mei Du
- Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Junping Chen
- Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Timothy J Lyons
- Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.
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Basith S, Cui M, Hong S, Choi S. Harnessing the Therapeutic Potential of Capsaicin and Its Analogues in Pain and Other Diseases. Molecules 2016; 21:molecules21080966. [PMID: 27455231 PMCID: PMC6272969 DOI: 10.3390/molecules21080966] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 06/27/2016] [Accepted: 07/15/2016] [Indexed: 12/14/2022] Open
Abstract
Capsaicin is the most predominant and naturally occurring alkamide found in Capsicum fruits. Since its discovery in the 19th century, the therapeutic roles of capsaicin have been well characterized. The potential applications of capsaicin range from food flavorings to therapeutics. Indeed, capsaicin and few of its analogues have featured in clinical research covered by more than a thousand patents. Previous records suggest pleiotropic pharmacological activities of capsaicin such as an analgesic, anti-obesity, anti-pruritic, anti-inflammatory, anti-apoptotic, anti-cancer, anti-oxidant, and neuro-protective functions. Moreover, emerging data indicate its clinical significance in treating vascular-related diseases, metabolic syndrome, and gastro-protective effects. The dearth of potent drugs for management of such disorders necessitates the urge for further research into the pharmacological aspects of capsaicin. This review summarizes the historical background, source, structure and analogues of capsaicin, and capsaicin-triggered TRPV1 signaling and desensitization processes. In particular, we will focus on the therapeutic roles of capsaicin and its analogues in both normal and pathophysiological conditions.
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Affiliation(s)
- Shaherin Basith
- National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
| | - Minghua Cui
- National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
| | - Sunhye Hong
- National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
| | - Sun Choi
- National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
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Yan D, An G, Kuo MT. C-Jun N-terminal kinase signalling pathway in response to cisplatin. J Cell Mol Med 2016; 20:2013-2019. [PMID: 27374471 PMCID: PMC5082413 DOI: 10.1111/jcmm.12908] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Accepted: 05/17/2016] [Indexed: 01/10/2023] Open
Abstract
Cisplatin (cis diamminedichloroplatinum II, cDDP) is one of the most effective cancer chemotherapeutic agents and is used in the treatment of many types of human malignancies. However, inherent tumour resistance is a major barrier to effective cisplatin therapy. So far, the mechanism of cDDP resistance has not been well defined. In general, cisplatin is considered to be a cytotoxic drug, for damaging DNA and inhibiting DNA synthesis, resulting in apoptosis via the mitochondrial death pathway or plasma membrane disruption. cDDP-induced DNA damage triggers signalling pathways that will eventually decide between cell life and death. As a member of the mitogen-activated protein kinases family, c-Jun N-terminal kinase (JNK) is a signalling pathway in response to extracellular stimuli, especially drug treatment, to modify the activity of numerous proteins locating in the mitochondria or the nucleus. Recent studies suggest that JNK signalling pathway plays a major role in deciding the fate of the cell and inducing resistance to cDDP-induced apoptosis in human tumours. c-Jun N-terminal kinase regulates several important cellular functions including cell proliferation, differentiation, survival and apoptosis while activating and inhibiting substrates for phosphorylation transcription factors (c-Jun, ATF2: Activating transcription factor 2, p53 and so on), which subsequently induce pro-apoptosis and pro-survival factors expression. Therefore, it is suggested that JNK signal pathway is a double-edged sword in cDDP treatment, simultaneously being a significant pro-apoptosis factor but also being associated with increased resistance to cisplatin-based chemotherapy. This review focuses on current knowledge concerning the role of JNK in cell response to cDDP, as well as their role in cisplatin resistance.
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Affiliation(s)
- Dong Yan
- Department of Oncology, Beijing Chao-Yang Hospital Affiliated with Capital Medical University, Beijing, China. .,Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - GuangYu An
- Department of Oncology, Beijing Chao-Yang Hospital Affiliated with Capital Medical University, Beijing, China
| | - Macus Tien Kuo
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Lin C, Jia SN, Yang F, Jia WH, Yu XJ, Yang JS, Yang WJ. The transcription factor p8 regulates autophagy during diapause embryo formation in Artemia parthenogenetica. Cell Stress Chaperones 2016; 21:665-75. [PMID: 27125785 PMCID: PMC4907998 DOI: 10.1007/s12192-016-0692-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 04/05/2016] [Accepted: 04/14/2016] [Indexed: 12/11/2022] Open
Abstract
Autophagy is an essential homeostatic process by which cytoplasmic components, including macromolecules and organelles, are degraded by lysosome. Increasing evidence suggests that phosphorylated AMP-activated protein kinase (p-AMPK) and target of rapamycin (TOR) play key roles in the regulation of autophagy. However, the regulation of autophagy in quiescent cells remains unclear, despite the fact that autophagy is known to be critical for normal development, regeneration, and degenerative diseases. Here, crustacean Artemia parthenogenetica was used as a model system because they produced and released encysted embryos that enter a state of obligate dormancy in cell quiescence to withstand various environmental threats. We observed that autophagy was increased before diapause stage but dropped to extremely low level in diapause cysts in Artemia. Western blot analyses indicated that the regulation of autophagy was AMPK/TOR independent during diapause embryo formation. Importantly, the level of p8 (Ar-p8), a stress-inducible transcription cofactor, was elevated at the stage just before diapause and was absent in encysted embryos, indicating that Ar-p8 may regulate autophagy. The results of Ar-p8 knockdown revealed that Ar-p8 regulated autophagy during diapause formation in Artemia. Moreover, we observed that activating transcription factors 4 and 6 (ATF4 and ATF6) responded to Ar-p8-regulated autophagy, indicating that autophagy targeted endoplasmic reticulum (ER) during diapause formation in Artemia. Additionally, AMPK/TOR-independent autophagy was validated in human gastric cancer MKN45 cells overexpressing Ar-p8. The findings presented here may provide insights into the role of p8 in regulating autophagy in quiescent cells.
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Affiliation(s)
- Cheng Lin
- College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Sheng-Nan Jia
- College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Fan Yang
- College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Wen-Huan Jia
- College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Xiao-Jian Yu
- College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Jin-Shu Yang
- College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Wei-Jun Yang
- College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China.
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Zhao JJ, Hu YW, Huang C, Ma X, Kang CM, Zhang Y, Guo FX, Lu JB, Xiu JC, Qiu YR, Sha YH, Gao JJ, Wang YC, Li P, Xu BM, Zheng L, Wang Q. Dihydrocapsaicin suppresses proinflammatory cytokines expression by enhancing nuclear factor IA in a NF-κB-dependent manner. Arch Biochem Biophys 2016; 604:27-35. [PMID: 27267730 DOI: 10.1016/j.abb.2016.06.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 05/09/2016] [Accepted: 06/02/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND Atherosclerosis is a chronic inflammatory disease and represents the leading cause of morbidity and mortality throughout the world. Accumulating evidences have showed that Dihydrocapsaicin (DHC) has been found to exert multiple pharmacological and physiological effects. Nevertheless, the effects and possible mechanism of DHC on proinflammatory response remain largely unexplained. METHODS AND RESULTS We found that DHC markedly upregulated NFIA and suppressed NF-κB expression in THP-1 macrophages. Up-regulation of proinflammatory cytokines induced by LPS including TNF-α, IL-1β and IL-6 were markedly suppressed by DHC treatment. We also observed that protein level of NFIA was significantly increased while NF-κB and proinflammatory cytokines were decreased by DHC treatment in apoE(-/-) mice. Lentivirus-mediated overexpression of NFIA suppressed NF-κB and proinflammatory cytokines expression both in THP-1 macrophages and plaque tissues of apoE-/- mice. Moreover, treatment with lentivirus-mediated overexpression of NFIA made the down-regulation of DHC on NF-κB and proinflammatory cytokines expression notably accentuated in THP-1 macrophages and apoE(-/-) mice. In addition, treatment with siRNA targeting NF-κB accentuated the suppression of proinflammatory cytokines by lentivirus-mediated overexpression of NFIA. CONCLUSION These observations demonstrated that DHC can significantly decrease proinflammatory cytokines through enhancing NFIA and inhibiting NF-κB expression and thus DHC may be a promising candidate as an anti-inflammatory drug for atherosclerosis as well as other disorders.
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Affiliation(s)
- Jing-Jing Zhao
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Yan-Wei Hu
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Chuan Huang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Xin Ma
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Chun-Min Kang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Yuan Zhang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Feng-Xia Guo
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Jing-Bo Lu
- Department of Vascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Jian-Cheng Xiu
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yu-Rong Qiu
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Yan-Hua Sha
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Ji-Juan Gao
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Yan-Chao Wang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Pan Li
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Bang-Ming Xu
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Lei Zheng
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
| | - Qian Wang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
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Abstract
Apoptosis is a primary characteristic in the pathogenesis of liver disease. Hepatic apoptosis is regulated by autophagic activity. However, mechanisms mediating their interaction remain to be determined. Basal level of autophagy ensures the physiological turnover of old and damaged organelles. Autophagy also is an adaptive response under stressful conditions. Autophagy can control cell fate through different cross-talk signals. A complex interplay between hepatic autophagy and apoptosis determines the degree of hepatic apoptosis and the progression of liver disease as demonstrated by pre-clinical models and clinical trials. This review summarizes recent advances on roles of autophagy that plays in pathophysiology of liver. The autophagic pathway can be a novel therapeutic target for liver disease.
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Key Words
- ALT, alanine aminotransferase
- AMBRA-1, activating molecule in Beclin-1-regulated autophagy
- APAP, N-acetyl-p-aminophenol
- ATP, adenosine triphosphate
- Atg, autophagy-related gene
- BH3, Bcl-2 homology domain-3
- BNIP, Bcl-2/adenovirus E1B 19 kd-interacting protein
- Barkor, Beclin-1-associated autophagy-related key regulator
- Bcl-2, B-cell lymphoma-2
- Bcl-xL, B-cell lymphoma extra long
- Beclin-1, Bcl-2-interacting protein-1
- CSE, cigarette smoke extract
- DISC, death-inducing signaling complex
- DNA, DNA
- DRAM, damage regulated autophagic modulator
- Drp1, dynamin-related protein 1
- ER stress, endoplasmic reticulum stress
- FADD, Fas-associated protein with death domain
- FFA, free fatty acids
- HBV, hepatitis B virus
- HBx, hepatitis B X protein
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- HSC, hepatic stellate cells
- LAMP-2, lysosome-associated membrane protein 2
- LD, lipid droplets
- MDBs, Mallory-Denk bodies
- MOMP, mitochondrial outer membrane permiabilization
- Microtubule LC3, microtubule light chain 3
- PCD, programmed cell death
- PI3KC3, phosphatidylinositol-3-kinase class-3
- RNA, ribonucleic acid
- ROS, reactive oxygen species
- TNFα, tumor necrosis factor-α
- TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling
- UVRAG, UV-resistance-associated gene
- Vps34, vacuolar protein sorting-34
- apoptosis
- autophagy
- c-FLIP, cellular FLICE-like inhibitor protein
- cross-talk
- liver injury
- mTOR, mammalian target of rapamycin
- mechanism
- siRNA, small interfering RNA
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Affiliation(s)
- Kewei Wang
- a Departments of Surgery; University of Illinois College of Medicine ; Peoria , IL , USA
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Halme M, Pesonen M, Salo H, Söderström M, Pasanen M, Vähäkangas K, Vanninen P. Comparison of in vitro metabolism and cytotoxicity of capsaicin and dihydrocapsaicin. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1009-1010:17-24. [DOI: 10.1016/j.jchromb.2015.11.042] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 11/19/2015] [Accepted: 11/21/2015] [Indexed: 12/20/2022]
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Fernandes ES, Cerqueira ARA, Soares AG, Costa SKP. Capsaicin and Its Role in Chronic Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 929:91-125. [PMID: 27771922 DOI: 10.1007/978-3-319-41342-6_5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A significant number of experimental and clinical studies published in peer-reviewed journals have demonstrated promising pharmacological properties of capsaicin in relieving signs and symptoms of non-communicable diseases (chronic diseases). This chapter provides an overview made from basic and clinical research studies of the potential therapeutic effects of capsaicin, loaded in different application forms, such as solution and cream, on chronic diseases (e.g. arthritis, chronic pain, functional gastrointestinal disorders and cancer). In addition to the anti-inflammatory and analgesic properties of capsaicin largely recognized via, mainly, interaction with the TRPV1, the effects of capsaicin on different cell signalling pathways will be further discussed here. The analgesic, anti-inflammatory or apoptotic effects of capsaicin show promising results in arthritis, neuropathic pain, gastrointestinal disorders or cancer, since evidence demonstrates that the oral or local application of capsaicin reduce inflammation and pain in rheumatoid arthritis, promotes gastric protection against ulcer and induces apoptosis of the tumour cells. Sadly, these results have been paralleled by conflicting studies, which indicate that high concentrations of capsaicin are likely to evoke deleterious effects, thus suggesting that capsaicin activates different pathways at different concentrations in both human and rodent tissues. Thus, to establish effective capsaicin doses for chronic conditions, which can be benefited from capsaicin therapeutic effects, is a real challenge that must be pursued.
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Affiliation(s)
- E S Fernandes
- Programa de Pós-Graduação, Universidade Ceuma, São Luís-MA, Brazil.,Vascular Biology Section, Cardiovascular Division, King's College London, London, UK
| | - A R A Cerqueira
- Department of Pharmacology, Institute of Biomedical Sciences (ICB), University of São Paulo (USP), Av. Prof. Lineu Prestes, 1524 - Room 326, Butantan, São Paulo, 05508-900, Sao Paulo, Brazil
| | - A G Soares
- Department of Pharmacology, Institute of Biomedical Sciences (ICB), University of São Paulo (USP), Av. Prof. Lineu Prestes, 1524 - Room 326, Butantan, São Paulo, 05508-900, Sao Paulo, Brazil
| | - Soraia K P Costa
- Department of Pharmacology, Institute of Biomedical Sciences (ICB), University of São Paulo (USP), Av. Prof. Lineu Prestes, 1524 - Room 326, Butantan, São Paulo, 05508-900, Sao Paulo, Brazil.
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Bowie M, Pilie P, Wulfkuhle J, Lem S, Hoffman A, Desai S, Petricoin E, Carter A, Ambrose A, Seewaldt V, Yu D, Ibarra Drendall C. Fluoxetine induces cytotoxic endoplasmic reticulum stress and autophagy in triple negative breast cancer. World J Clin Oncol 2015; 6:299-311. [PMID: 26677444 PMCID: PMC4675916 DOI: 10.5306/wjco.v6.i6.299] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 09/08/2015] [Accepted: 10/27/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mechanism of action of lipophilic antidepressant fluoxetine (FLX) in representative molecular subtypes of breast cancer.
METHODS: The anti-proliferative effects and mechanistic action of FLX in triple-negative (SUM149PT) and luminal (T47D and Au565) cancer cells and non-transformed MCF10A were investigated. Reverse phase protein microarray (RPPM) was performed with and without 10 μmol/L FLX for 24 and 48 h to determine which proteins are significantly changed. Viability and cell cycle analysis were also performed to determine drug effects on cell growth. Western blotting was used to confirm the change in protein expression examined by RPPM or pursue other signaling proteins.
RESULTS: The FLX-induced cell growth inhibition in all cell lines was concentration- and time-dependent but less pronounced in early passage MCF10A. In comparison to the other lines, cell growth reduction in SUM149PT coincided with significant induction of endoplasmic reticulum (ER) stress and autophagy after 24 and 48 h of 10 μmol/L FLX, resulting in decreased translation of proteins along the receptor tyrosine kinase/Akt/mammalian target of rapamycin pathways. The increase in autophagy marker, cleaved microtubule-associated protein 1 light chain 3, in SUM149PT after 24 h of FLX was likely due to increased metabolic demands of rapidly dividing cells and ER stress. Consequently, the unfolded protein response mediated by double-stranded RNA-dependent protein kinase-like ER kinase resulted in inhibition of protein synthesis, growth arrest at the G1 phase, autophagy, and caspase-7-mediated cell death.
CONCLUSION: Our study suggests a new role for FLX as an inducer of ER stress and autophagy, resulting in death of aggressive triple negative breast cancer SUM149PT.
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Bhardwaj M, Paul S, Jakhar R, Kang SC. Potential role of vitexin in alleviating heat stress-induced cytotoxicity: Regulatory effect of Hsp90 on ER stress-mediated autophagy. Life Sci 2015; 142:36-48. [DOI: 10.1016/j.lfs.2015.10.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 09/25/2015] [Accepted: 10/10/2015] [Indexed: 12/19/2022]
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Li X, Liu C, Ip BC, Hu KQ, Smith DE, Greenberg AS, Wang XD. Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015; 34:138. [PMID: 26560698 PMCID: PMC4642781 DOI: 10.1186/s13046-015-0254-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 11/04/2015] [Indexed: 01/14/2023]
Abstract
Background Tumor progression locus 2 (TPL2), a serine-threonine kinase, functions as a critical regulator of inflammatory pathways and mediates oncogenic events. The potential role of Tpl2 in nonalcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) development remains unknown. Methods Both wild-type and Tpl2 knockout male mice were initiated by a hepatic carcinogen (diethylnitrosamine, i.p. with a single dose of 25 mg.kg−1)at 2 weeks of age, and then were given the high carbohydrate diet feeding to induce hepatic steatosis, inflammation, adenoma and HCC for 24 weeks. Results Tpl2 knockout mice had significantly lower incidences of liver tumor and developed hepatocellular adenoma only, which is contrast to wild-type mice where they all developed HCC. Tpl2 knockout mice had significantly down-regulated phosphorylation of JNK and ERK, and levels of mRNA expression of pro-inflammatory cytokines (Il-1β, Il-18, Mcp-1 and Nalp3), which correlated with the reduced incidence and number of hepatic inflammatory foci. Furthermore, Tpl2 ablation resulted in decreased hepatic steatosis and expression of de novo lipogenesis related markers (ACC, SCD1, SREBP1C and AKT phosphorylation), as well as reduction of endoplasmic reticulum stress biomarkers PERK and eIF-2a. Conclusion The study revealed for the first time that Tpl2 plays a significant role in promoting HCC development by its pro-inflammatory effect, which suggested that Tpl2 could be a molecular target for HCC prevention.
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Affiliation(s)
- Xinli Li
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA, 02111, USA.,School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, 215123, PR China
| | - Chun Liu
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA, 02111, USA
| | - Blanche C Ip
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA, 02111, USA
| | - Kang-Quan Hu
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA, 02111, USA
| | | | - Andrew S Greenberg
- Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, 02111, USA
| | - Xiang-Dong Wang
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA, 02111, USA.
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Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury. PLoS One 2015; 10:e0140025. [PMID: 26444017 PMCID: PMC4596863 DOI: 10.1371/journal.pone.0140025] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 09/21/2015] [Indexed: 12/20/2022] Open
Abstract
We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase–3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase–3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo.
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Hypoxia-Induced Iron Accumulation in Oligodendrocytes Mediates Apoptosis by Eliciting Endoplasmic Reticulum Stress. Mol Neurobiol 2015; 53:4713-27. [PMID: 26319559 DOI: 10.1007/s12035-015-9389-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 08/11/2015] [Indexed: 10/23/2022]
Abstract
This study was aimed at evaluating the role of increased iron accumulation in oligodendrocytes and its role in their apoptosis in the periventricular white matter damage (PWMD) following a hypoxic injury to the neonatal brain. In response to hypoxia, in the PWM, there was increased expression of proteins involved in iron acquisition, such as iron regulatory proteins (IRP1, IRP2) and transferrin receptor in oligodendrocytes. Consistent with this, following a hypoxic exposure, there was increased accumulation of iron in primary cultured oligodendrocytes. The increased concentration of iron within hypoxic oligodendrocytes was found to elicit ryanodine receptor (RyR) expression, and the expression of endoplasmic reticulum (ER) stress markers such as binding-immunoglobulin protein (BiP) and inositol-requiring enzyme (IRE)-1α. Associated with ER stress, there was reduced adenosine triphosphate (ATP) levels within hypoxic oligodendrocytes. However, treatment with deferoxamine reduced the increased expression of RyR, BiP, and IRE-1α and increased ATP levels in hypoxic oligodendrocytes. Parallel to ER stress there was enhanced reactive oxygen species production within mitochondria of hypoxic oligodendrocytes, which was attenuated when these cells were treated with deferoxamine. At the ultrastructural level, hypoxic oligodendrocytes frequently showed dilated ER and disrupted mitochondria, which became less evident in those treated with deferoxamine. Associated with these subcellular changes, the apoptosis of hypoxic oligodendrocytes was evident with an increase in p53 and caspase-3 expression, which was attenuated when these cells were treated with deferoxamine. Thus, the present study emphasizes that the excess iron accumulated within oligodendrocytes in hypoxic PWM could result in their death by eliciting ER stress and mitochondrial disruption.
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46
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Lee YH, Chen HY, Su LJ, Chueh PJ. Sirtuin 1 (SIRT1) Deacetylase Activity and NAD⁺/NADH Ratio Are Imperative for Capsaicin-Mediated Programmed Cell Death. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:7361-7370. [PMID: 26255724 DOI: 10.1021/acs.jafc.5b02876] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Capsaicin is considered a chemopreventive agent by virtue of its selective antigrowth activity, commonly associated with apoptosis, against cancer cells. However, noncancerous cells possess relatively higher tolerance to capsaicin, although the underlying mechanism for this difference remains unclear. Hence, this study aimed to elucidate the differential effects of capsaicin on cell lines from lung tissues by addressing the signal pathway leading to two types of cell death. In MRC-5 human fetal lung cells, capsaicin augmented silent mating type information regulation 1 (SIRT1) deacetylase activity and the intracellular NAD(+)/NADH ratio, decreasing acetylation of p53 and inducing autophagy. In contrast, capsaicin decreased the intracellular NAD(+)/NADH ratio, possibly through inhibition of tumor-associated NADH oxidase (tNOX), and diminished SIRT1 expression leading to enhanced p53 acetylation and apoptosis. Moreover, SIRT1 depletion by RNA interference attenuated capsaicin-induced apoptosis in A549 cancer cells and autophagy in MRC-5 cells, suggesting a vital role for SIRT1 in capsaicin-mediated cell death. Collectively, these data not only explain the differential cytotoxicity of capsaicin but shed light on the distinct cellular responses to capsaicin in cancerous and noncancerous cell lines.
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Affiliation(s)
- Yi-Hui Lee
- Institute of Biomedical Sciences, National Chung Hsing University , Taichung 40227, Taiwan
| | - Huei-Yu Chen
- Institute of Biomedical Sciences, National Chung Hsing University , Taichung 40227, Taiwan
| | - Lilly J Su
- Institute of Biomedical Sciences, National Chung Hsing University , Taichung 40227, Taiwan
| | - Pin Ju Chueh
- Institute of Biomedical Sciences, National Chung Hsing University , Taichung 40227, Taiwan
- Graduate Institute of Basic Medicine, China Medical University , Taichung 40402, Taiwan
- Department of Medical Research, China Medical University Hospital , Taichung 40402, Taiwan
- Department of Biotechnology, Asia University , Taichung 41354, Taiwan
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Tiwari RV, Parajuli P, Sylvester PW. γ-Tocotrienol-induced endoplasmic reticulum stress and autophagy act concurrently to promote breast cancer cell death. Biochem Cell Biol 2015; 93:306-20. [PMID: 25844964 DOI: 10.1139/bcb-2014-0123] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The anticancer effects of γ-tocotrienol are associated with the induction of autophagy and endoplasmic reticulum (ER) stress-mediated apoptosis, but a direct relationship between these events has not been established. Treatment with 40 μmol/L of γ-tocotrienol caused a time-dependent decrease in cancer cell viability that corresponds to a concurrent increase in autophagic and endoplasmic reticulum (ER) stress markers in MCF-7 and MDA-MB-231 human breast cancer cells. γ-Tocotrienol treatment was found to cause a time-dependent increase in early phase (Beclin-1, LC3B-II) and late phase (LAMP-1 and cathepsin-D) autophagy markers, and pretreatment with autophagy inhibitors Beclin-1 siRNA, 3-MA or Baf1 blocked these effects. Furthermore, blockage of γ-tocotrienol-induced autophagy with Beclin-1 siRNA, 3-MA, or Baf1 induced a modest, but significant, reduction in γ-tocotrienol-induced cytotoxicity. γ-Tocotrienol treatment was also found to cause a decrease in mitogenic Erk1/2 signaling, an increase in stress-dependent p38 and JNK1/2 signaling, as well as an increase in ER stress apoptotic markers, including phospho-PERK, phospho-eIF2α, Bip, IRE1α, ATF-4, CHOP, and TRB3. In summary, these finding demonstrate that γ-tocotrienol-induced ER stress and autophagy occur concurrently, and together act to promote human breast cancer cell death.
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Affiliation(s)
- Roshan V Tiwari
- School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA.,School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA
| | - Parash Parajuli
- School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA.,School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA
| | - Paul W Sylvester
- School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA.,School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA
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Yang Z, Liu Y, Liao J, Gong C, Sun C, Zhou X, Wei X, Zhang T, Gao Q, Ma D, Chen G. Quercetin induces endoplasmic reticulum stress to enhance cDDP cytotoxicity in ovarian cancer: involvement of STAT3 signaling. FEBS J 2015; 282:1111-25. [PMID: 25611565 DOI: 10.1111/febs.13206] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 12/13/2014] [Accepted: 01/16/2015] [Indexed: 12/21/2022]
Abstract
There is an urgent need to make cisplatin (cDDP) more effective and less toxic in the treatment of ovarian cancer for its systemic side effects and high resistance rate. In this study, we investigated the effect of quercetin (Qu) pretreatment on the potentiation of cDDP in ovarian cancer. We found that Qu pretreatment significantly enhanced cDDP cytotoxicity in an ovarian cancer cell line and primary cancer cells. In addition, we demonstrated that Qu elicited obvious endoplasmic reticulum stress (ERS) and activated all three branches of ERS in ovarian cancer. Specific inhibitors of each ERS pathway, as well as the general ERS stabilizer tauroursodeoxycholic acid, notably diminished such enhancing effects. Furthermore, Qu notably suppressed STAT3 phosphorylation, leading to downregulation of the BCL-2 gene downstream of STAT3. Moreover, blocking ERS restored the protein levels of phosphorylated STAT3 as well as BCL-2 expression, thus abolishing the chemosensitization potency of Qu; these results revealed that Qu affected the STAT3 pathway to enhance cDDP cytotoxicity, and this effect involved ERS signaling. In a xenograft mouse model of ovarian cancer, Qu enhanced the antitumor effect of cDDP. Tumors from mice treated with cDDP in combination with Qu pretreatment had repressed STAT3 phosphorylation, lower BCL-2 and higher apoptosis levels compared with those from the other groups. Meanwhile, Qu markedly reduced the elevation of blood creatinine during cDDP intervention. These data indicate that Qu pretreatment potentiates the antitumor effects of cDDP in ovarian cancer while protecting the kidneys against damage. Therefore the strategy of Qu pretreatment may be beneficial in enhancing the therapeutic efficacy of cDDP against ovarian cancer.
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Affiliation(s)
- Zongyuan Yang
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Zou X, Xu J, Yao S, Li J, Yang Y, Yang L. Endoplasmic reticulum stress-mediated autophagy protects against lipopolysaccharide-induced apoptosis in HL-1 cardiomyocytes. Exp Physiol 2014; 99:1348-58. [PMID: 24951501 DOI: 10.1113/expphysiol.2014.079012] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Apoptosis of cardiomyocytes limits the contractile efficiency of the heart during sepsis. Prosurvival autophagy has been proposed as a novel mechanism to maintain normal heart function. Here, we demonstrated that autophagy was activated in lipopolysaccharide (LPS)-treated HL-1 cells, and it counteracted the LPS-induced apoptosis. We investigated further the mechanism by which LPS triggered autophagy in HL-1 cells. We discovered that endoplasmic reticulum (ER) stress played an important role in LPS-triggered autophagy. The ER activated a survival pathway through the ER-localized transmembrane protein PERK, which was essential for LPS-induced autophagy. Lipopolysaccharide increased expression of GRP78, phosphorylated PERK and phosphorylated eukaryotic initiation factor 2α. Similar results were observed after administration of tunicamycin, a well-known ER stressor. Most importantly, we found that 4-phenylbutyrate, an inhibitor of ER stress, suppressed LPS-activated autophagy in the presence of LPS in HL-1 cells. The same results were observed after small interfering RNA-mediated silencing of PERK protein. We also noticed that LPS-induced apoptosis appeared early, at 4 h. Our findings revealed that PERK, one arm of ER stress, facilitated survival of LPS-treated HL-1 cells by promoting autophagy, and could serve as a potential therapeutic strategy to alleviate septic myocardial dysfunction.
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Affiliation(s)
- Xiaojing Zou
- Department of Anesthesiology, Laboratory of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Jianjun Xu
- Department of Anesthesiology, Laboratory of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China Department of Anesthesiology, Daqing Oilfield General Hospital, Daqing, Heilongjiang, PR China
| | - Shanglong Yao
- Department of Anesthesiology, Laboratory of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Jian Li
- Department of Anesthesiology, Laboratory of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Yan Yang
- Department of Anesthesiology, Laboratory of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Le Yang
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
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Basu S, Rajakaruna S, Reyes B, Van Bockstaele E, Menko AS. Suppression of MAPK/JNK-MTORC1 signaling leads to premature loss of organelles and nuclei by autophagy during terminal differentiation of lens fiber cells. Autophagy 2014; 10:1193-211. [PMID: 24813396 PMCID: PMC4203547 DOI: 10.4161/auto.28768] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Although autophagic pathways are essential to developmental processes, many questions still remain regarding the initiation signals that regulate autophagy in the context of differentiation. To address these questions we studied the ocular lens, as the programmed elimination of nuclei and organelles occurs in a precisely regulated spatiotemporal manner to form the organelle-free zone (OFZ), a characteristic essential for vision acuity. Here, we report our discovery that inactivation of MAPK/JNK induces autophagy for formation of the OFZ through its regulation of MTORC1, where MAPK/JNK signaling is required for both MTOR activation and RPTOR/RAPTOR phosphorylation. Autophagy pathway proteins including ULK1, BECN1/Beclin 1, and MAP1LC3B2/LC3B-II were upregulated in the presence of inhibitors to either MAPK/JNK or MTOR, inducing autophagic loss of organelles to form the OFZ. These results reveal that MAPK/JNK is a positive regulator of MTORC1 signaling and its developmentally regulated inactivation provides an inducing signal for the coordinated autophagic removal of nuclei and organelles required for lens function.
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Affiliation(s)
- Subhasree Basu
- Department of Pathology, Anatomy and Cell Biology; Thomas Jefferson University; Philadelphia, PA USA
| | - Suren Rajakaruna
- Department of Pathology, Anatomy and Cell Biology; Thomas Jefferson University; Philadelphia, PA USA
| | - Beverly Reyes
- Department of Neuroscience; Farber Institute for Neuroscience; Thomas Jefferson University; Philadelphia, PA USA
| | - Elisabeth Van Bockstaele
- Department of Neuroscience; Farber Institute for Neuroscience; Thomas Jefferson University; Philadelphia, PA USA
| | - A Sue Menko
- Department of Pathology, Anatomy and Cell Biology; Thomas Jefferson University; Philadelphia, PA USA
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