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Wang X, Sun Q, Li J, Lai B, Pei X, Chen N. Effect of Fangxia-Dihuang Decoction on doxorubicin-induced cognitive impairment in breast cancer animal model. Front Oncol 2025; 15:1515498. [PMID: 40356765 PMCID: PMC12066564 DOI: 10.3389/fonc.2025.1515498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 04/02/2025] [Indexed: 05/15/2025] Open
Abstract
Objective Based on the murine model, this study explored the efficacy of Fangxia-Dihuang Decoction (FXDH) in interfering with cognitive impairment induced by doxorubicin (DOX) after chemotherapy for breast cancer. Methods Build 4T1 breast cancer xenograft tumor model in Balb/c mice, intraperitoneal injection of DOX (5mg/kg) once a week, build the model of DOX induced chemotherapy related cognitive impairment (CRCI), and the administration lasted for three weeks. From the first week, while DOX was given, FXDH was given high, medium and low doses by gavage every day. Conduct Y-maze and Novel object recognition (NOR) tests, detect inflammatory factors and oxidative stress-related indicators in serum and hippocampus, observe neuroinflammation and neurodegenerative changes through immunofluorescence and Nissl staining. Observation of heart and liver injury through blood routine and cardiac Hematoxylin-Eosin(HE)Staining. Results Administration of FXDH significantly improved cognitive impairment in mice. FXDH reduced the levels of pro-inflammatory cytokines IL-6, IL-12p70, and TNF-α (P<0.05), and increased the levels of anti-inflammatory cytokines IL-10 and IL-4 (P<0.05). FXDH increased the levels of GSH, GSH-PX, SOD, and CAT in serum and hippocampus (P<0.05), and decreased the level of MDA (P<0.05). The results of Nissl staining and immunofluorescence staining showed that FXDH improved the neurodegenerative lesions caused by DOX and the neuroinflammatory response in the hippocampus (P<0.05). The intermediate dose group of FXDH showed better efficacy. The results of blood routine and cardiac HE staining showed that compared with the 4T1 group, the serum ALT, AST, CK, LDH, and CKMB in DOX group mice were significantly increased (P<0.05). After FXDH administration, all indicators in mice were decreased, but there was no statistical difference. FXDH improved the disordered arrangement of myocardial cells, uneven cytoplasmic staining, and loose and disordered arrangement of myocardial fibers caused by DOX. Conclusion In the animal model, FXDH has the effect of anti-cognitive impairment after chemotherapy for breast cancer, and can improve the DOX induced learning, memory and cognitive impairment in mice. FXDH can reverse DOX induced neuroinflammation by improving the neurodegenerative changes caused by DOX, reducing pro-inflammatory cytokine levels in mouse serum and hippocampus, increasing anti-inflammatory cytokine levels, and reducing oxidative stress response.
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Affiliation(s)
- Xuan Wang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China
- The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Qiqi Sun
- The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Jianrong Li
- The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Baoyong Lai
- The Xiamen Hospital of Beijing University of Chinese Medicine, Xiamen, China
| | - Xiaohua Pei
- The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Nana Chen
- The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
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Shokrzadeh S, Moghim S, Shokrzadeh M, Aghajanshakeri S. An added value of azithromycin: mitigation of doxorubicin-associated oxidative damage and genotoxicity in normal human bronchial epithelium cells. Mutagenesis 2025; 40:126-136. [PMID: 39373202 DOI: 10.1093/mutage/geae024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 10/05/2024] [Indexed: 10/08/2024] Open
Abstract
Doxorubicin, a well-known and widely used antineoplastic agent with direct ROS-accumulating activity, has proven effective in treating various cancer types. However, its non-specific cytotoxicity towards non-cancerous cells prompts concerns regarding potential adverse effects. Azithromycin is an antibiotic for treating bacterial infections and an anti-inflammatory agent, particularly beneficial in managing respiratory conditions like bronchitis and sinusitis. Despite azithromycin's well-documented antibacterial properties, its potential cellular/genomic protective effects remain unexplored. As an in vitro model, BEAS-2B cells (normal human bronchial epithelium cells) were employed in this study to assess whether azithromycin possesses any protective properties against doxorubicin-induced cellular toxicity. Cells in pretreatment culture were treated to various amounts of azithromycin (3.125, 6.25, 12.5, 25, and 50 μg/ml) in combination with doxorubicin at IC50 (0.08 μg/ml). Doxorubicin at 0.08 μg/ml highlighted cytotoxicity, oxidative stress, and genotoxicity. Azithromycin at 25 and 50 μg/ml markedly modulated oxidative stress and genomic damage by decreasing the ROS and LPO amounts and suppressing DNA fragmentation in the comet assay parameters. Consequently, azithromycin may be regarded as a cytomodulating, antigenotoxic, and antioxidant agent.
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Affiliation(s)
| | - Shahrzad Moghim
- Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Shokrzadeh
- Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Shaghayegh Aghajanshakeri
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
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Chen JK, Ramesh S, Islam MN, Shibu MA, Kuo CH, Hsieh DJY, Lin SZ, Kuo WW, Huang CY, Ho TJ. Artemisia argyi mitigates doxorubicin-induced cardiotoxicity by inhibiting mitochondrial dysfunction through the IGF-IIR/Drp1/GATA4 signaling pathway. Biotechnol Appl Biochem 2025; 72:388-401. [PMID: 39375847 DOI: 10.1002/bab.2671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 09/03/2024] [Accepted: 09/05/2024] [Indexed: 10/09/2024]
Abstract
Doxorubicin (DOX) is mostly utilized as a wide range of antitumor anthracycline to treat different cancers. The severe antagonistic impacts of DOX on cardiotoxicity constrain its clinical application. Many mechanisms are involved in cardiac toxicity induced by DOX in the human body. Mitochondria is a central part of fatty acid and glucose metabolism. Thus, impaired mitochondrial metabolism can increase heart failure risk, which can play a vital role in cardiomyocyte mitochondrial dysfunction. This study aimed to assess the possible cardioprotective effect of water-extracted Artemisia argyi (AA) against the side effect of DOX in H9c2 cells and whether these protective effects are mediated through IGF-IIR/Drp1/GATA4 signaling pathways. Although several studies proved that AA extract has benefits for various diseases, its cardiac effects have not yet been identified. The H9c2 cells were exposed to 1 μM to establish a model of cardiac toxicity. The results revealed that water-extracted AA could block the expression of IGF-IIR/calcineurin signaling pathways induced by DOX. Notably, our results also showed that AA treatment markedly attenuated Akt phosphorylation and cleaved caspase 3, and the nuclear translocation markers NFATC3 and p-GATA4. Using actin staining for hypertrophy, we determined that AA can reduce the effect of mitochondrial reactive oxygen species and cell size. These findings suggest that water-extracted AA could be a suitable candidate for preventing DOX-induced cardiac damage.
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Affiliation(s)
- Jhong-Kuei Chen
- Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
| | - Samiraj Ramesh
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Department of Research and Innovation, Institute of Biotechnology, Saveetha School of Engineering (SSE), Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India
| | - Md Nazmul Islam
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | | | - Chia-Hua Kuo
- Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan
| | - Dennis Jine-Yuan Hsieh
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shinn-Zong Lin
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan
- Ph.D. Program for Biotechnology Industry, China Medical University, Taichung, Taiwan
- School of Pharmacy, China Medical University, Taichung, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
| | - Tsung-Jung Ho
- Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
- School of Post-Baccalaureate Chinese Medicine, College of Medicine, Tzu Chi University, Hualien, Taiwan
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Zhou R, Liu T, Qin Y, Xie J, Zhang S, Xie Y, Lao J, He W, Zeng H, Tang X, Tian X, Qin Y. Polygonatum cyrtonema Hua polysaccharides alleviate muscle atrophy and fat lipolysis by regulating the gut microenvironment in chemotherapy-induced cachexia. Front Pharmacol 2025; 16:1503785. [PMID: 40129936 PMCID: PMC11931129 DOI: 10.3389/fphar.2025.1503785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 02/04/2025] [Indexed: 03/26/2025] Open
Abstract
Introduction: Polygonatum cyrtonema Hua (PC) is an essential herbal medicine in China, known for improving muscle quality and enhancing physical function; its active ingredients are polysaccharides (PCPs). A previous study revealed the anti-atrophy effects of PCPs in cachectic mice. However, whether the effects of PCPs on anti-atrophy are associated with gut microenvironment remain elusive. This research endeavored to assess the medicinal efficacy of PCPs in alleviating muscle atrophy and fat lipolysis and explore the potential mechanisms. Methods: A cancer cachexia model was induced by male C57BL/6 mice bearing Lewis lung tumor cells and chemotherapy. The pharmacodynamics of PCPs (32 and 64 mg/kg/day) was investigated through measurements of tumor-free body weight, gastrocnemius muscle weight, soleus muscle weight, epididymal fat weight, tissue histology analysis, and pro-inflammatory cytokines. Immunohistochemistry and Western blotting assays were further used to confirm the effects of PCPs. 16S rRNA sequencing, LC-MS and GC-MS-based metabolomics were used to analyze the gut microbiota composition and metabolite alterations. Additionally, the agonist of free fatty acid receptor 2 (FFAR2)-a crucial short-chain fatty acid (SCFA) signaling molecule-was used to investigate the role of gut microbiota metabolites, specifically SCFAs, in the treatment of cancer cachexia, with comparisons to PCPs. Results: This study demonstrated that PCPs significantly mitigated body weight loss, restored muscle fiber atrophy and mitochondrial disorder, alleviated adipose tissue wasting, strengthened the intestinal barrier integrity, and decreased the intestinal inflammation in chemotherapy-induced cachexia. Furthermore, the reversal of specific bacterial taxa including Klebsiella, Akkermansia, norank_f__Desulfovibrionaceae, Enterococcus, NK4A214_group, Eubacterium_fissicatena_group, Eubacterium_nodatum_group, Erysipelatoclostridium, Lactobacillus, Monoglobus, Ruminococcus, Odoribacter, and Enterorhabdus, along with alterations in metabolites such as amino acids (AAs), eicosanoids, lactic acid and (SCFAs), contributed to the therapeutic effects of PCPs. Conclusion: Our findings suggest that PCPs can be used as prebiotic drugs targeting the microbiome-metabolomics axis in cancer patients undergoing chemotherapy.
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Affiliation(s)
- Rongrong Zhou
- The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, China
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, China Academy of Chinese Medical Sciences, Beijng, China
| | - Tingting Liu
- Institute of Chinese Medicine Resources, Hunan Academy of Chinese Medicine, Changsha, China
| | - You Qin
- Institute of Chinese Medicine Resources, Hunan Academy of Chinese Medicine, Changsha, China
| | - Jing Xie
- Institute of Chinese Medicine Resources, Hunan Academy of Chinese Medicine, Changsha, China
| | - Shuihan Zhang
- Institute of Chinese Medicine Resources, Hunan Academy of Chinese Medicine, Changsha, China
| | - Yi Xie
- Institute of Chinese Medicine Resources, Hunan Academy of Chinese Medicine, Changsha, China
| | - Jia Lao
- The ResGreen Group, Changsha, China
| | - Wei He
- The ResGreen Group, Changsha, China
| | - Hongliang Zeng
- Institute of Chinese Medicine Resources, Hunan Academy of Chinese Medicine, Changsha, China
| | - Xueyang Tang
- Institute of Chinese Medicine Resources, Hunan Academy of Chinese Medicine, Changsha, China
| | - Xuefei Tian
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Changsha, China
| | - Yuhui Qin
- The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, China
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
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Gamal NK, El-Naga RN, Ayoub IM, George MY. Neuromodulatory effect of troxerutin against doxorubicin and cyclophosphamide-induced cognitive impairment in rats: Potential crosstalk between gut-brain and NLRP3 inflammasome axes. Int Immunopharmacol 2025; 149:114216. [PMID: 39919456 DOI: 10.1016/j.intimp.2025.114216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 08/29/2024] [Accepted: 01/31/2025] [Indexed: 02/09/2025]
Abstract
"Chemobrain" refers to the cognitive impairment induced by chemotherapy. The doxorubicin and cyclophosphamide cocktail has been used for various cancers, especially breast cancer. However, both have been linked to chemobrain as well as gastrointestinal toxicity. Despite being distinct organs, the gut and the brain have a bidirectional connection between them known as the gut-brain axis. This research aimed to study the neuroprotective effect of troxerutin, a rutin derivative, in chemobrain induced by doxorubicin and cyclophosphamide via a potential impact on the gut-inflammasome-brain axis. Troxerutin was administered at 75, 150, and 300 mg/kg doses. Furthermore, behavioral, histological, and acetylcholinesterase assessments were performed. Accordingly, the highest dose of troxerutin was selected to investigate the potential underlying mechanisms. Troxerutin treatment reversed the chemotherapy-fecal metabolite alterations. Additionally, troxerutin demonstrated positive effects against deterioration of intestinal integrity, permeability, and microbial endotoxins translocation, as evidenced by its effect on tight junction proteins; ZO-1, and claudin-1 expression, and lipopolysaccharide serum levels. Consequently, troxerutin hindered lipopolysaccharide-induced oxidative damage, systemic inflammation, and neuroinflammation. Moreover, troxerutin demonstrated antioxidant effects via its impact on lipid peroxidation, catalase levels, and the Nrf2/HO-1 pathway. Furthermore, chemotherapy-induced inflammation was opposed by troxerutin via downregulation of NLRP3, caspase-1, and the downstream cytokines; IL-18 and IL-1β. Importantly, troxerutin did not abrogate the anticancer activity of doxorubicin and cyclophosphamide in human MCF7 cells. Collectively, our study suggested the potentiality of troxerutin as a therapeutic choice against chemobrain by inhibiting the gut-inflammasome-brain axis and hindering acetylcholinesterase, oxidative stress, and neuroinflammation.
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Affiliation(s)
- Nada K Gamal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University 11566 Cairo, Egypt
| | - Reem N El-Naga
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University 11566 Cairo, Egypt
| | - Iriny M Ayoub
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo 11566 Egypt
| | - Mina Y George
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University 11566 Cairo, Egypt.
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Ho J, Sukati S, Taylor T, Carter S, Fuller B, Marmo A, Sorge C, D'Orazio J, Butterfield DA, Bondada S, Weiss H, St Clair DK, Chaiswing L. Extracellular vesicles released by ALL patients contain HNE-adducted proteins: Implications of collateral damage. Free Radic Biol Med 2025; 227:312-321. [PMID: 39643137 PMCID: PMC11786608 DOI: 10.1016/j.freeradbiomed.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/19/2024] [Accepted: 12/02/2024] [Indexed: 12/09/2024]
Abstract
Off-target neuronal injury is a serious side-effect observed in cancer survivors. It has previously been shown that pediatric acute lymphoblastic leukemia (ALL) survivors have a decline in neurocognition compared to healthy age-matched counterparts. Elevated oxidative stress has been documented to be a mediator in off-target tissue damage in cancer survivors. Early detection of oxidative stress markers may provide an opportunity to prevent off-target tissue damage. Extracellular vesicles (EVs) have surfaced as a potential diagnostic tool due to molecular cargo they contain. We investigated the potential for EVs to be a sensitive indicator of oxidative stress and off-target tissue damage by isolating EVs from pediatric ALL patients throughout their first 2 months of treatment. EVs were measured throughout the collection points for: 1) number of EV particles generated using nanoparticle tracking analysis (NTA); 2) markers of neurons (NeuN), astrocyte activation (GFAP), neuronal stability (BDNF), 3) markers of pre-B cell ALL (CD19 and CD22); and) 4-hydroxy-2-nonenal (HNE) adducted proteins. HNE protein adductions were measured in the patient sera and CSF. Pro-inflammatory cytokine levels were also measured in patient sera because of their contribution to oxidative stress and neuronal injury. Our results: 1) demonstrate EVs are a sensitive indicator of oxidative damage; 2) suggest EVs as a marker of a decline in neuronal stability; and 3) show the presence of leukemia has a greater contribution to pro-inflammatory cytokine production in the patient's serum than the cancer treatment. Specifically, we observed a significant decrease in cytokine levels (e.g., TNF-α, IL-1β, IL-6, and IL-8) following the initiation of treatment, highlighting the influence of leukemia burden on systemic inflammation. The results support the utilization of EVs as a sensitive marker of oxidative stress and off-target tissue damage.
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Affiliation(s)
- Jenni Ho
- Department of Toxicology and Cancer Biology, University of Kentucky, USA; Markey Cancer Center, University of Kentucky, USA
| | - Suriyan Sukati
- Department of Medical Technology, Walailak University, Thailand
| | - Tamara Taylor
- Department of Pediatrics, University of Kentucky, USA
| | - Sherry Carter
- Department of Pediatrics, University of Kentucky, USA
| | | | - Amy Marmo
- Department of Pediatrics, University of Kentucky, USA
| | - Caryn Sorge
- Department of Pediatrics, University of Kentucky, USA
| | - John D'Orazio
- Markey Cancer Center, University of Kentucky, USA; Department of Pediatrics, University of Kentucky, USA
| | - D Allan Butterfield
- Markey Cancer Center, University of Kentucky, USA; Department of Chemistry, University of Kentucky, USA
| | - Subbarao Bondada
- Markey Cancer Center, University of Kentucky, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, USA
| | - Heidi Weiss
- Markey Cancer Center, University of Kentucky, USA; Department of Surgery and Biostatistics, University of Kentucky, USA
| | - Daret K St Clair
- Department of Toxicology and Cancer Biology, University of Kentucky, USA; Markey Cancer Center, University of Kentucky, USA
| | - Luksana Chaiswing
- Department of Toxicology and Cancer Biology, University of Kentucky, USA; Markey Cancer Center, University of Kentucky, USA.
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Modanlou M, Mahdipour M, Mobarak H. Effectiveness of stem cell therapy for male infertility restoration: A systematic review. J Investig Med 2025; 73:229-252. [PMID: 39584230 DOI: 10.1177/10815589241305317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2024]
Abstract
Cell therapy has emerged as a prominent leader in regenerative medicine, offering potential solutions for various disorders, including infertility. Half of all infertility cases are related to male factors. The objective of this study is to systematically summarize the existing knowledge regarding studies on stem cell-based therapy for the regeneration of impaired spermatogenesis. Initial searching was performed through main databases (e.g., PubMed, Scopus, Cochrane Library, and Embase) until December 2023. Articles conducted on stem cell transplantation into the testis of infertile models were considered. The titles and abstracts of articles were carefully evaluated and screened by independent authors. Nonrelated articles were deleted. The desired outcomes of infertility treatment after stem cell transplantation were attentively evaluated in the final selected articles. In the primary search, 3237 published studies were identified. Finally, 39 studies were included based on the eligibility criteria. In all studies except for two articles, all the outcomes considered, including germ cells/spermatogonia stem cell differentiation, spermatogenesis restoration, defective testicular tissue regeneration, improved sperm quality parameters, and hormonal levels, as well as increased expression of fertility-related markers and fertility rate, were observed after stem cell transplantation. Transplantation of stem cells, especially MSCs could be a safe and effective method for the treatment of male infertility patients, such as azoospermic cases. Further research to investigate the efficiency of different stem cell sources, providing nutrient conditions for the isolation and differentiation of stem cells, and exploring the paracrine effects of MSCs in male infertility therapy, could be useful.
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Affiliation(s)
- Mohammad Modanlou
- School of Medical sciences, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Mahdi Mahdipour
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Halimeh Mobarak
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
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Al Khafaji AT, Barakat AM, Shayyal AJ, Taan AA, Aboqader Al-Aouadi RF. Managing Doxorubicin Cardiotoxicity: Insights Into Molecular Mechanisms and Protective Strategies. J Biochem Mol Toxicol 2025; 39:e70155. [PMID: 39887483 DOI: 10.1002/jbt.70155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/30/2024] [Accepted: 01/16/2025] [Indexed: 02/01/2025]
Abstract
Cancer ranks as the second leading cause of death in the United States and poses a significant health challenge globally. Numerous therapeutic options exist for treating cancer, with chemotherapy being one of the most prominent. Chemotherapy involves the use of antineoplastic drugs, either alone or in combination with other medications, to target and kill cancer cells. However, these drugs can also adversely affect healthy cells, leading to various side effects. Among the most commonly used chemotherapy agents are anthracyclines, which include doxorubicin, daunorubicin, and epirubicin. Doxorubicin is particularly notable for its effectiveness but is also associated with significant cardiotoxicity, a common concern for patients undergoing chemotherapy. Unfortunately, there is currently no definitive treatment to prevent or reverse this cardiotoxicity. The cardiac effects of doxorubicin can manifest in several ways, including changes in electrocardiograms, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, heart failure, and congestive heart failure. These complications may arise during treatment, shortly after it concludes, or even weeks later. Various mechanisms have been proposed to explain doxorubicin-induced cardiotoxicity. Key factors include the inhibition of topoisomerase IIβ, mitochondrial damage, reactive oxygen species (ROS) production due to iron metabolism, increased oxidative stress, heightened inflammatory responses, and elevated rates of apoptosis and necrosis within cardiac tissue. This review article will provide a comprehensive overview of the current state of knowledge regarding doxorubicin-induced cardiomyopathy. We will explore the underlying molecular mechanisms contributing to this condition and discuss emerging therapeutic strategies aimed at mitigating its impact on cancer survivors.
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Affiliation(s)
| | | | | | - Ali Adnan Taan
- Nasr City Hospital for Health Insurance, Ministry of Health, Cairo, Egypt
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Mondal S, Park S, Nguyen VT, Doan VHM, Choi J, Ly CD, Phan DT, Truong TT, Vo TH, Nguyen DT, Pal U, Lee B, Oh J. Precision Cancer Therapy Enabled Anti-Epidermal Growth Factor Receptor-Conjugated Manganese Core Phthalocyanine Bismuth Nanocomposite for Dual Imaging-Guided Breast Cancer Treatment. Biomater Res 2024; 2024:0092. [PMID: 39525484 PMCID: PMC11542904 DOI: 10.34133/bmr.0092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 09/04/2024] [Accepted: 09/24/2024] [Indexed: 11/16/2024] Open
Abstract
Cancer remains a formidable global health challenge, demanding the exploration of innovative treatment modalities with minimized side effects. One promising avenue involves the synergistic integration of targeted photothermal/photodynamic therapy (PTT/PDT), utilizing specially designed functional nanomaterials for precise cancer diagnosis and treatment. This study introduces a composite biomaterial, anti-epidermal growth factor receptor-conjugated manganese core phthalocyanine bismuth (anti-EGFR-MPB), synthesized for precise cancer imaging and treatment. The biomaterial, synthesized via a solvothermal process, effectively treats and images breast cancer in mouse models. Its biomimetic design targets cancer cells precisely, with dual imaging for real-time monitoring. The biomimetic design of the composite enables precise targeting of cancer cells, whereas the dual imaging allows for real-time visualization and monitoring of the treatment. In vivo examinations confirm substantial damage to tumor tissues with no recurrence following 808-nm laser irradiation. The composite shows strong fluorescence/photoacoustic imaging (PAI) contrast, aiding malignancy detection. Biological assays and histological analyses confirmed the efficacy of the nanocomposite in inducing apoptosis in cancer cells. The integrated targeted dual image-guided phototherapy offered by this composite substantially enhances the precision and efficacy of cancer therapy, achieving an impressive photothermal efficiency of ~33.8%. Our findings demonstrate the utility of the anti-EGFR-MPB nanocomposite for both in vitro and in vivo photoacoustic image-guided PTT and PDT. The optimal treatment strategy for triple-negative breast cancer is found to be the use of 250 μg/ml of nanocomposite irradiated with 1.0 W/cm2 808-nm laser for 7 min.
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Affiliation(s)
- Sudip Mondal
- Digital Healthcare Research Center, Pukyong National University
| | - Sumin Park
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Van Tu Nguyen
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Vu Hoang Minh Doan
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Jaeyeop Choi
- Smart Gym-Based Translational Research Center for Active Senior’s Healthcare, Pukyong National University, Busan 48513, Republic of Korea
| | - Cao Duong Ly
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Duc Tri Phan
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Thi Thuy Truong
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Tan Hung Vo
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Dinh Tuan Nguyen
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Umapada Pal
- Institute of Physics, Autonomous University of Puebla, Puebla, Pue. 72570, Mexico
| | - Byeongil Lee
- Digital Healthcare Research Center, Pukyong National University
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
- Smart Gym-Based Translational Research Center for Active Senior’s Healthcare, Pukyong National University, Busan 48513, Republic of Korea
- Department of Smart Healthcare, Pukyong National University, Busan 48513, Republic of Korea
| | - Junghwan Oh
- Digital Healthcare Research Center, Pukyong National University
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
- Smart Gym-Based Translational Research Center for Active Senior’s Healthcare, Pukyong National University, Busan 48513, Republic of Korea
- Department of Smart Healthcare, Pukyong National University, Busan 48513, Republic of Korea
- Ohlabs Corp., Busan 48513, Republic of Korea
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10
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Barbosa-Azevedo M, Dias-Carvalho A, Carvalho F, Costa VM. Chemotherapy-induced cognitive impairment and glia: A new take on chemobrain? Toxicol Appl Pharmacol 2024; 492:117085. [PMID: 39236990 DOI: 10.1016/j.taap.2024.117085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 07/03/2024] [Accepted: 09/02/2024] [Indexed: 09/07/2024]
Abstract
The significant rise in cancer survivorship stands out as one of the most notable achievements of modern science. However, this comes with a significant burden, as cancer treatment is not without adverse effects. Lately, there has been a growing focus on cognitive dysfunction associated with cancer treatment, often referred to as 'chemobrain'. It significantly impacts the quality of life for cancer survivors. The underlying mechanisms studied so far usually focus on neurons, while other cells of the central nervous system are often overlooked. This review seeks to place the hypothesis that glial cells may play a role in the development of chemotherapy-induced cognitive dysfunction. It summarizes the primary mechanisms proposed to date while underscoring the existing gaps in this research field. Inflammation and release of pro-inflammatory mediators by M1 microglia and A1 astrocytes are the most prevalent findings after chemotherapy. However, activation of A1 astrocytes by some chemotherapeutic agents may contribute to neuronal degeneration, alterations in synaptic branches, as well as glutamate excitotoxicity, which can contribute to cognitive impairment. Furthermore, the reduction in the number of oligodendrocytes after chemotherapy may also impact the myelin sheath, contributing to 'chemobrain'. Furthermore, some chemotherapeutic drugs activate M1 microglia, which is associated with decreased neuroplasticity and, possibly, cognitive impairment. In conclusion, data regarding the effects of chemotherapy on glial cells are scarce, and it is essential to understand how these cells are affected after cancer treatment to enable reliable therapeutic or preventive actions on cancer-treated patients.
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Affiliation(s)
- Maria Barbosa-Azevedo
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Ana Dias-Carvalho
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Félix Carvalho
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Vera Marisa Costa
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
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11
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Chu YL, Pi JC, Yao YF, Chen XY, Peng XP, Li WJ. Polyphenol (-)-Epigallocatechin Gallate (EGCG) mitigated kidney injury by regulating metabolic homeostasis and mitochondrial dynamics involvement with Drp1-mediated mitochondrial fission in mice. Food Chem Toxicol 2024; 191:114906. [PMID: 39095006 DOI: 10.1016/j.fct.2024.114906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/05/2024] [Accepted: 07/30/2024] [Indexed: 08/04/2024]
Abstract
The study aimed to examine effects of (-)-epigallocatechin-3-gallate (EGCG) on energy metabolism and mitochondrial dynamics in mouse model of renal injury caused by doxorubicin (DOX). Here, mice were divided into Control group, EGCG-only treated group, DOX group, and three doses of EGCG plus DOX groups. Our results showed that EGCG behaved beneficial effects against kidney injury via attenuation of pathological changes in kidney tissue, which was confirmed by reducing serum creatinine (SCr), blood urea nitrogen (BUN), and apoptosis. Subsequently, changes in reactive oxygen species generation, malondialdehyde content, and activities of antioxidant enzymes were considerably ameliorated in EGCG + DOX groups when compared to DOX group. Furthermore, EGCG-evoked renal protection was associated with increases of mitochondrial membrane potential and decreases of mitochondrial fission protein Dynamin-related protein 1 (Drp1). Moreover, changing glycolysis into mitochondrial oxidative phosphorylation was observed, evidenced by controlling activities of malate dehydrogenase (MDH) and hexokinase (HK) in EGCG + DOX groups when compared to DOX group, indicating that reprogramming energy metabolism was linked to EGCG-induced renal protection in mice. Therefore, EGCG was demonstrated to have a protective effect against kidney injury by reducing oxidative damage, metabolic disorders, and mitochondrial dysfunction, suggesting that EGCG has potential as a feasible strategy to prevent kidney injury.
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Affiliation(s)
- Yue-Lei Chu
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, 330047, China
| | - Jin-Chan Pi
- Jinchan Pi, College of Future Technology, Nanchang University, Nanchang, 330031, China
| | - Yu-Fei Yao
- Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, China
| | - Xuan-Ying Chen
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, 330046, China
| | - Xiao-Ping Peng
- Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University. Nanchang, 330046, China
| | - Wen-Juan Li
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, 330047, China.
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12
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Cuoghi S, Caraffi R, Anderlini A, Baraldi C, Enzo E, Vandelli MA, Tosi G, Ruozi B, Duskey JT, Ottonelli I. Challenges of enzyme therapy: Why two players are better than one. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2024; 16:e1979. [PMID: 38955512 DOI: 10.1002/wnan.1979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 04/29/2024] [Accepted: 05/28/2024] [Indexed: 07/04/2024]
Abstract
Enzyme-based therapy has garnered significant attention for its current applications in various diseases. Despite the notable advantages associated with the use of enzymes as therapeutic agents, that could have high selectivity, affinity, and specificity for the target, their application faces challenges linked to physico-chemical and pharmacological properties. These limitations can be addressed through the encapsulation of enzymes in nanoplatforms as a comprehensive solution to mitigate their degradation, loss of activity, off-target accumulation, and immunogenicity, thus enhancing bioavailability, therapeutic efficacy, and circulation time, thereby reducing the number of administrations, and ameliorating patient compliance. The exploration of novel nanomedicine-based enzyme therapeutics for the treatment of challenging diseases stands as a paramount goal in the contemporary scientific landscape, but even then it is often not enough. Combining an enzyme with another therapeutic (e.g., a small molecule, another enzyme or protein, a monoclonal antibody, or a nucleic acid) within a single nanocarrier provides innovative multidrug-integrated therapy and ensures that both the actives arrive at the target site and exert their therapeutic effect, leading to synergistic action and superior therapeutic efficacy. Moreover, this strategic approach could be extended to gene therapy, a field that nowadays has gained increasing attention, as enzymes acting at genomic level and nucleic acids may be combined for synergistic therapy. This multicomponent therapeutic approach opens opportunities for promising future developments. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Affiliation(s)
- Sabrina Cuoghi
- Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Riccardo Caraffi
- Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
- Clinical and Experimental Medicine PhD Program, Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandro Anderlini
- Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Cecilia Baraldi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Elena Enzo
- Centre for Regenerative Medicine "Stefano Ferrari", University of Modena and Reggio Emilia, Modena, Italy
| | - Maria Angela Vandelli
- Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Giovanni Tosi
- Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Barbara Ruozi
- Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Jason Thomas Duskey
- Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Ilaria Ottonelli
- Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
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Aquilani R, Brugnatelli S, Maestri R, Iadarola P, Corallo S, Pagani A, Serra F, Bellini A, Buonocore D, Dossena M, Boschi F, Verri M. Chemotherapy-Induced Changes in Plasma Amino Acids and Lipid Oxidation of Resected Patients with Colorectal Cancer: A Background for Future Studies. Int J Mol Sci 2024; 25:5300. [PMID: 38791339 PMCID: PMC11121634 DOI: 10.3390/ijms25105300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 05/07/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Previous studies have documented that FOLFOX and XELOX therapies negatively impact the metabolism of skeletal muscle and extra-muscle districts. This pilot study tested whether three-month FOLFOX or XELOX therapy produced changes in plasma amino acid levels (PAAL) (an estimation of whole-body amino acid metabolism) and in plasma levels of malondialdehyde (MDA), a marker of lipid hyper oxidation. Fourteen ambulatory, resected patients with colorectal cancer scheduled to receive FOLFOX (n = 9) or XELOX (n = 5) therapy, after overnight fasting, underwent peripheral venous blood sampling, to determine PAAL and MDA before, during, and at the end of three-month therapy. Fifteen healthy matched subjects (controls) only underwent measures of PAAL at baseline. The results showed changes in 87.5% of plasma essential amino acids (EAAs) and 38.4% of non-EAAs in patients treated with FOLFOX or XELOX. These changes in EAAs occurred in two opposite directions: EAAs decreased with FOLFOX and increased or did not decrease with XELOX (interactions: from p = 0.034 to p = 0.003). Baseline plasma MDA levels in both FOLFOX and XELOX patients were above the normal range of values, and increased, albeit not significantly, during therapy. In conclusion, three-month FOLFOX or XELOX therapy affected plasma EAAs differently but not the baseline MDA levels, which were already high.
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Affiliation(s)
- Roberto Aquilani
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy; (R.A.); (P.I.); (A.B.); (D.B.); (M.D.)
| | - Silvia Brugnatelli
- Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.B.); (S.C.); (A.P.); (F.S.)
| | - Roberto Maestri
- Department of Biomedical Engineering of the Montescano Institute, Istituti Clinici Scientifici Maugeri IRCCS, 27040 Montescano, Italy;
| | - Paolo Iadarola
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy; (R.A.); (P.I.); (A.B.); (D.B.); (M.D.)
| | - Salvatore Corallo
- Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.B.); (S.C.); (A.P.); (F.S.)
| | - Anna Pagani
- Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.B.); (S.C.); (A.P.); (F.S.)
| | - Francesco Serra
- Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.B.); (S.C.); (A.P.); (F.S.)
| | - Anna Bellini
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy; (R.A.); (P.I.); (A.B.); (D.B.); (M.D.)
| | - Daniela Buonocore
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy; (R.A.); (P.I.); (A.B.); (D.B.); (M.D.)
| | - Maurizia Dossena
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy; (R.A.); (P.I.); (A.B.); (D.B.); (M.D.)
| | - Federica Boschi
- Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy;
| | - Manuela Verri
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy; (R.A.); (P.I.); (A.B.); (D.B.); (M.D.)
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14
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Nagy A, Börzsei D, Hoffmann A, Török S, Veszelka M, Almási N, Varga C, Szabó R. A Comprehensive Overview on Chemotherapy-Induced Cardiotoxicity: Insights into the Underlying Inflammatory and Oxidative Mechanisms. Cardiovasc Drugs Ther 2024:10.1007/s10557-024-07574-0. [PMID: 38492161 DOI: 10.1007/s10557-024-07574-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/05/2024] [Indexed: 03/18/2024]
Abstract
While oncotherapy has made rapid progress in recent years, side effects of anti-cancer drugs and treatments have also come to the fore. These side effects include cardiotoxicity, which can cause irreversible cardiac damages with long-term morbidity and mortality. Despite the continuous in-depth research on anti-cancer drugs, an improved knowledge of the underlying mechanisms of cardiotoxicity are necessary for early detection and management of cardiac risk. Although most reviews focus on the cardiotoxic effect of a specific individual chemotherapeutic agent, the aim of our review is to provide comprehensive insight into various agents that induced cardiotoxicity and their underlying mechanisms. Characterization of these mechanisms are underpinned by research on animal models and clinical studies. In order to gain insight into these complex mechanisms, we emphasize the role of inflammatory processes and oxidative stress on chemotherapy-induced cardiac changes. A better understanding and identification of the interplay between chemotherapy and inflammatory/oxidative processes hold some promise to prevent or at least mitigate cardiotoxicity-associated morbidity and mortality among cancer survivors.
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Affiliation(s)
- András Nagy
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Denise Börzsei
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Alexandra Hoffmann
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Szilvia Török
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Médea Veszelka
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Nikoletta Almási
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Csaba Varga
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Renáta Szabó
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary.
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15
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Ye Z, Li J, Shi J, Song Y, Liu Y, Hou J. Glycosidase-activated H 2S donorsto enhance chemotherapy efficacy. Bioorg Med Chem Lett 2024; 100:129644. [PMID: 38316370 DOI: 10.1016/j.bmcl.2024.129644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/27/2024] [Accepted: 01/31/2024] [Indexed: 02/07/2024]
Abstract
Hydrogen sulfide (H2S) plays a critical role in cancer biology. Herein, we developed a series of glycosidase-triggered hydrogen sulfide (H2S) donors by connecting sugar moieties (including glucose, galactose and mannose) to COS donors via a self-immolative spacer. In the presence of corresponding glycosidases, H2S was gradually released from these donors in PBS buffer with releasing efficiencies from 36 to 67 %. H2S release was also detected by H2S probe WSP-1 after treatment HepG2 cells with Man1. Cytotoxicities of these glycosylated H2S donors were evaluated against HepG2 by MTT assay. Among them, Man1 and Man2 exhibited an obvious reduction of cell viability in HepG2 cells, with cell viability as 37.6 % for 80 μM of Man. Consistently, significant apoptosis was observed in HepG2 cells after treatment with Man1 and Man2. Finally, We evaluated the potential of Man1 for combination therapy with doxorubicin. A synergistic effect was observed between Man1 and Doxorubicin in HepG2 and Hela cells. All these results indicated glycosidase-activated H2S donorshave promising potential for cancer therapy.
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Affiliation(s)
- Zizhen Ye
- Tianjin Key Laboratory on Technologies Enabling Development of ClinicalTherapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China
| | - Jixiang Li
- Tianjin Key Laboratory on Technologies Enabling Development of ClinicalTherapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China
| | - Jiarui Shi
- Tianjin Key Laboratory on Technologies Enabling Development of ClinicalTherapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China
| | - Yuguang Song
- Tianjin Key Laboratory on Technologies Enabling Development of ClinicalTherapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China
| | - Yangping Liu
- Tianjin Key Laboratory on Technologies Enabling Development of ClinicalTherapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
| | - Jingli Hou
- Tianjin Key Laboratory on Technologies Enabling Development of ClinicalTherapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
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16
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Kisielewska M, Rakoczy K, Skowron I, Górczyńska J, Kacer J, Bocheńska A, Choromańska A. Utilizing Extracellular Vesicles for Eliminating 'Unwanted Molecules': Harnessing Nature's Structures in Modern Therapeutic Strategies. Molecules 2024; 29:948. [PMID: 38474460 DOI: 10.3390/molecules29050948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 02/09/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Extracellular vesicles (EVs) are small phospholipid bilayer-bond structures released by diverse cell types into the extracellular environment, maintaining homeostasis of the cell by balancing cellular stress. This article provides a comprehensive overview of extracellular vesicles, their heterogeneity, and diversified roles in cellular processes, emphasizing their importance in the elimination of unwanted molecules. They play a role in regulating oxidative stress, particularly by discarding oxidized toxic molecules. Furthermore, endoplasmic reticulum stress induces the release of EVs, contributing to distinct results, including autophagy or ER stress transmission to following cells. ER stress-induced autophagy is a part of unfolded protein response (UPR) and protects cells from ER stress-related apoptosis. Mitochondrial-derived vesicles (MDVs) also play a role in maintaining homeostasis, as they carry damaged mitochondrial components, thereby preventing inflammation. Moreover, EVs partake in regulating aging-related processes, and therefore they can potentially play a crucial role in anti-aging therapies, including the treatment of age-related diseases such as Alzheimer's disease or cardiovascular conditions. Overall, the purpose of this article is to provide a better understanding of EVs as significant mediators in both physiological and pathological processes, and to shed light on their potential for therapeutic interventions targeting EV-mediated pathways in various pathological conditions, with an emphasis on age-related diseases.
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Affiliation(s)
| | - Katarzyna Rakoczy
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Izabela Skowron
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Julia Górczyńska
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Julia Kacer
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Agata Bocheńska
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Anna Choromańska
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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17
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Budamagunta V, Kumar A, Rani A, Manohar Sindhu S, Yang Y, Zhou D, Foster TC. Senolytic treatment alleviates doxorubicin-induced chemobrain. Aging Cell 2024; 23:e14037. [PMID: 38225896 PMCID: PMC10861213 DOI: 10.1111/acel.14037] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/21/2023] [Accepted: 10/23/2023] [Indexed: 01/17/2024] Open
Abstract
Doxorubicin (Dox), a widely used treatment for cancer, can result in chemotherapy-induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox treatment has also been used as a model of aging. However, it is unclear if Dox induces brain changes similar to that observed during aging since Dox does not readily enter the brain. Rather, the mechanism for chemobrain likely involves the induction of peripheral cellular senescence and the release of senescence-associated secretory phenotype (SASP) factors and these SASP factors can enter the brain to disrupt cognition. We examined the effect of Dox on peripheral and brain markers of aging and cognition. In addition, we employed the senolytic, ABT-263, which also has limited access to the brain. The results indicate that plasma SASP factors enter the brain, activating microglia, increasing oxidative stress, and altering gene transcription. In turn, the synaptic function required for memory was reduced in response to altered redox signaling. ABT-263 prevented or limited most of the Dox-induced effects. The results emphasize a link between cognitive decline and the release of SASP factors from peripheral senescent cells and indicate some differences as well as similarities between advanced age and Dox treatment.
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Affiliation(s)
- Vivekananda Budamagunta
- Department of Neuroscience, McKnight Brain InstituteUniversity of FloridaGainesvilleFloridaUSA
- Genetics and Genomics Graduate Program, Genetics InstituteUniversity of FloridaGainesvilleFloridaUSA
- Department of Pharmacodynamics, College of PharmacyUniversity of FloridaGainesvilleFloridaUSA
| | - Ashok Kumar
- Department of Neuroscience, McKnight Brain InstituteUniversity of FloridaGainesvilleFloridaUSA
| | - Asha Rani
- Department of Neuroscience, McKnight Brain InstituteUniversity of FloridaGainesvilleFloridaUSA
| | - Sahana Manohar Sindhu
- Genetics and Genomics Graduate Program, Genetics InstituteUniversity of FloridaGainesvilleFloridaUSA
| | - Yang Yang
- Department of Pharmacodynamics, College of PharmacyUniversity of FloridaGainesvilleFloridaUSA
| | - Daohong Zhou
- Department of Pharmacodynamics, College of PharmacyUniversity of FloridaGainesvilleFloridaUSA
- Department of Biochemistry and Structural BiologyUniversity of Texas Health Science Center at San AntonioSan AntonioTexasUSA
| | - Thomas C. Foster
- Department of Neuroscience, McKnight Brain InstituteUniversity of FloridaGainesvilleFloridaUSA
- Genetics and Genomics Graduate Program, Genetics InstituteUniversity of FloridaGainesvilleFloridaUSA
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18
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Alqahtani NF, Alfaifi MY, Shati AA, Elbehairi SEI, Elshaarawy RFM, Serag WM, Hassan YA, El-Sayed WN. Exploring the chondroitin sulfate nanogel's potential in combating nephrotoxicity induced by cisplatin and doxorubicin-An in-vivo study on rats. Int J Biol Macromol 2024; 258:128839. [PMID: 38134998 DOI: 10.1016/j.ijbiomac.2023.128839] [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: 07/21/2023] [Revised: 12/02/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023]
Abstract
In this study, we aim to unveil the potential of itaconyl chondroitin sulfate nanogel (ICSNG) in tackling chronic kidney diseases triggered by the administration of CDDP and doxorubicin (Adriamycin, ADR). To that end, the new drug delivery system (ICSNG) was initially prepared, characterized, and loaded with the target drugs. Thereafter, the in-vivo studies were performed using five equally divided groups of 100 male Sprague-Dawley (SD) rats. Biochemical evaluation and immunohistochemistry studies have revealed the renal toxicity and the ameliorative effects of ICSNG on renal function. When ICSNG-based treatments were contrasted with the CDDP and ADR infected groups, they significantly increased paraoxonase-1 (PON-1), superoxide dismutase (SOD), catalase (CAT) and albumin activity and significantly decreased nitric oxide (NO), tumor necrosis factor alpha (TNF-α), creatinine, urea, and cyclooxygenase-2 (COX-2) activity (p < 0.001). The findings of the current study imply that ICSNG may be able to lessen renal inflammation and damage in chronic kidney disorders brought on by the administration of CDDP and ADR. Interestingly, according to the estimated selectivity indices, the ICSNG-encapsulated drugs have demonstrated superior selectivity for cancer MCF-7 cells, over healthy HSF cells, in comparison to the bare drugs.
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Affiliation(s)
- Norah F Alqahtani
- Department of Chemistry, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia
| | - Mohammad Y Alfaifi
- King Khalid University, Faculty of Science, Biology Department, Abha 9004, Saudi Arabia
| | - Ali A Shati
- King Khalid University, Faculty of Science, Biology Department, Abha 9004, Saudi Arabia
| | | | - Reda F M Elshaarawy
- Department of Chemistry, Faculty of Science, Suez University, 43533 Suez, Egypt; Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany.
| | - Waleed M Serag
- Department of Chemistry, Faculty of Science, Suez University, 43533 Suez, Egypt
| | - Yasser A Hassan
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Al-Kitab University, Kirkuk, Iraq; Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Al-Qalam University College, Kirkuk, Iraq; Department of pharmaceutics and Pharmaceutical Technology, Faculty of pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - W N El-Sayed
- Department of Chemistry, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia
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19
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Li M, Tang Q, Li S, Yang X, Zhang Y, Tang X, Huang P, Yin D. Inhibition of autophagy enhances the anticancer effect of Schisandrin B on head and neck squamous cell carcinoma. J Biochem Mol Toxicol 2024; 38:e23585. [PMID: 37986106 DOI: 10.1002/jbt.23585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 10/10/2023] [Accepted: 11/10/2023] [Indexed: 11/22/2023]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is among the most common malignant tumors worldwide and has a poor prognosis. Autophagy regulation has been proposed as a possible treatment option for HNSCC. Schisandrin B (Sch B) exerts anticancer effects by regulating apoptosis and autophagy, but the anticancer effect of Sch B in HNSCC remains unclear. This study aimed to investigate the effects of Sch B on human Cal27 HNSCC cells and to further reveal its potential regulatory mechanisms. The anticancer effect of Sch B was evaluated in vitro by flow cytometry, clonogenic assays, and Western blot analysis. The regulatory mechanism of Sch B-induced apoptosis and autophagy was further explored by polymerase chain reaction, luciferase assay, and reactive oxygen species (ROS) detection. The results showed that Sch B significantly induced apoptosis and autophagy in Cal27 cells and that inhibition of autophagy enhanced the apoptotic effect of Sch B on Cal27 cells. Additionally, Sch B-activated autophagy in Cal27 cells was dependent on the nuclear factor-kappa B (NF-κB) pathway, and ROS acted as a regulator of the NF-B pathway. N-acetylcysteine, a scavenger of ROS, inhibited Sch B-dependent autophagy via the NF-κB pathway. Based on the results, Sch B is a potential therapeutic agent for HNSCC and activates the NF-κB pathway by increasing ROS production, which subsequently promotes autophagy in HNSCC cells. Therefore, the strategy of enhancing the anticancer effect of Sch B by inhibiting autophagy deserves further attention.
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Affiliation(s)
- Mengmeng Li
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Qinglai Tang
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Shisheng Li
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xinming Yang
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Ying Zhang
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xiaojun Tang
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Peiying Huang
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Danhui Yin
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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20
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Lässig M, Mustonen V, Nourmohammad A. Steering and controlling evolution - from bioengineering to fighting pathogens. Nat Rev Genet 2023; 24:851-867. [PMID: 37400577 PMCID: PMC11137064 DOI: 10.1038/s41576-023-00623-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2023] [Indexed: 07/05/2023]
Abstract
Control interventions steer the evolution of molecules, viruses, microorganisms or other cells towards a desired outcome. Applications range from engineering biomolecules and synthetic organisms to drug, therapy and vaccine design against pathogens and cancer. In all these instances, a control system alters the eco-evolutionary trajectory of a target system, inducing new functions or suppressing escape evolution. Here, we synthesize the objectives, mechanisms and dynamics of eco-evolutionary control in different biological systems. We discuss how the control system learns and processes information about the target system by sensing or measuring, through adaptive evolution or computational prediction of future trajectories. This information flow distinguishes pre-emptive control strategies by humans from feedback control in biotic systems. We establish a cost-benefit calculus to gauge and optimize control protocols, highlighting the fundamental link between predictability of evolution and efficacy of pre-emptive control.
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Affiliation(s)
- Michael Lässig
- Institute for Biological Physics, University of Cologne, Cologne, Germany.
| | - Ville Mustonen
- Organismal and Evolutionary Biology Research Programme, Department of Computer Science, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
| | - Armita Nourmohammad
- Department of Physics, University of Washington, Seattle, WA, USA.
- Department of Applied Mathematics, University of Washington, Seattle, WA, USA.
- Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA.
- Herbold Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, WA, USA.
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21
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O’Leary BR, Kalen AL, Pope AN, Goswami PC, Cullen JJ. Hydrogen Peroxide Mediates Pharmacological Ascorbate Induced Radio-Sensitization of Pancreatic Cancer Cells by Enhancing G2-accumulation and Reducing Cyclin B1 Protein Levels. Radiat Res 2023; 200:444-455. [PMID: 37758045 PMCID: PMC10699322 DOI: 10.1667/rade-22-00182.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 08/24/2023] [Indexed: 10/03/2023]
Abstract
Pharmacological ascorbate (P-AscH-, high dose, intravenous vitamin C) preferentially sensitizes human pancreas ductal adenocarcinoma (PDAC) cells to radiation-induced toxicity compared to non-tumorigenic epithelial cells. Radiation-induced G2-checkpoint activation contributes to the resistance of cancer cells to DNA damage induced toxicity. We hypothesized that P-AscH- induced radio-sensitization of PDAC cells is mediated by perturbations in the radiation induced activation of the G2-checkpoint pathway. Both non-tumorigenic pancreatic ductal epithelial and PDAC cells display decreased clonogenic survival and increased doubling times after radiation treatment. In contrast, the addition of P-AscH- to radiation increases clonogenic survival and decreases the doubling time of non-tumorigenic epithelial cells but decreasing clonogenic survival and increasing the doubling time of PDAC cells. Results from the mitotic index and propidium iodide assays showed that while the P-AscH- treatments did not affect radiation-induced G2-checkpoint activation, it enhanced G2-accumulation. The addition of catalase reverses the increases in G2-accumulation, indicating a peroxide-mediated mechanism. In addition, P-AscH- treatment of PDAC cells suppresses radiation-induced accumulation of cyclin B1 protein levels. Both translational and post-translational pathways appear to regulate cyclin B1 protein levels after the combination treatment of PDAC cells with P-AscH- and radiation. The protein changes seen are reversed by the addition of catalase suggesting that hydrogen peroxide mediates P-AscH- induced radiation sensitization of PDAC cells by enhancing G2-accumulation and reducing cyclin B1 protein levels.
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Affiliation(s)
- Brianne R. O’Leary
- Departments of Surgery and Free Radical and Radiation Biology Division, The University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Amanda L. Kalen
- Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Amanda N. Pope
- Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Prabhat C. Goswami
- Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Joseph J. Cullen
- Departments of Surgery and Free Radical and Radiation Biology Division, The University of Iowa Carver College of Medicine, Iowa City, Iowa
- Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa
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22
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Emori C, Boucher Z, Bolcun-Filas E. CHEK2 signaling is the key regulator of oocyte survival after chemotherapy. SCIENCE ADVANCES 2023; 9:eadg0898. [PMID: 37862420 PMCID: PMC10588956 DOI: 10.1126/sciadv.adg0898] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 09/06/2023] [Indexed: 10/22/2023]
Abstract
Cancer treatments can damage the ovarian follicle reserve, leading to primary ovarian insufficiency and infertility among survivors. Checkpoint kinase 2 (CHEK2) deficiency prevents elimination of oocytes in primordial follicles in female mice exposed to radiation and preserves their ovarian function and fertility. Here, we demonstrate that CHEK2 also coordinates the elimination of oocytes after exposure to standard-of-care chemotherapy drugs. CHEK2 activates two downstream targets-TAp63 and p53-which direct oocyte elimination. CHEK2 knockout or pharmacological inhibition preserved ovarian follicle reserve after radiation and chemotherapy. However, the lack of specificity for CHEK2 among available inhibitors limits their potential for clinical development. These findings demonstrate that CHEK2 is a master regulator of the ovarian cellular response to damage caused by radiation and chemotherapy and warrant the development of selective inhibitors specific to CHEK2 as a potential avenue for ovario-protective treatments.
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Affiliation(s)
- Chihiro Emori
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
- Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 5650871, Japan
| | - Zachary Boucher
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
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23
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Li W, Lv M, Zhang T, Zhou M, Zheng L, Song T, Zhao M. Peptide Characterization of Bovine Myocardium Hydrolysates and Its Ameliorative Effects on Doxorubicin-Induced Myocardial Injury in H9c2 Cells and in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:14562-14574. [PMID: 37782333 DOI: 10.1021/acs.jafc.3c02339] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
The prevalence and mortality of heart disease have a persistent existence, and it is important to develop active substances with cardioprotective properties. It has been reported that peptides from animal heart hydrolysates possess cardioprotective activity, but those mechanisms and the sequence of peptides are still unrevealed. In the present study, the extracts of bovine myocardium were prepared by enzymatic hydrolysis (BHH-A) and water extraction (BHH-W). The cardioprotective function of peptides was verified in the DOX-induced H9c2 cells and myocardial injury mice. The mass spectrometry was used to contrast the differences of active ingredients between BHH-W and BHH-A. Results suggested that both BHH-A and BHH-W could increase the activity of antioxidant enzymes in cardiomyocytes and reduce the inflammatory level and apoptosis of myocardial cells. The improvement effects of BHH-A on myocardial injury in mice were better than those of BHH-W. The analysis of peptide composition demonstrated that the contents with N-segment hydrophobic amino acids were higher in the peptides identified in BHH-A. Hence, BHH-A could be used as a potential active substance to improve DOX-induced myocardial injury by reducing oxidative damage, inflammation, and cardiomyocyte apoptosis, and its activity may be related to the richness of small molecular peptides and hydrophobic amino acids.
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Affiliation(s)
- Wen Li
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, P. R. China
| | - Miao Lv
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, P. R. China
| | - Tiantian Zhang
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, People's Republic of China
| | - Minzhi Zhou
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, P. R. China
| | - Lin Zheng
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, P. R. China
| | - Tianyuan Song
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, People's Republic of China
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang 310018, China
| | - Mouming Zhao
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, P. R. China
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24
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Mattioli R, Ilari A, Colotti B, Mosca L, Fazi F, Colotti G. Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming. Mol Aspects Med 2023; 93:101205. [PMID: 37515939 DOI: 10.1016/j.mam.2023.101205] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/15/2023] [Accepted: 07/17/2023] [Indexed: 07/31/2023]
Abstract
Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, their use in therapy has been complicated by severe side effects and toxicity that occur during or after treatment, including cardiotoxicity. The mode of action of anthracyclines is complex, with several mechanisms proposed. It is possible that their high toxicity is due to the large set of processes involved in anthracycline action. The development of resistance is a major barrier to successful treatment when using anthracyclines. This resistance is based on a series of mechanisms that have been studied and addressed in recent years. This work provides an overview of the anthracyclines used in cancer therapy. It discusses their mechanisms of activity, toxicity, and chemoresistance, as well as the approaches used to improve their activity, decrease their toxicity, and overcome resistance.
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Affiliation(s)
- Roberto Mattioli
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Andrea Ilari
- Institute of Molecular Biology and Pathology, Italian National Research Council IBPM-CNR, Rome, Italy
| | - Beatrice Colotti
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Luciana Mosca
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Francesco Fazi
- Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy
| | - Gianni Colotti
- Institute of Molecular Biology and Pathology, Italian National Research Council IBPM-CNR, Rome, Italy.
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25
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Kang M, Chai K, Lee S, Oh JH, Bae JS, Payne GF. Revealing Redox Behavior of Molybdenum Disulfide and Its Application as Rechargeable Antioxidant Reservoir. ACS APPLIED MATERIALS & INTERFACES 2023; 15:41362-41372. [PMID: 37610347 DOI: 10.1021/acsami.3c08659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
Molybdenum disulfide (MoS2) is a representative two-dimensional transition metal dichalcogenide and has a unique electronic structure and associated physicochemical properties. The redox property of MoS2 has recently attracted significant attention from various fields, such as biomedical applications. Intriguingly, MoS2 functions as an antioxidant in certain applications and as a pro-oxidant in others. We use the mediated electrochemical probing method to understand the redox behavior of MoS2. This method reveals that MoS2 (i) has a reversible and fast redox activity at a mild potential (between -0.20 and +0.25 V vs Ag/AgCl), (ii) functions as an antioxidant for molecules that have different redox mechanisms (electron or hydrogen atom transfer), and (iii) is electrochemically or molecularly rechargeable. Finally, we show that MoS2 reduces oxidized molecules more efficiently than the potent natural antioxidant, curcumin. This study enhances our understanding of MoS2 and shows its potential as an advanced antioxidant reservoir.
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Affiliation(s)
- Mijeong Kang
- Department of Optics and Mechatronics Engineering, Pusan National University, Busan 46241, Republic of Korea
| | - Kyunghwan Chai
- Department of Optics and Mechatronics Engineering, Pusan National University, Busan 46241, Republic of Korea
| | - Seunghun Lee
- Department of Physics, Pukyong National University, Busan 48513, Republic of Korea
| | - Ju Hyun Oh
- Department of Physics, Pukyong National University, Busan 48513, Republic of Korea
| | - Jong-Seong Bae
- Busan Center, Korea Basic Science Institute, Busan 46742, Republic of Korea
| | - Gregory F Payne
- Institute for Bioscience and Biotechnology Research, University of Maryland, College Park, Maryland 20742, United States
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26
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Hannon Barroeta P, O'Sullivan MJ, Zisterer DM. The role of the Nrf2/GSH antioxidant system in cisplatin resistance in malignant rhabdoid tumours. J Cancer Res Clin Oncol 2023; 149:8379-8391. [PMID: 37079050 PMCID: PMC10374708 DOI: 10.1007/s00432-023-04734-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 03/31/2023] [Indexed: 04/21/2023]
Abstract
PURPOSE Malignant rhabdoid tumour (MRT) is a rare and aggressive childhood malignancy that occurs in the kidneys or central nervous system and is associated with very poor prognosis. Chemoresistance is a major issue in the treatment of this malignancy leading to an urgent need for a greater understanding of its underlying mechanisms in MRT and novel treatment strategies for MRT patients. The balance between oxidative stress mediated by reactive oxygen species (ROS) and the antioxidant system has become a subject of interest in cancer therapy research. Studies have implicated key players of the antioxidant system in chemotherapeutic including the well-known antioxidant glutathione (GSH) and the transcription factor nuclear erythroid-related factor-2 (Nrf2). METHODS: This study evaluated the role of these components in the response of MRT cells to treatment with the commonly used chemotherapeutic agent, cisplatin. RESULTS This study characterised the basal levels of GSH, ROS and Nrf2 in a panel of MRT cell lines and found a correlation between the expression profile of the antioxidant defence system and cisplatin sensitivity. Results showed that treatment with ROS scavenger N-acetylcysteine (NAC) protected cells from cisplatin-induced ROS and apoptosis. Interestingly, depleting GSH levels with the inhibitor buthionine sulphoximine (BSO) enhanced cisplatin-induced ROS and sensitised cells to cisplatin. Lastly, targeting Nrf2 with the small molecule inhibitor ML385 or by siRNA diminished GSH levels, enhanced ROS and sensitised resistant MRT cells to cisplatin. CONCLUSIONS These results suggest that targeting the Nrf2/GSH antioxidant system may present a novel therapeutic strategy to combat chemoresistance in rhabdoid tumours.
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Affiliation(s)
- Patricia Hannon Barroeta
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse St, Dublin, D02 R590, Ireland.
| | - Maureen J O'Sullivan
- The National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, D12 N512, Ireland
| | - Daniela M Zisterer
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse St, Dublin, D02 R590, Ireland
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27
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Nguyen A, Patel AB, Kioutchoukova IP, Diaz MJ, Lucke-Wold B. Mechanisms of Mitochondrial Oxidative Stress in Brain Injury: From Pathophysiology to Therapeutics. OXYGEN 2023; 3:163-178. [PMID: 37082315 PMCID: PMC10111246 DOI: 10.3390/oxygen3020012] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/22/2023]
Abstract
Mitochondrial oxidative stress has been implicated in various forms of brain injury, both traumatic and non-traumatic. Due to its oxidative demand, the brain is intimately dependent on its mitochondrial functioning. However, there remains appreciable heterogeneity in the development of these injuries regarding ROS and their effect on the sequelae. These include traumatic insults such as TBIs and intracranial hemorrhaging secondary to this. In a different vein, such injuries may be attributed to other etiologies such as infection, neoplasm, or spontaneous hemorrhage (strokes, aneurysms). Clinically, the manner of treatment may also be adjusted in relation to each injury and its unique progression in the context of ROS. In the current review, then, the authors highlight the role of mitochondrial ROS in various forms of brain injury, emphasizing both the collective and unique elements of each form. Lastly, these narratives are met with the current therapeutic landscape and the role of emerging therapies in treating reactive oxygen species in brain injuries.
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Affiliation(s)
- Andrew Nguyen
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Anjali B. Patel
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | | | - Michael J. Diaz
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, 1600 SW Archer Rd., Gainesville, FL 32610, USA
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28
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Morishita S, Suzuki K, Okayama T, Inoue J, Tanaka T, Nakano J, Fukushima T. Recent Findings in Physical Exercise for Cancer Survivors. Phys Ther Res 2023; 26:10-16. [PMID: 37181484 PMCID: PMC10169310 DOI: 10.1298/ptr.r0023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 02/10/2023] [Indexed: 05/16/2023]
Abstract
In recent years, the number of cancer survivors has been increasing each year due to advances in the early diagnosis and treatment of cancer. Cancer survivors present a variety of physical and psychological complications due to cancer and its treatment. Physical exercise is an effective nonpharmacological treatment for complications in cancer survivors. Furthermore, recent evidence has shown that physical exercise improves the prognosis of cancer survivors. The benefits of physical exercise have been widely reported, and guidelines for physical exercise for cancer survivors have been published. These guidelines recommend that cancer survivors engage in moderate- or vigorous-intensity aerobic exercises and/or resistance training. However, many cancer survivors have a poor commitment to physical exercise. In the future, it is necessary to promote physical exercise among cancer survivors through outpatient rehabilitation and community support.
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Affiliation(s)
- Shinichiro Morishita
- Department of Physical Therapy, School of Health Sciences, Fukushima Medical University, Japan
| | | | - Taro Okayama
- Division of Rehabilitation Medicine, Shizuoka Cancer Center, Japan
| | - Junichiro Inoue
- Division of Rehabilitation Medicine, Kobe University Hospital International Clinical Cancer Research Center, Japan
| | - Takashi Tanaka
- Department of Rehabilitation, Hyogo Medical University Hospital, Japan
| | - Jiro Nakano
- Faculty of Rehabilitation, Kansai Medical University, Japan
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29
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Fleming B, Edison P, Kenny L. Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management. BMJ 2023; 380:e071726. [PMID: 36921926 DOI: 10.1136/bmj-2022-071726] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
Cognitive impairment is a debilitating side effect experienced by patients with cancer treated with systemically administered anticancer therapies. With around 19.3 million new cases of cancer worldwide in 2020 and the five year survival rate growing from 50% in 1970 to 67% in 2013, an urgent need exists to understand enduring side effects with severe implications for quality of life. Whereas cognitive impairment associated with chemotherapy is recognized in patients with breast cancer, researchers have started to identify cognitive impairment associated with other treatments such as immune, endocrine, and targeted therapies only recently. The underlying mechanisms are diverse and therapy specific, so further evaluation is needed to develop effective therapeutic interventions. Drug and non-drug management strategies are emerging that target mechanistic pathways or the cognitive deficits themselves, but they need to be rigorously evaluated. Clinically, consistent use of objective diagnostic tools is necessary for accurate diagnosis and clinical characterization of cognitive impairment in patients treated with anticancer therapies. This should be supplemented with clinical guidelines that could be implemented in daily practice. This review summarizes the recent advances in the mechanisms, clinical characterization, and novel management strategies of cognitive impairment associated with treatment of non-central nervous system cancers.
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Affiliation(s)
- Ben Fleming
- Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Paul Edison
- Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK
- College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK
| | - Laura Kenny
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
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30
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Hossain MI, Nanda SS, Selvan ST, Yi DK. Recent Insights into NIR-Light-Responsive Materials for Photothermal Cell Treatments. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:3318. [PMID: 36234446 PMCID: PMC9565779 DOI: 10.3390/nano12193318] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 09/17/2022] [Accepted: 09/20/2022] [Indexed: 06/16/2023]
Abstract
Controlling cells using photo-responsive materials is highly indispensable in the current biomedical sector. Considering the potential side effects of nanoparticles, it has become a challenge to control cells with photo-responsive materials. Recent studies have described several methods for controlling cell behavior using nanoparticles subjected to the near-infrared (NIR) laser light operating at the wavelength of 808 nm to 980 nm and at the power densities of 0.33 to 0.72 W·cm-2. The challenge here is the preparation of biocompatible nanoparticles for both in vivo and in vitro studies and understanding cell behavior with an external light source recommended for biological application. Earlier studies have well documented many approaches and associated mechanisms for controlling cell behavior and the interaction between nanoparticles, cells, and appropriate external light sources. In this review, various nanomaterials such as metal nanomaterials and carbon-based nanomaterials are compared systematically regarding the effects of controlling cell behavior and inflammation by studying their mechanisms, route of administration, dose, and adverse effects such as toxicity and the interaction of nanoparticles with a specific wavelength of the light. Future directions should focus on stable and efficient light-responsive materials with minimal cytotoxicity.
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Affiliation(s)
- Md Imran Hossain
- Department of Chemistry, Myongji University, Yongin 17058, Korea
| | | | - Subramanian Tamil Selvan
- Alpha Biomedical Pte Ltd., 21 Biopolis Road, Nucleos North Tower #02-03, Singapore 138567, Singapore
| | - Dong Kee Yi
- Department of Chemistry, Myongji University, Yongin 17058, Korea
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31
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The human hypoxia-inducible factor 1alpha gene in anthracycline-induced heart failure. COR ET VASA 2022. [DOI: 10.33678/cor.2022.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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32
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Yifei sanjie Pills Alleviate Chemotherapy-Related Fatigue by Reducing Skeletal Muscle Injury and Inhibiting Tumor Growth in Lung Cancer Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:2357616. [PMID: 36045663 PMCID: PMC9423986 DOI: 10.1155/2022/2357616] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/02/2022] [Indexed: 11/18/2022]
Abstract
Chemotherapy-related fatigue (CRF), one of the most severe adverse effects observed in cancer patients, has been theoretically related to oxidative stress, and antioxidant treatment might be one of the most valuable therapeutic approaches. However, there are still few effective pharmacological therapies. Yifei Sanjie pills (YFSJ), a classical formula used to treat lung cancer as complementary and alternative medicine, have been proved to alleviate CRF of lung cancer patients in clinical practices. However, the underlying mechanisms have not been clarified. In this study, our data showed that YFSJ alleviated CRF presented as reversing the decline of swimming time and locomotor activity induced by cisplatin (DDP). Moreover, YFSJ significantly reduces the accidence of mitophagy and mitochondrial damage and reduces apoptosis in skeletal muscle tissues caused by DDP. It probably works by decreasing the oxidative stress, inhibiting the activation of the AMPK/mTOR pathway, decreasing protein expression levels of Beclin1 and other autophagy-related proteins, and attenuating the activation of Cytochrome c (cyto. C), Cleaved Caspase-9 (c-Casp 9), and other apoptosis-related proteins. Furthermore, YFSJ enhanced DDP sensitivity by specifically promoting oxidative stress and activating apoptosis and autophagy in the tumor tissues of mice. It was also found that YFSJ reduced the loss of body weight caused by DDP, reversed the ascent of serum concentrations of alanine aminotransferase (ALT), aminotransferase (AST), and creatinine (CREA), increased the spleen index, and prolonged the survival time of mice. Taken together, these results revealed that YFSJ could alleviate CRF by reducing mitophagy and apoptosis induced by oxidative stress in skeletal muscle; these results also displayed the effects of YFSJ on enhancing chemotherapy sensitivity, improving quality of life, and prolonging survival time in lung cancer mice received DDP chemotherapy.
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Alam Z, Shang X, Effat K, Kanwal F, He X, Li Y, Xu C, Niu W, War AR, Zhang Y. The potential role of prebiotics, probiotics, and synbiotics in adjuvant cancer therapy especially colorectal cancer. J Food Biochem 2022; 46:e14302. [PMID: 35816322 DOI: 10.1111/jfbc.14302] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 12/13/2022]
Abstract
Cancer is a global health issue that is rising swiftly with younger people and an increased number of patients. The role of human microbiota in the pathophysiology of tumors has been paid more and more attention. Microecologics including prebiotics, probiotics, and synbiotics are among the best validated/proven resources for the application of microbiological prophylaxis and therapy. There is strong evidence that microecologics have anti-cancer activity and their potential association with cancer is significant. In this review, we will focus on the role of prebiotics, probiotics, and synbiotics in tumor suppression in maintaining the colon barrier, metabolism, immune regulation, inhibition of host tumor cell proliferation, and epidemiological-based recommendations. Besides, other signs illuminate the role of microecological agents to adjunct the cancer treatment and counter the toxic side effects of cancer drugs. In addition, we will explore their role in chemotherapy, where these probiotics can be used as an adjunct to chemotherapy, counteracting the toxic side effects of chemotherapy drugs to minimize or optimize the therapeutic effect. In the treatment of cancer, we can see the role of prebiotics, probiotics, synbiotics, and their application in cancer patients, and the effectiveness effect can be considered as a clinical benefit. PRACTICAL APPLICATIONS: A large number of studies have shown that microecologics including prebiotics, probiotics, and synbiotics play an important role in regulating intestinal microecology and contribute to the prevention and treatment of cancer, indicating that prebiotics, probiotics, and synbiotics have the potential to be used as microecological modulators in the adjuvant therapy of cancer. However, it is not clear what is the anti-tumor mechanism of these microecologics and how they antagonize the side effects of cancer chemotherapy and protect normal cells. This paper reviews the role of prebiotics, probiotics, and synbiotics in tumor suppression in maintaining the colon barrier, metabolism, immune regulation, and prevention of rapid growth of host cells, as well as their potential role in cancer chemotherapy. This review helps to better understand the relationship between prebiotics, probiotics, and synbiotics with immune regulation, intestinal microecology, metabolic regulation, and cell proliferation and provides strong evidence for their potential application as microecologics in cancer adjuvant therapy.
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Affiliation(s)
- Zahoor Alam
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Xiaoya Shang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Khansa Effat
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Freeha Kanwal
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Xiaoqin He
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Yanye Li
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Chunlan Xu
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Weining Niu
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Abdul Rouf War
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Yong Zhang
- Department of Surgical Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Extracellular Vesicles and Cancer Therapy: Insights into the Role of Oxidative Stress. Antioxidants (Basel) 2022; 11:antiox11061194. [PMID: 35740091 PMCID: PMC9228181 DOI: 10.3390/antiox11061194] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 02/04/2023] Open
Abstract
Oxidative stress plays a significant role in cancer development and cancer therapy, and is a major contributor to normal tissue injury. The unique characteristics of extracellular vesicles (EVs) have made them potentially useful as a diagnostic tool in that their molecular content indicates their cell of origin and their lipid membrane protects the content from enzymatic degradation. In addition to their possible use as a diagnostic tool, their role in how normal and diseased cells communicate is of high research interest. The most exciting area is the association of EVs, oxidative stress, and pathogenesis of numerous diseases. However, the relationship between oxidative stress and oxidative modifications of EVs is still unclear, which limits full understanding of the clinical potential of EVs. Here, we discuss how EVs, oxidative stress, and cancer therapy relate to one another; how oxidative stress can contribute to the generation of EVs; and how EVs’ contents reveal the presence of oxidative stress. We also point out the potential promise and limitations of using oxidatively modified EVs as biomarkers of cancer and tissue injury with a focus on pediatric oncology patients.
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Qi Y, Yuan Y, Qian Z, Ma X, Yuan W, Song Y. Injectable and Self-Healing Polysaccharide Hydrogel Loading Molybdenum Disulfide Nanoflakes for Synergistic Photothermal-Photodynamic Therapy of Breast Cancer. Macromol Biosci 2022; 22:e2200161. [PMID: 35676757 DOI: 10.1002/mabi.202200161] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/26/2022] [Indexed: 11/08/2022]
Abstract
In order to overcome the limitation of traditional therapies for cancer and improve the accuracy of treatment, more advantageous cancer treatment methods need to be explored and studied. As a result, photothermal photodynamic therapy of breast cancer using bovine serum albumin (BSA) modifies molybdenum disulfide nanoflakes. Then the well-dispersed BSA-MoS2 NFs are loaded in the injectable and self-healing polysaccharide hydrogel which is prepared by the reaction of oxidized sodium alginate (OSA) and hydroxypropyl chitosan (HPCS) through the formation of Schiff base bonds. The injection and self-healing properties of the nanocomposite hydrogel are investigated. In vitro photothermal and photodynamic investigations demonstrate that BSA-MoS2 NFs possess obvious photothermal conversion and production of reactive oxygen species (ROS) under the irradiation of near infrared (NIR) laser (808 nm). In vivo anticancer investigation indicates that the nanocomposite hydrogel can be directly injected and remain in the tumor sites and achieve the synergistic photothermal-photodynamic therapy of cancer.
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Affiliation(s)
- Yujie Qi
- Department of Interventional and Vascular Surgery, Shanghai Tenth People's Hospital, School of Materials Science and Engineering, Tongji University, Shanghai, 201804, P. R. China
| | - Yifeng Yuan
- Department of Interventional and Vascular Surgery, Shanghai Tenth People's Hospital, School of Materials Science and Engineering, Tongji University, Shanghai, 201804, P. R. China
| | - Zhiyi Qian
- Department of Interventional and Vascular Surgery, Shanghai Tenth People's Hospital, School of Materials Science and Engineering, Tongji University, Shanghai, 201804, P. R. China
| | - Xiaodie Ma
- Department of Interventional and Vascular Surgery, Shanghai Tenth People's Hospital, School of Materials Science and Engineering, Tongji University, Shanghai, 201804, P. R. China
| | - Weizhong Yuan
- Department of Interventional and Vascular Surgery, Shanghai Tenth People's Hospital, School of Materials Science and Engineering, Tongji University, Shanghai, 201804, P. R. China
| | - Ye Song
- Department of Ultrasongraphy, The affiliated Zhoupu Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, 201318, P. R. China
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Yan J, Lai H, Zeng B, Wang L, Xing F, Xiao P. Photoinduced free radical-releasing systems and their anticancer properties. Photochem Photobiol Sci 2022; 21:1405-1417. [PMID: 35553411 DOI: 10.1007/s43630-022-00231-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/11/2022] [Indexed: 11/26/2022]
Abstract
Cancer has been a serious threat and impact on the health and life of human. Phototherapy is considered as a promising therapeutic method to replace the traditional treatment in clinic owing to its noninvasive nature and high efficiency. Photoinitiators have long been used in the field of photopolymerization; however, few studies have been carried out on their potential as anticancer agents under light irradiation. In this study, the effect of a photoinitiator, diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide (TPO), on breast cancer is investigated and the related mechanism is elucidated. It is found that TPO has low dark toxicity and significant phototoxicity. TPO can inhibit cell growth and development and promote cell apoptosis through a mitochondrial pathway under light irradiation. Further studies show that cell apoptosis is induced by free radicals produced from the photolysis of TPO to activate JNK phosphorylation. Overall, we identify the antitumor effects of TPO in vitro for the first time, and provides a proof of concept for its application as a novel photolatent therapeutic drug.
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Affiliation(s)
- Jieyu Yan
- Department of Immunobiology, College of Life Science and Technology, Jinan University, #601 Huangpu West Avenue, Guangzhou, 510632, China
| | - Haiwang Lai
- Department of Immunobiology, College of Life Science and Technology, Jinan University, #601 Huangpu West Avenue, Guangzhou, 510632, China.
| | - Boning Zeng
- Department of Immunobiology, College of Life Science and Technology, Jinan University, #601 Huangpu West Avenue, Guangzhou, 510632, China
| | - Liqing Wang
- Department of Immunobiology, College of Life Science and Technology, Jinan University, #601 Huangpu West Avenue, Guangzhou, 510632, China
| | - Feiyue Xing
- Department of Immunobiology, College of Life Science and Technology, Jinan University, #601 Huangpu West Avenue, Guangzhou, 510632, China.
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, 510632, China.
| | - Pu Xiao
- Research School of Chemistry, The Australian National University, Canberra, ACT, 2601, Australia.
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Sukati S, Ho J, Chaiswing L, Sompol P, Pandit H, Wei W, Izumi T, Chen Q, Weiss H, Noel T, Bondada S, Allan Butterfield D, St. Clair DK. Extracellular vesicles released after cranial radiation: An insight into an early mechanism of brain injury. Brain Res 2022; 1782:147840. [PMID: 35183524 PMCID: PMC8918058 DOI: 10.1016/j.brainres.2022.147840] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 02/12/2022] [Accepted: 02/15/2022] [Indexed: 12/16/2022]
Abstract
Cranial radiation is important for treating both primary brain tumors and brain metastases. A potential delayed side effect of cranial radiation is neurocognitive function decline. Early detection of CNS injury might prevent further neuronal damage. Extracellular vesicles (EVs) have emerged as a potential diagnostic tool because of their unique membranous characteristics and cargos. We investigated whether EVs can be an early indicator of CNS injury by giving C57BJ/6 mice 10 Gy cranial IR. EVs were isolated from sera to quantify: 1) number of EVs using nanoparticle tracking analysis (NTA); 2) Glial fibrillary acidic protein (GFAP), an astrocyte marker; and 3) protein-bound 4-hydroxy-2-nonenal (HNE) adducts, an oxidative damage marker. Brain tissues were prepared for immunohistochemistry staining and protein immunoblotting. The results demonstrate: 1) increased GFAP levels (p < 0.05) in EVs, but not brain tissue, in the IR group; and 2) increased HNE-bound protein adduction levels (p < 0.05). The results support using EVs as an early indicator of cancer therapy-induced neuronal injury.
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Was H, Borkowska A, Bagues A, Tu L, Liu JYH, Lu Z, Rudd JA, Nurgali K, Abalo R. Mechanisms of Chemotherapy-Induced Neurotoxicity. Front Pharmacol 2022; 13:750507. [PMID: 35418856 PMCID: PMC8996259 DOI: 10.3389/fphar.2022.750507] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 03/02/2022] [Indexed: 12/15/2022] Open
Abstract
Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in the clinic as the main cancer treatment either alone or as an adjuvant therapy before and after surgery. Although the use of chemotherapeutic drugs improved the survival of cancer patients, these drugs are notorious for causing many severe side effects that significantly reduce the efficacy of anti-cancer treatment and patients’ quality of life. Many widely used chemotherapy drugs including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, and thalidomide analogs may cause direct and indirect neurotoxicity. In this review we discuss the main effects of chemotherapy on the peripheral and central nervous systems, including neuropathic pain, chemobrain, enteric neuropathy, as well as nausea and emesis. Understanding mechanisms involved in chemotherapy-induced neurotoxicity is crucial for the development of drugs that can protect the nervous system, reduce symptoms experienced by millions of patients, and improve the outcome of the treatment and patients’ quality of life.
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Affiliation(s)
- Halina Was
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland
| | - Agata Borkowska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland.,Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Ana Bagues
- Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain.,High Performance Research Group in Experimental Pharmacology (PHARMAKOM-URJC), URJC, Alcorcón, Spain.,Unidad Asociada I+D+i del Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Longlong Tu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Julia Y H Liu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Zengbing Lu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - John A Rudd
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.,The Laboratory Animal Services Centre, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.,Department of Medicine Western Health, University of Melbourne, Melbourne, VIC, Australia.,Regenerative Medicine and Stem Cells Program, Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia
| | - Raquel Abalo
- Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain.,Unidad Asociada I+D+i del Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.,High Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut-URJC), URJC, Alcorcón, Spain.,Grupo de Trabajo de Ciencias Básicas en Dolor y Analgesia de la Sociedad Española del Dolor, Madrid, Spain
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Exploratory Analysis of Associations Between Whole Blood Mitochondrial Gene Expression and Cancer-Related Fatigue Among Breast Cancer Survivors. Nurs Res 2022; 71:411-417. [PMID: 35416182 PMCID: PMC9420746 DOI: 10.1097/nnr.0000000000000598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Cancer-related fatigue is a prevalent, debilitating, and persistent condition. Mitochondrial dysfunction is a putative contributor to cancer-related fatigue, but relationships between mitochondrial function and cancer-related fatigue are not well understood. OBJECTIVES We investigated the relationships between mitochondrial DNA (mtDNA) gene expression and cancer-related fatigue, as well as the effects of fish and soybean oil supplementation on these relationships. METHODS A secondary analysis was performed on data from a randomized controlled trial of breast cancer survivors 4-36 months posttreatment with moderate-severe cancer-related fatigue. Participants were randomized to take 6 g fish oil, 6 g soybean oil, or 3 g each daily for 6 weeks. At pre- and postintervention, participants completed the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire and provided whole blood for assessment of mtDNA gene expression. The expression of 12 protein-encoding genes was reduced to a single dimension using principal component analysis for use in regression analysis. Relationships between mtDNA expression and cancer-related fatigue were assessed using linear regression. RESULTS Among 68 participants, cancer-related fatigue improved and expression of all mtDNA genes decreased over 6 weeks with no effect of treatment group on either outcome. Participants with lower baseline mtDNA gene expression had greater improvements in cancer-related fatigue. No significant associations were observed between mtDNA gene expression and cancer-related fatigue at baseline or changes in mtDNA gene expression and changes in cancer-related fatigue. DISCUSSION Data from this exploratory study add to the growing literature that mitochondrial dysfunction may contribute to the etiology and pathophysiology of cancer-related fatigue.
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40
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Chaturvedi P, George V, Shrestha N, Wang M, Dee MJ, Zhu X, Liu B, Egan J, D'Eramo F, Spanoudis C, Gallo V, Echeverri C, You L, Kong L, Fang B, Jeng EK, Rhode PR, Wong HC. Immunotherapeutic HCW9218 augments anti-tumor activity of chemotherapy via NK cell-mediated reduction of therapy-induced senescent cells. Mol Ther 2022; 30:1171-1187. [PMID: 35051615 PMCID: PMC8899672 DOI: 10.1016/j.ymthe.2022.01.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/12/2022] [Accepted: 01/12/2022] [Indexed: 11/26/2022] Open
Abstract
Therapy induced senescence (TIS) in tumors and TIS cancer cells secrete proinflammatory senescence-associated secretory phenotype (SASP) factors. SASP factors promote TIS cancer cells to re-enter the growth cycle with stemness characteristics, resulting in chemo-resistance and disease relapse. Herein, we show that the immunotherapeutic HCW9218, comprising transforming growth factor-β (TGF-β) receptor II and interleukin (IL)-15/IL-15 receptor α domains, enhances metabolic and cytotoxic activities of immune cells and reduces TIS tumor cells in vivo to improve the efficacy of docetaxel and gemcitabine plus nab-paclitaxel against B16F10 melanoma and SW1990 pancreatic tumors, respectively. Mechanistically, HCW9218 treatment reduces the immunosuppressive tumor microenvironment and enhances immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immuno-depletion analysis suggests that HCW9218-activated natural killer cells play a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhances efficacy of tumor antigen-specific and anti-programmed death-ligand 1 (PD-L1) antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment decreases TIS cells and lowers SASP factors in off-target tissues caused by chemotherapy of tumor-bearing mice. Collectively, HCW9218 has the potential to significantly enhance anti-tumor efficacy of chemotherapy, therapeutic antibodies, and checkpoint blockade by eliminating TIS cancer cells while reducing TIS-mediated proinflammatory side effects in normal tissues.
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Affiliation(s)
| | | | | | - Meng Wang
- HCW Biologics Inc., Miramar, FL 33025, USA
| | | | | | - Bai Liu
- HCW Biologics Inc., Miramar, FL 33025, USA
| | - Jack Egan
- HCW Biologics Inc., Miramar, FL 33025, USA
| | | | | | | | | | - Lijing You
- HCW Biologics Inc., Miramar, FL 33025, USA
| | - Lin Kong
- HCW Biologics Inc., Miramar, FL 33025, USA
| | - Byron Fang
- HCW Biologics Inc., Miramar, FL 33025, USA
| | | | | | - Hing C. Wong
- HCW Biologics Inc., Miramar, FL 33025, USA,Corresponding author: Hing C. Wong, PhD, HCW Biologics Inc., 2929 N. Commerce Parkway, Miramar, FL 33025, USA.
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41
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Leng J, Dai X, Cheng X, Zhou H, Wang D, Zhao J, Ma K, Cui C, Wang L, Guo Z. Biomimetic Cucurbitacin B-Polydopamine Nanoparticles for Synergistic Chemo-Photothermal Therapy of Breast Cancer. Front Bioeng Biotechnol 2022; 10:841186. [PMID: 35223801 PMCID: PMC8864241 DOI: 10.3389/fbioe.2022.841186] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/13/2022] [Indexed: 11/23/2022] Open
Abstract
Breast cancer is the most common malignant tumor in women. Researchers have found that the combined use of multiple methods to treat tumors is a promising strategy. Here, we have developed a biomimetic nano-platform PDA@MB for tumor targeted photothermal therapy (PTT) combined with chemotherapy. The 4T1 cell membrane loaded with cucurbitacin B (CuB) was used to coat polydopamine (PDA) nanoparticles, which gave PDA@MB nanoparticles the ability to target tumors and escape immune cells from phagocytosis. PDA@MB showed excellent photothermal performance including high photothermal conversion efficiency and photostability, and exhibited outstanding in vitro PTT effect under NIR laser irradiation. The high temperature ruptured the PDA@MB membrane to release CuB, which changed the tumor hypoxic environment, down-regulated the FAK/MMP signaling pathway, and significantly inhibited the metastasis and proliferation of tumor cells. The results of in vivo experiments indicated that the tumor growth of the 4T1 mouse tumor model was significantly inhibited. Additionally, toxicity studies showed that PDA@MB had good biocompatibility and safety. In conclusion, this study provides a promising chemo-photothermal therapy (CPT) nano-platform for precise and effective breast cancer therapy.
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Affiliation(s)
- Junke Leng
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Xiaofeng Dai
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Xiao Cheng
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Hao Zhou
- School of Food and Environment, Dalian University of Technology, Panjin, China
| | - Dong Wang
- Panjin People’s Hospital, Panjin, China
| | - Jing Zhao
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Kun Ma
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Changhao Cui
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Li Wang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Zhaoming Guo
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
- *Correspondence: Zhaoming Guo,
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Mondal S, Montaño-Priede JL, Nguyen VT, Park S, Choi J, Doan VHM, Vo TMT, Vo TH, Large N, Kim CS, Oh J. Computational analysis of drug free silver triangular nanoprism theranostic probe plasmonic behavior for in-situ tumor imaging and photothermal therapy. J Adv Res 2022; 41:23-38. [PMID: 36328751 PMCID: PMC9637560 DOI: 10.1016/j.jare.2022.02.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 12/15/2022] Open
Abstract
Designing drug-free polyvinyl alcohol coated stable silver triangular nano-prisms (PVA-SNT). Computational simulation of optical and photothermal properties with high in vivo experimental similarity. Stable PVA-SNT enables photoacoustic imaging-guided photothermal therapy of breast cancer. PVA-SNT exhibits enhanced photostability and high photothermal conversion efficiency. Introduction The advanced features of plasmonic nanomaterials enable initial high accuracy detection with different therapeutic intervention. Computational simulations could estimate the plasmonic heat generation with a high accuracy and could be reliably compared to experimental results. This proposed combined theoretical-experimental strategy may help researchers to better understand other nanoparticles in terms of plasmonic efficiency and usability for future nano-theranostic research. Objectives To develop innovative computationally-driven approach to quantify any plasmonic nanoparticles photothermal efficiency and effects before their use as therapeutic agents. Methods This report introduces drug free plasmonic silver triangular nanoprisms coated with polyvinyl alcohol biopolymer (PVA-SNT), for in vivo photoacoustic imaging (PAI) guided photothermal treatment (PTT) of triple-negative breast cancer mouse models. The synthesized PVA-SNT nanoparticles were characterized and a computational electrodynamic analysis was performed to evaluate and predict the optical and plasmonic photothermal properties. The in vitro biocompatibility and in vivo tumor abalation study was performed with MDA-MB-231 human breast cancer cell line and in nude mice model. Results The drug free 140 μg∙mL−1 PVA-SNT nanoparticles with 1.0 W∙cm−2 laser irradiation for 7 min proved to be an effective and optimized theranostic approach in terms of PAI guided triple negative breast cancer treatment. The PVA-SNT nanoparticles exhibits excellent biosafety, photostability, and strong efficiency as PAI contrast agent to visualize tumors. Histological analysis and fluorescence-assisted cell shorter assay results post-treatment apoptotic cells, more importantly, it shows substantial damage to in vivo tumor tissues, killing almost all affected cells, with no recurrence. Conclusion This is a first complete study on computational simulations to estimate the plasmonic heat generation followed by drug free plasmonic PAI guided PTT for cancer treatment. This computationally-driven theranostic approach demonstrates an innovative thought regarding the nanoparticles shape, size, concentration, and composition which could be useful for the prediction of photothermal heat generation in precise nanomedicine applications.
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Affiliation(s)
- Sudip Mondal
- New-senior Healthcare Innovation Center (BK21 Plus), Pukyong National University, Busan 48513, Republic of Korea
| | - José Luis Montaño-Priede
- Department of Physics and Astronomy, The University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, United States
| | - Van Tu Nguyen
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Sumin Park
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Jaeyeop Choi
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Vu Hoang Minh Doan
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Thi Mai Thien Vo
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Tan Hung Vo
- Industry 4.0 Convergence Bionics Engineering, Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Nicolas Large
- Department of Physics and Astronomy, The University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, United States
| | - Chang-Seok Kim
- Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 46241, Republic of Korea
| | - Junghwan Oh
- New-senior Healthcare Innovation Center (BK21 Plus), Pukyong National University, Busan 48513, Republic of Korea; Department of Physics and Astronomy, The University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, United States; Ohlabs Corp., Busan 48513, Republic of Korea.
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van den Boogaard WMC, Komninos DSJ, Vermeij WP. Chemotherapy Side-Effects: Not All DNA Damage Is Equal. Cancers (Basel) 2022; 14:627. [PMID: 35158895 PMCID: PMC8833520 DOI: 10.3390/cancers14030627] [Citation(s) in RCA: 162] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence of numerous features of accelerated aging, seriously affecting quality of life, has now become one of the most pressing problems associated with (pediatric) cancer treatment. Chemotherapies frequently target and damage the DNA, causing mutations or genome instability, a major hallmark of both cancer and aging. However, there are numerous types of chemotherapeutic drugs that are genotoxic and interfere with DNA metabolism in different ways, each with their own biodistribution, kinetics, and biological fate. Depending on the type of DNA lesion produced (e.g., interference with DNA replication or RNA transcription), the organ or cell type inflicted (e.g., cell cycle or differentiation status, metabolic state, activity of clearance and detoxification mechanisms, the cellular condition or micro-environment), and the degree of exposure, outcomes of cancer treatment can largely differ. These considerations provide a conceptual framework in which different classes of chemotherapeutics contribute to the development of toxicities and accelerated aging of different organ systems. Here, we summarize frequently observed side-effects in (pediatric) ex-cancer patients and discuss which types of DNA damage might be responsible.
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Affiliation(s)
- Winnie M. C. van den Boogaard
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (W.M.C.v.d.B.); (D.S.J.K.)
- Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, The Netherlands
| | - Daphne S. J. Komninos
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (W.M.C.v.d.B.); (D.S.J.K.)
- Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, The Netherlands
| | - Wilbert P. Vermeij
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (W.M.C.v.d.B.); (D.S.J.K.)
- Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, The Netherlands
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Trivedi T, Guise TA. Systemic effects of abnormal bone resorption on muscle, metabolism, and cognition. Bone 2022; 154:116245. [PMID: 34718221 DOI: 10.1016/j.bone.2021.116245] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 10/21/2021] [Accepted: 10/25/2021] [Indexed: 12/11/2022]
Abstract
Skeletal tissue is dynamic, undergoing constant remodeling to maintain musculoskeletal integrity and balance in the human body. Recent evidence shows that apart from maintaining homeostasis in the local microenvironment, the skeleton systemically affects other tissues. Several cancer-associated and noncancer-associated bone disorders can disrupt the physiological homeostasis locally in the bone microenvironment and indirectly contribute to dysregulation of systemic body function. The systemic effects of bone on the regulation of distant organ function have not been widely explored. Recent evidence suggests that bone can interact with skeletal muscle, pancreas, and brain by releasing factors from mineralized bone matrix. Currently available bone-targeting therapies such as bisphosphonates and denosumab inhibit bone resorption, decrease morbidity associated with bone destruction, and improve survival. Bisphosphonates have been a standard treatment for bone metastases, osteoporosis, and cancer treatment-induced bone diseases. The extraskeletal effects of bisphosphonates on inhibition of tumor growth are known. However, our knowledge of the effects of bisphosphonates on muscle weakness, hyperglycemia, and cognitive defects is currently evolving. To be able to identify the molecular link between bone and distant organs during abnormal bone resorption and then treat these abnormalities and prevent their systemic effects could improve survival benefits. The current review highlights the link between bone resorption and its systemic effects on muscle, pancreas, and brain.
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Affiliation(s)
- Trupti Trivedi
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Theresa A Guise
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
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Dias-Carvalho A, Ferreira M, Ferreira R, Bastos MDL, Sá SI, Capela JP, Carvalho F, Costa VM. Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events. Arch Toxicol 2022; 96:11-78. [PMID: 34725718 DOI: 10.1007/s00204-021-03171-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 09/23/2021] [Indexed: 01/22/2023]
Abstract
Cognitive dysfunction has been one of the most reported and studied adverse effects of cancer treatment, but, for many years, it was overlooked by the medical community. Nevertheless, the medical and scientific communities have now recognized that the cognitive deficits caused by chemotherapy have a strong impact on the morbidity of cancer treated patients. In fact, chemotherapy-induced cognitive dysfunction or 'chemobrain' (also named also chemofog) is at present a well-recognized effect of chemotherapy that could affect up to 78% of treated patients. Nonetheless, its underlying neurotoxic mechanism is still not fully elucidated. Therefore, this work aimed to provide a comprehensive review using PubMed as a database to assess the studies published on the field and, therefore, highlight the clinical manifestations of chemobrain and the putative neurotoxicity mechanisms.In the last two decades, a great number of papers was published on the topic, mainly with clinical observations. Chemotherapy-treated patients showed that the cognitive domains most often impaired were verbal memory, psychomotor function, visual memory, visuospatial and verbal learning, memory function and attention. Chemotherapy alters the brain's metabolism, white and grey matter and functional connectivity of brain areas. Several mechanisms have been proposed to cause chemobrain but increase of proinflammatory cytokines with oxidative stress seem more relevant, not excluding the action on neurotransmission and cellular death or impaired hippocampal neurogenesis. The interplay between these mechanisms and susceptible factors makes the clinical management of chemobrain even more difficult. New studies, mainly referring to the underlying mechanisms of chemobrain and protective measures, are important in the future, as it is expected that chemobrain will have more clinical impact in the coming years, since the number of cancer survivors is steadily increasing.
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Affiliation(s)
- Ana Dias-Carvalho
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
| | - Mariana Ferreira
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Rita Ferreira
- LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Maria de Lourdes Bastos
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Susana Isabel Sá
- Unit of Anatomy, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
- Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine, University of Porto, Porto, Portugal
| | - João Paulo Capela
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, Porto, Portugal
| | - Félix Carvalho
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Vera Marisa Costa
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
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Pondugula SR, Harshan A, Ramesh S, Govindarajulu M, Almaghrabi M, Majrashi M, Abbott KL, Nadar R, Alturki M, Salamat JM, Smith F, Majeed M, Nagabhushanam K, Moore T, Ren J, Dhanasekaran M. Cardioprotective Effects of Oroxylum indicum Extract Against Doxorubicin and Cyclophosphamide-Induced Cardiotoxicity. Cardiovasc Toxicol 2022; 22:67-77. [PMID: 34623620 DOI: 10.1007/s12012-021-09701-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/28/2021] [Indexed: 11/26/2022]
Abstract
Administration of Chemotherapeutics, especially doxorubicin (DOX) and cyclophosphamide (CPS), is commonly associated with adverse effects such as myelosuppression and cardiotoxicity. At this time, few approved therapeutic options are currently available for the management of chemotherapy-associated cardiotoxicity. Thus, identification of novel therapeutics with potent cardioprotective properties and minimal adverse effects are pertinent in treating Doxorubicin and Cyclophosphamide-induced cardiotoxicity. Oroxylum indicum extract (OIE, Sabroxy®) is a natural product known to possess several beneficial biological functions including antioxidant, anti-inflammatory and cytoprotective effects. We therefore set to investigate the cardioprotective effects of OIE against Doxorubicin and Cyclophosphamide-induced cardiotoxicity and explore the potential cardioprotective mechanisms involved. Adult male mice were treated with DOX and CPS in combination, OIE alone, or a combination of OIE and DOX & CPS. Swimming test was performed to assess cardiac function. Markers of oxidative stress were assessed by levels of reactive oxygen species (ROS), nitrite, hydrogen peroxide, catalase, and glutathione content. The activity of interleukin converting enzyme and cyclooxygenase was determined as markers of inflammation. Mitochondrial function was assessed by measuring Complex-I activity. Apoptosis was assessed by Caspase-3 and protease activity. Mice treated with DOX and CPS exhibited reduced swim rate, increased oxidative stress, increased inflammation, and apoptosis in the heart tissue. These cardiotoxic effects were significantly reduced by co-administration of OIE. Furthermore, computational molecular docking studies revealed potential binding of DOX and CPS to tyrosine hydroxylase which validated our in vivo findings regarding the inhibition of tyrosine hydroxylase activity. Our current findings indicated that OIE counteracts Doxorubicin and Cyclophosphamide-induced cardiotoxicity-through inhibition of ROS-mediated apoptosis and by blocking the effect on tyrosine hydroxylase. Taken together, our findings suggested that OIE possesses cardioprotective effects to counteract potentially fatal cardiac complications associated with chemotherapy treatment.
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Affiliation(s)
- Satyanarayana R Pondugula
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, 36849, USA.
| | - Aisha Harshan
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA
| | - Sindhu Ramesh
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA
| | - Manoj Govindarajulu
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA
| | - Mohammed Almaghrabi
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA
- Department of Medicinal Chemistry, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Mohammed Majrashi
- Department of Pharmacology, Faculty of Medicine, University of Jeddah, Jeddah, 23881, Saudi Arabia
| | - Kodye L Abbott
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, 36849, USA
| | - Rishi Nadar
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA
| | - Mansour Alturki
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA
| | - Julia M Salamat
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, 36849, USA
| | - Forrest Smith
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA
| | - Muhammed Majeed
- Sabinsa Corporation, 20 Lake Drive, East Windsor, NJ, 08520, USA
| | | | - Timothy Moore
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA
| | - Jun Ren
- Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 200032, China
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98195, USA
| | - Muralikrishnan Dhanasekaran
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA.
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Das R, Fernandez JG. Biomaterials for Mimicking and Modelling Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1379:139-170. [DOI: 10.1007/978-3-031-04039-9_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Sahu K, Langeh U, Singh C, Singh A. Crosstalk between anticancer drugs and mitochondrial functions. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100047. [PMID: 34909674 PMCID: PMC8663961 DOI: 10.1016/j.crphar.2021.100047] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/12/2021] [Accepted: 08/17/2021] [Indexed: 01/12/2023] Open
Abstract
Chemotherapy is an important component of cancer treatment, which has side effects like vomiting, peripheral neuropathy, and numerous organ toxicity but the most significant outcomes of chemotherapy are cognitive impairment, which is mainly referred to as chemobrain or CICI (chemotherapy-induced cognitive impairment). It is characterized by difficulty with language, concentrating, processing speed, learning, and memory, as it affects the hippocampus areas of the brain. Mitochondrial dysfunction and oxidative stress are one of the major mechanisms causing chemobrain. The generation of reactive oxygen species (byproducts of oxidative phosphorylation) mainly occurs in mitochondria that play a prominent role in the induction of oxidative stress. The homeostasis of ROS in the mitochondria is maintained by mitochondrial antioxidant mechanism via enzymes like catalase, glutathione, and superoxide dismutase. Lungs and breast cancer are the two most common types of cancer, which are the most leading cancers in the world with about 4.18 million cases. In this review we exposed the current knowledge regarding chemotherapy-induced oxidative stress and mitochondrial dysfunction to cause cognitive impairment.We especially focused on the antineoplastic agent (ADRIAMYCIN, CYCLOPHOSPHAMIDE), platinum group agent CISPLATIN, antimetabolite agents (METHOTREXATE), and nitrogen mustard agent (CARMUSTINE) which increase oxidative stress and inflammatory markers in the PNS (peripheral nervous system) as well as the central nervous system. We also highlight the behavioural and functional changes in the brain.
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Affiliation(s)
- Kuleshwar Sahu
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Urvashi Langeh
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Charan Singh
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Arti Singh
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
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de Oliveira Cardoso E, Santiago KB, Conti BJ, Conte FL, Tasca KI, Romagnoli GG, de Assis Golim M, Rainho CA, Bastos JK, Sforcin JM. Brazilian green propolis: A novel tool to improve the cytotoxic and immunomodulatory action of docetaxel on MCF-7 breast cancer cells and on women monocyte. Phytother Res 2021; 36:448-461. [PMID: 34862831 DOI: 10.1002/ptr.7345] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 11/02/2021] [Accepted: 11/12/2021] [Indexed: 12/14/2022]
Abstract
Docetaxel (DTX) is used against breast cancer despite its side effects such as toxicity and immunosuppression. Here we investigated the cytotoxic and immunomodulatory effects of the ethanol solution extract of propolis (EEP) in combination with DTX on MCF-7 breast cancer cells and on women's monocyte. The cytotoxic potential of EEP + DTX was assessed by MTT assay and the type of tumor cell death was evaluated by flow cytometry. The effects of EEP + DTX on the migration and invasion of MCF-7 cells were analyzed. Cytokine production by monocytes was assessed by ELISA and the expression of cell surface markers was evaluated by flow cytometry. We also assessed the fungicidal activity of monocytes against Candida albicans and the generation of reactive oxygen species (ROS). Finally, the impact of the supernatants of treated monocytes in the viability, migration, and invasiveness of tumor cells was assessed. EEP enhanced the cytotoxicity of DTX alone against MCF-7 cells by inducing necrosis and inhibiting their migratory ability. EEP + DTX exerted no cytotoxic effects on monocytes and stimulated HLA-DR expression, TNF-α, and IL-6 production, exerted an immunorestorative action in the fungicidal activity, and reduced the oxidative stress. Our findings have practical implications and reveal new insights for complementary medicine.
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Affiliation(s)
- Eliza de Oliveira Cardoso
- Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Campus Botucatu, São Paulo, Brazil
| | - Karina Basso Santiago
- Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Campus Botucatu, São Paulo, Brazil
| | - Bruno José Conti
- Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Campus Botucatu, São Paulo, Brazil
| | - Fernanda Lopes Conte
- Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Campus Botucatu, São Paulo, Brazil
| | - Karen Ingrid Tasca
- Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Campus Botucatu, São Paulo, Brazil
| | | | - Marjorie de Assis Golim
- Botucatu Blood Center, School of Medicine, São Paulo State University (UNESP), Campus Botucatu, São Paulo, Brazil
| | - Cláudia Aparecida Rainho
- Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Campus Botucatu, São Paulo, Brazil
| | - Jairo Kenupp Bastos
- Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, Brazil
| | - José Maurício Sforcin
- Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Campus Botucatu, São Paulo, Brazil
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50
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Ursprung S, Mossop H, Gallagher FA, Sala E, Skells R, Sipple JAN, Mitchell TJ, Chhabra A, Fife K, Matakidou A, Young G, Walker A, Thomas MG, Ortuzar MC, Sullivan M, Protheroe A, Oades G, Venugopal B, Warren AY, Stone J, Eisen T, Wason J, Welsh SJ, Stewart GD. The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol. BMC Cancer 2021; 21:1238. [PMID: 34794412 PMCID: PMC8600815 DOI: 10.1186/s12885-021-08965-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 11/04/2021] [Indexed: 02/26/2023] Open
Abstract
BACKGROUND Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). METHODS WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. DISCUSSION WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. TRIAL REGISTRATION ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 .
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Affiliation(s)
| | - Helen Mossop
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Ferdia A Gallagher
- CRUK Cambridge Centre, University of Cambridge, Cambridge, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Evis Sala
- CRUK Cambridge Centre, University of Cambridge, Cambridge, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Richard Skells
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- AstraZeneca, Cambridge, UK
| | - Jamal A N Sipple
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Thomas J Mitchell
- CRUK Cambridge Centre, University of Cambridge, Cambridge, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Wellcome Sanger Institute, Hinxton, UK
| | - Anita Chhabra
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Kate Fife
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Athena Matakidou
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Gemma Young
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Amanda Walker
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Martin G Thomas
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | - Mark Sullivan
- Oxford University Hospitals National Health Service Foundation Trust, Oxford, UK
| | - Andrew Protheroe
- Oxford University Hospitals National Health Service Foundation Trust, Oxford, UK
| | - Grenville Oades
- Department of Urology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Balaji Venugopal
- Institute of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK
| | - Anne Y Warren
- CRUK Cambridge Centre, University of Cambridge, Cambridge, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | - Tim Eisen
- CRUK Cambridge Centre, University of Cambridge, Cambridge, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - James Wason
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - Sarah J Welsh
- CRUK Cambridge Centre, University of Cambridge, Cambridge, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Grant D Stewart
- CRUK Cambridge Centre, University of Cambridge, Cambridge, UK.
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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