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Guo Z, He L, Wang W, Tian S, Lin R. FUT2-dependent fucosylation of LAMP1 promotes the apoptosis of colorectal cancer cells by regulating the autophagy-lysosomal pathway. Cancer Lett 2025; 619:217643. [PMID: 40112906 DOI: 10.1016/j.canlet.2025.217643] [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: 12/23/2024] [Revised: 03/06/2025] [Accepted: 03/15/2025] [Indexed: 03/22/2025]
Abstract
Fucosyltransferase 2 (FUT2) is an enzyme that adds fucose to proteins or lipids via α-1,2-fucosylation in the intestinal mucosa. While FUT2 deficiency is linked to increased susceptibility to inflammatory bowel disease (IBD), its role in colorectal cancer (CRC) is unclear, and the molecular mechanisms involved remain largely unknown. We established an azoxymethane (AOM) and dextran sulfate sodium (DSS) model to induce CRC. FUT2 expression was assessed in human CRC tissues, AOM/DSS-induced mouse models, and CRC cell lines using qRT-PCR, western blotting, and UEA-I staining. FUT2 knockout (FUT2△IEC) mice were treated with AOM/DSS, and FUT2-overexpressing CRC cells were created to evaluate the effects of FUT2 on apoptosis in both in vitro and in vivo settings through Western blot analyses and functional assays. N-glycoproteomics, UEA-I chromatography, and co-immunoprecipitation were utilized to identify regulatory mechanisms and target fucosylated proteins. FUT2 expression and α-1,2-fucosylation were significantly decreased in CRC. FUT2 deficiency worsened AOM/DSS-induced CRC and reduced tumor apoptosis, while FUT2 overexpression induced apoptosis and inhibited proliferation in CRC cells and xenografts. Mechanistically, FUT2 appears to suppress autophagy by impairing lysosomal function and directly targeting and fucosylating LAMP1, contributing to lysosomal dysfunction. Our study reveals a fucosylation-dependent antitumor mechanism of FUT2 in CRC, suggesting potential therapeutic strategies for CRC treatment.
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Affiliation(s)
- Zijun Guo
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Lingnan He
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New Area, Shanghai, China
| | - Weijun Wang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuxin Tian
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rong Lin
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Islam S, Sarkar O, Mukherjee S, Chattopadhyay A. Long-Term Impact of Cr(VI) Exposure in Swiss Albino Mice: ROS-Driven Modulation of Autophagy and Cellular Fate. Biol Trace Elem Res 2025:10.1007/s12011-025-04599-w. [PMID: 40180680 DOI: 10.1007/s12011-025-04599-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/26/2025] [Indexed: 04/05/2025]
Abstract
Hexavalent chromium [Cr(VI)], due to its high solubility and permeability, is significantly more toxic than trivalent chromium [Cr(III)] as it generates reactive oxygen species (ROS) during cellular reduction. Industrial discharges have led to increasing Cr(VI) contamination in surface and groundwater, posing serious environmental and public health concerns. In our previous study, we demonstrated that exposure to 5 ppm Cr(VI) for 4 and 8 months adversely affected body weight, water consumption, and liver function in Swiss albino mice. Histological analyses revealed tissue alterations, disrupted DNA repair gene expression in liver tissue, and a marked increase in apoptotic gene expression after 8 months of exposure. Building on these findings, we employed the same Cr(VI) concentration (5 ppm via drinking water) over 4 and 8 months in the present study. Our results showed a significant increase in ROS generation in the liver, brain, and kidney tissues at both time intervals. Additionally, the presence of autophagolysosomes was markedly elevated after chronic Cr(VI) exposure in each tissue. We also observed altered expression patterns of key autophagy-related genes (Atg5, Beclin1, and Lc3) and mTor in these tissues. Immunohistochemical analysis further confirmed a significant increase in LC3B expression after 4 months of exposure. Our findings suggest that heightened intracellular oxidative stress triggers a protective autophagy response, mediated via mTOR signaling, to maintain cellular integrity. However, prolonged toxic insult and ROS accumulation may eventually shift pro-survival autophagy toward apoptotic cell death in the liver and brain tissues.
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Affiliation(s)
- Shehnaz Islam
- Department of Zoology, Visva-Bharati, Santiniketan, 731235, West Bengal, India
| | - Olivia Sarkar
- Department of Zoology, Visva-Bharati, Santiniketan, 731235, West Bengal, India
| | - Sunanda Mukherjee
- Department of Zoology, Visva-Bharati, Santiniketan, 731235, West Bengal, India
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El-Sheikh M, Mesalam AA, Mesalam A, Kong IK. Acrylamide and Its Metabolite Glycidamide Induce Reproductive Toxicity During In Vitro Maturation of Bovine Oocytes. TOXICS 2025; 13:223. [PMID: 40137550 PMCID: PMC11946555 DOI: 10.3390/toxics13030223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 03/10/2025] [Accepted: 03/16/2025] [Indexed: 03/29/2025]
Abstract
Acrylamide (ACR) and its metabolite glycidamide (GLY) are contaminants with known toxic effects, especially in reproductive systems. However, the mechanisms underlying their embryotoxic effects remain inadequately understood. In the current study, we investigated the effects of ACR and GLY exposure on oocyte and embryo developmental competence, focusing on DNA damage, apoptosis, autophagy, and epigenetic regulation. Oocytes were exposed to varying concentrations of ACR and GLY during in vitro maturation. The results demonstrated that both ACR and GLY significantly reduced cleavage and blastocyst developmental rates in a dose-dependent manner. Consequently, treated oocytes exhibited actin organization disruption, increased DNA damage, and heightened apoptosis compared to the control. Autophagy-related markers, including LC3A, LC3B, and ATG7, were significantly elevated in the treatment groups. Moreover, both ACR and GLY compounds altered the expression of the epigenetic and MAPK signaling pathway regulators, such as DPPA3, EZH1, EZH2, EED, DUSP1, and ASK1. These disruptions collectively impaired embryonic development. This study underscores the adverse effects of ACR and GLY on reproductive health, driven by oxidative stress, genotoxicity, dysregulated autophagy, and epigenetic alterations.
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Affiliation(s)
- Marwa El-Sheikh
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre (NRC), Dokki, Cairo 12622, Egypt
| | - Ahmed Atef Mesalam
- Department of Therapeutic Chemistry, Pharmaceutical and Drug Industries Research Institute, National Research Centre (NRC), Dokki, Cairo 12622, Egypt;
| | - Ayman Mesalam
- Department of Theriogenology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt;
| | - Il-Keun Kong
- Division of Applied Life Science (BK21 Four), Gyeongsang National University, Jinju 52828, Republic of Korea
- Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 52828, Republic of Korea
- The King Kong Corp., Ltd., Gyeongsang National University, Jinju 52828, Republic of Korea
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Nogueira NDS, Portal TM, Nogueira TDS, Miranda AES, Campos E, Monteiro de Barros C. Neuronal degeneration, mitochondrial dysfunction, and disturbance of movements induced by rotenone in the ascidian Styela plicata. Neurotoxicology 2025; 108:69-80. [PMID: 40074177 DOI: 10.1016/j.neuro.2025.03.003] [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: 04/24/2024] [Revised: 03/01/2025] [Accepted: 03/07/2025] [Indexed: 03/14/2025]
Abstract
Parkinson's disease (PD), a movement disorder caused by dopaminergic degeneration in the midbrain, has been induced in various organisms after injection of different neurotoxins, such as rotenone (ROT), which affect mitochondrial complex I. Due to the conserved characteristics of ascidians, these animals constitute an interesting model for comparative and genetic studies of neurodegenerative diseases. In this study, we investigated the effects of ROT on the ascidian nervous system, evaluating apoptosis, catecholaminergic enzymes, behavioral deficits, and mitochondrial dysfunction. The study revealed morphological disorganization, inducing vacuolation in the ascidian brain. Neuronal death was confirmed by elevated transcriptional levels of caspase-3 and intense caspase-3 staining by immunofluorescence. In addition, there was reduced staining for dopa-decarboxylase (DDC), which is involved in dopamine biosynthesis. Furthermore, the mitochondria exhibited dysfunction in their membrane potential, followed by a decrease in the hydrolytic activity of ATP synthase and high transcriptional levels of ubiquitin. Finally, after administration of the drug l-3,4-dihydroxyphenylalanine (L-DOPA), recovery of motor movements was observed, as revealed by behavioral tests. Overall, the current research provides new data on the effects of rotenone on the ascidian brain, inducing neuronal death, mitochondrial dysfunction, and siphon movement disorders in the ascidian Styela plicata.
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Affiliation(s)
- Nathany da Silva Nogueira
- Laboratório Integrado de Biociências Translacionais, Instituto de Biodiversidade e Sustentabilidade - NUPEM, Universidade Federal do Rio de Janeiro - UFRJ, Rio de Janeiro, Macaé 27965-045, Brazil; Pós-Graduação Multicêntrico em Ciências Fisiológicas, Instituto de Biodiversidade e Sustentabilidade - NUPEM, Universidade Federal do Rio de Janeiro - UFRJ, Rio de Janeiro, Macaé 27965-045, Brazil.
| | - Taynan Motta Portal
- Laboratório Integrado de Biociências Translacionais, Instituto de Biodiversidade e Sustentabilidade - NUPEM, Universidade Federal do Rio de Janeiro - UFRJ, Rio de Janeiro, Macaé 27965-045, Brazil; Programa de Pós-graduação em Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro - UENF, Campo dos Goytacazes, Rio de Janeiro 28013-602, Brazil.
| | - Thuany da Silva Nogueira
- Laboratório Integrado de Biociências Translacionais, Instituto de Biodiversidade e Sustentabilidade - NUPEM, Universidade Federal do Rio de Janeiro - UFRJ, Rio de Janeiro, Macaé 27965-045, Brazil; Pós-Graduação Multicêntrico em Ciências Fisiológicas, Instituto de Biodiversidade e Sustentabilidade - NUPEM, Universidade Federal do Rio de Janeiro - UFRJ, Rio de Janeiro, Macaé 27965-045, Brazil.
| | - Aurenita Emile Sá Miranda
- Laboratório Integrado de Biociências Translacionais, Instituto de Biodiversidade e Sustentabilidade - NUPEM, Universidade Federal do Rio de Janeiro - UFRJ, Rio de Janeiro, Macaé 27965-045, Brazil.
| | - Eldo Campos
- Laboratório Integrado de Biociências Translacionais, Instituto de Biodiversidade e Sustentabilidade - NUPEM, Universidade Federal do Rio de Janeiro - UFRJ, Rio de Janeiro, Macaé 27965-045, Brazil; Pós-Graduação Multicêntrico em Ciências Fisiológicas, Instituto de Biodiversidade e Sustentabilidade - NUPEM, Universidade Federal do Rio de Janeiro - UFRJ, Rio de Janeiro, Macaé 27965-045, Brazil.
| | - Cintia Monteiro de Barros
- Laboratório Integrado de Biociências Translacionais, Instituto de Biodiversidade e Sustentabilidade - NUPEM, Universidade Federal do Rio de Janeiro - UFRJ, Rio de Janeiro, Macaé 27965-045, Brazil; Pós-Graduação Multicêntrico em Ciências Fisiológicas, Instituto de Biodiversidade e Sustentabilidade - NUPEM, Universidade Federal do Rio de Janeiro - UFRJ, Rio de Janeiro, Macaé 27965-045, Brazil.
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da Silva ÁC, Scholl JN, de Fraga Dias A, Weber AF, Morrone FB, Cruz-López O, Conejo-García A, Campos JM, Sévigny J, Figueiró F, Battastini AMO. Preclinical evaluation of bozepinib in bladder cancer cell lines: modulation of the NPP1 enzyme. Purinergic Signal 2025; 21:39-50. [PMID: 37906424 PMCID: PMC11958895 DOI: 10.1007/s11302-023-09975-6] [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: 05/05/2023] [Accepted: 10/20/2023] [Indexed: 11/02/2023] Open
Abstract
Bladder cancer (BC) is the most common cancer of the urinary tract. Bozepinib (BZP), a purine-derived molecule, is a potential compound for the treatment of cancer. Purinergic signaling consists of the activity of nucleosides and nucleotides present in the extracellular environment, modulating a variety of biological actions. In cancer, this signaling is mainly controlled by the enzymatic cascade involving the NTPDase/E-NPP family and ecto-5'-nucleotidase/CD73, which hydrolyze extracellular adenosine triphosphate (ATP) to adenosine (ADO). The aim of this work is to evaluate the activity of BZP in the purinergic system in BC cell lines and to compare its in vitro antitumor activity with cisplatin, a chemotherapeutic drug widely used in the treatment of BC. In this study, two different BC cell lines, grade 1 RT4 and the more aggressive grade 3 T24, were used along with a human fibroblast cell line MRC-5, a cell used to predict the selectivity index (SI). BZP shows strong antitumor activity, with notable IC50 values (8.7 ± 0.9 µM for RT4; 6.7 ± 0.7 µM for T24), far from the SI for cisplatin (SI for BZP: 19.7 and 25.7 for RT4 and T24, respectively; SI for cisplatin: 1.7 for T24). BZP arrests T24 cells in the G2/M phase of the cell cycle, inducing early apoptosis. Moreover, BZP increases ATP and ADP hydrolysis and gene/protein expression of the NPP1 enzyme in the T24 cell line. In conclusion, BZP shows superior activity compared to cisplatin against BC cell lines in vitro.
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Affiliation(s)
- Álisson Coldebella da Silva
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil
| | - Juliete Nathali Scholl
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil
| | - Amanda de Fraga Dias
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil
| | - Augusto Ferreira Weber
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil
| | - Fernanda Bueno Morrone
- Laboratório de Farmacologia Aplicada, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Olga Cruz-López
- Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Ana Conejo-García
- Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Joaquín María Campos
- Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Jean Sévigny
- Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, Canada
- Axe maladies infectieuses et immunitaires, Centre de recherche du CHU de Québec - Université Laval, Quebec city, QC, Canada
| | - Fabrício Figueiró
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Ana Maria Oliveira Battastini
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil.
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Chen F, Xu K, Han Y, Ding J, Ren J, Wang Y, Ma Z, Cao F. Mitochondrial dysfunction in pancreatic acinar cells: mechanisms and therapeutic strategies in acute pancreatitis. Front Immunol 2024; 15:1503087. [PMID: 39776917 PMCID: PMC11703726 DOI: 10.3389/fimmu.2024.1503087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Acute pancreatitis (AP) is an inflammatory disease of the pancreas and a complex process involving multiple factors, with mitochondrial damage playing a crucial role. Mitochondrial dysfunction is now considered a key driver in the development of AP. This dysfunction often presents as increased oxidative stress, altered membrane potential and permeability, and mitochondrial DNA damage and mutations. Under stress conditions, mitochondrial dynamics and mitochondrial ROS production increase, leading to decreased mitochondrial membrane potential, imbalanced calcium homeostasis, and activation of the mitochondrial permeability transition pore. The release of mitochondrial DNA (mtDNA), recognized as damage-associated molecular patterns, can activate the cGAS-STING1 and NF-κB pathway and induce pro-inflammatory factor expression. Additionally, mtDNA can activate inflammasomes, leading to interleukin release and subsequent tissue damage and inflammation. This review summarizes the relationship between mitochondria and AP and explores mitochondrial protective strategies in the diagnosis and treatment of this disease. Future research on the treatment of acute pancreatitis can benefit from exploring promising avenues such as antioxidants, mitochondrial inhibitors, and new therapies that target mitochondrial dysfunction.
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Affiliation(s)
- Fan Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Kedong Xu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreatic Disease Center of Xi’an Jiaotong University, Xi’an, China
| | - Yimin Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jiachun Ding
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jiaqiang Ren
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yaochun Wang
- Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zhenhua Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreatic Disease Center of Xi’an Jiaotong University, Xi’an, China
| | - Fang Cao
- Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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Hassan D, Menges CW, Testa JR, Bellacosa A. AKT kinases as therapeutic targets. J Exp Clin Cancer Res 2024; 43:313. [PMID: 39614261 PMCID: PMC11606119 DOI: 10.1186/s13046-024-03207-4] [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: 07/24/2024] [Accepted: 10/03/2024] [Indexed: 12/01/2024] Open
Abstract
AKT, or protein kinase B, is a central node of the PI3K signaling pathway that is pivotal for a range of normal cellular physiologies that also underlie several pathological conditions, including inflammatory and autoimmune diseases, overgrowth syndromes, and neoplastic transformation. These pathologies, notably cancer, arise if either the activity of AKT or its positive or negative upstream or downstream regulators or effectors goes unchecked, superimposed on by its intersection with a slew of other pathways. Targeting the PI3K/AKT pathway is, therefore, a prudent countermeasure. AKT inhibitors have been tested in many clinical trials, primarily in combination with other drugs. While some have recently garnered attention for their favorable profile, concern over resistance and off-target effects have continued to hinder their widespread adoption in the clinic, mandating a discussion on alternative modes of targeting. In this review, we discuss isoform-centric targeting that may be more effective and less toxic than traditional pan-AKT inhibitors and its significance for disease prevention and treatment, including immunotherapy. We also touch on the emerging mutant- or allele-selective covalent allosteric AKT inhibitors (CAAIs), as well as indirect, novel AKT-targeting approaches, and end with a briefing on the ongoing quest for more reliable biomarkers predicting sensitivity and response to AKT inhibitors, and their current state of affairs.
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Affiliation(s)
- Dalal Hassan
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
- Thomas Jefferson University, 901 Walnut St, Philadelphia, PA, 19107, USA
| | - Craig W Menges
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Joseph R Testa
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Alfonso Bellacosa
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
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Mocarski ES. Cytomegalovirus Biology Viewed Through a Cell Death Suppression Lens. Viruses 2024; 16:1820. [PMID: 39772130 PMCID: PMC11680106 DOI: 10.3390/v16121820] [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: 10/28/2024] [Revised: 11/22/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025] Open
Abstract
Cytomegaloviruses, species-specific members of the betaherpesviruses, encode an impressive array of immune evasion strategies committed to the manipulation of the host immune system enabling these viruses to remain for life in a stand-off with host innate and adaptive immune mechanisms. Even though they are species-restricted, cytomegaloviruses are distributed across a wide range of different mammalian species in which they cause systemic infection involving many different cell types. Regulated, or programmed cell death has a recognized potential to eliminate infected cells prior to completion of viral replication and release of progeny. Cell death also naturally terminates replication during the final stages of replication. Over the past two decades, the host defense potential of known programmed cell death pathways (apoptosis, necroptosis, and pyroptosis), as well as a novel mitochondrial serine protease pathway have been defined through studies of cytomegalovirus-encoded cell death suppressors. Such virus-encoded inhibitors prevent virus-induced, cytokine-induced, and stress-induced death of infected cells while also moderating inflammation. By evading cell death and consequent inflammation as well as innate and adaptive immune clearance, cytomegaloviruses represent successful pathogens that become a critical disease threat when the host immune system is compromised. This review will discuss cell death programs acquired for mammalian host defense against cytomegaloviruses and enumerate the range of modulatory strategies this type of virus employs to balance host defense in favor of lifelong persistence.
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Affiliation(s)
- Edward S. Mocarski
- Department of Microbiology & Immunology, Stanford Medical School, Stanford University, Stanford, CA 94305, USA;
- Department of Microbiology & Immunology, Emory Medical School, Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
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Yang X, Zheng R, Zhang H, Ou Z, Wan S, Lin D, Yan J, Jin M, Tan J. Optineurin regulates motor and learning behaviors by affecting dopaminergic neuron survival in mice. Exp Neurol 2024; 383:115007. [PMID: 39428042 DOI: 10.1016/j.expneurol.2024.115007] [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: 08/05/2024] [Revised: 09/17/2024] [Accepted: 10/16/2024] [Indexed: 10/22/2024]
Abstract
Optineurin (OPTN) is an autophagy receptor that participates in the degradation of damaged mitochondria, protein aggregates, and invading pathogens. OPTN is closely related to various types of neurodegenerative diseases. However, the role of OPTN in the central nervous system is unclear. Here, we found that OPTN dysregulation in the compact part of substantia nigra (SNc) led to motor and learning deficits in animal models. Knockdown of OPTN increased total and phosphorylated α-synuclein levels which induced microglial activation and dopaminergic neuronal loss in the SNc. Overexpression of OPTN can't reverse the motor and learning phenotypes. Mechanistic analysis revealed that upregulation of OPTN increased α-synuclein phosphorylation independent of its autophagy receptor activity, which further resulted in microglial activation and dopaminergic neuronal loss similar to OPTN downregulation. Our study uncovers the crucial role of OPTN in maintaining dopaminergic neuron survival and motor and learning functions which are disrupted in PD patients.
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Affiliation(s)
- Xianfei Yang
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541199, China
| | - Ruoling Zheng
- Shantou Longhu People's Hospital, Shantou 515041, China
| | - Hongyao Zhang
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541199, China
| | - Zixian Ou
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541199, China
| | - Sha Wan
- Department of Anatomy, College of Basic Medicine, Guilin Medical University, Guilin 541199, China
| | - Dongfeng Lin
- Shantou University Mental Health Center, Shantou University, Shantou 515063, China
| | - Jianguo Yan
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541199, China; Department of Physiology, College of Basic Medicine, Guilin Medical University, Guilin 541199, China
| | - Mingyue Jin
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541199, China
| | - Jie Tan
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541199, China; Department of Physiology, College of Basic Medicine, Guilin Medical University, Guilin 541199, China; Clinical Research Center for Neurological Diseases of Guangxi Province, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China.
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Chang MC, Wang SR, Lin DPC, Chang HH. Hepatic inflammation, ballooning, and pyknosis caused by LED light exposure in a mouse model, with differential effects by age and gender. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 284:116984. [PMID: 39265263 DOI: 10.1016/j.ecoenv.2024.116984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/23/2024] [Accepted: 08/29/2024] [Indexed: 09/14/2024]
Abstract
Light-emitting diode (LED) is commonly used in lighting and digital devices in modern life, which delivers higher levels of blue light than other light sources. Previous work indicated that exposure to blue lights increases serum oxidative stress and affects hepatic functions in animals. However, the detailed hepatic pathogenesis caused by blue lights remains largely elusive. This study investigated the characteristics of hepatic injuries caused by LED light exposure in a mouse model. C57BL/6 mice were exposed the LED lights at 1000 lux, 12 h per day for 45 days or at 4500 lux, 1 h per day for 7 days. The mice were aged 8 weeks or 36 weeks in both genders and maintained under a 12 h light/dark cycle without alteration of diet pattern. Liver tissue sections were obtained for hematoxylin and eosin (H&E) and immunohistochemical staining. The mice with 1000 lux exposure displayed severe liver injuries, including inflammation, ballooning, and pyknosis, which were found to a lesser extent in the 4500 lux mice, and aging aggravated the hepatic injuries. The hepatocellular ballooning was found more severe in the males than the females. In contrast, the females expressed the F4/80 and TNF-α inflammatory markers more evidently. Taken together, LED light exposure may have detrimental effects on liver health, particularly in vulnerable groups such as the elderly and the females with excessive exposure to LED lights, even if they maintain a normal diet and regular light/dark cycles. The potential risk should be considered by both the clinicians and the public.
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Affiliation(s)
- Min-Chun Chang
- Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan
| | - Shih-Rong Wang
- Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan
| | - David Pei-Cheng Lin
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taiwan; Department of Ophthalmology, Chung Shan Medical University Hospital, Taiwan.
| | - Han-Hsin Chang
- Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan; Department of Ophthalmology, Chung Shan Medical University Hospital, Taiwan.
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11
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Li M, Tian Y, Wen X, Fu J, Gao J, Zhu Y. Inhibition of thioredoxin reductase and upregulation of apoptosis genes for effective anti-tumor sono-chemotherapy using a meso-organosilica nanomedicine. Biomater Sci 2024; 12:3918-3932. [PMID: 38939985 DOI: 10.1039/d4bm00583j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2024]
Abstract
The thioredoxin system is involved in cancer development and therefore is a promising target for cancer chemotherapy. Thioredoxin reductase (TrxR) is a key component of the thioredoxin (Trx) system, and is overexpressed in many cancers to inhibit apoptosis-related proteins. Alternatively, inhibition of thioredoxin reductase and upregulation of apoptosis factors provide a therapeutic strategy for anti-tumor treatment. In this study, an ultrasound-activatable meso-organosilica nanomedicine was prepared by integrating chloroquine (CQ) into hollow mesoporous organosilica (CQ@MOS). The meso-organosilica nanomedicine can inhibit the activity of thioredoxin reductase, elevate cellular reactive oxygen species (ROS) levels, upregulate the pro-apoptotic factors in the c-Jun N-terminal kinase (JNK) apoptosis pathway and induce autophagy inhibition, further resulting in mitochondrial membrane potential (MMP) depolarization and cellular ATP content decrease, ultimately causing significant damage to tumor cells. Moreover, CQ@MOS can efficiently deliver chloroquine into cancer cells and promote an enhanced sonodynamic effect for effective anti-tumor chemotherapy and sonodynamic therapy. This study may enlighten us on a new anti-tumor strategy and suggest its promising applications in cancer treatments.
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Affiliation(s)
- Mengwen Li
- Key Laboratory of Inorganic Coating Materials CAS, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
- Center of Materials Science and Optoelectronics Engineer, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yue Tian
- Key Laboratory of Inorganic Coating Materials CAS, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
| | - Xiaoming Wen
- Key Laboratory of Inorganic Coating Materials CAS, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
- Center of Materials Science and Optoelectronics Engineer, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jingke Fu
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Engineering Research Center of Innovative Orthopaedic Instruments and Personalized Medicine, Shanghai 200011, PR China
| | - Jianyong Gao
- Department of Stomatology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China.
| | - Yingchun Zhu
- Key Laboratory of Inorganic Coating Materials CAS, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
- Center of Materials Science and Optoelectronics Engineer, University of Chinese Academy of Sciences, Beijing 100049, China
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12
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Badal KK, Zhao Y, Raveendra BL, Lozano-Villada S, Miller KE, Puthanveettil SV. PKA Activity-Driven Modulation of Bidirectional Long-Distance transport of Lysosomal vesicles During Synapse Maintenance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.28.601272. [PMID: 38979384 PMCID: PMC11230415 DOI: 10.1101/2024.06.28.601272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
The bidirectional long-distance transport of organelles is crucial for cell body-synapse communication. However, the mechanisms by which this transport is modulated for synapse formation, maintenance, and plasticity are not fully understood. Here, we demonstrate through quantitative analyses that maintaining sensory neuron-motor neuron synapses in the Aplysia gill-siphon withdrawal reflex is linked to a sustained reduction in the retrograde transport of lysosomal vesicles in sensory neurons. Interestingly, while mitochondrial transport in the anterograde direction increases within 12 hours of synapse formation, the reduction in lysosomal vesicle retrograde transport appears three days after synapse formation. Moreover, we find that formation of new synapses during learning induced by neuromodulatory neurotransmitter serotonin further reduces lysosomal vesicle transport within 24 hours, whereas mitochondrial transport increases in the anterograde direction within one hour of exposure. Pharmacological inhibition of several signaling pathways pinpoints PKA as a key regulator of retrograde transport of lysosomal vesicles during synapse maintenance. These results demonstrate that synapse formation leads to organelle-specific and direction specific enduring changes in long-distance transport, offering insights into the mechanisms underlying synapse maintenance and plasticity.
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Affiliation(s)
- Kerriann. K. Badal
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, 130 Scripps Way, Jupiter, FL 33458, USA
- Integrative Biology PhD Program, Charles E. Schmidt College of Science, Florida Atlantic University, Jupiter, FL 33458, USA
| | - Yibo. Zhao
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Bindu L Raveendra
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, 130 Scripps Way, Jupiter, FL 33458, USA
| | - Sebastian Lozano-Villada
- Harriet L. Wilkes Honors College, Florida Atlantic University, 5353 Parkside Drive, Jupiter, FL 33458, USA
| | - Kyle. E. Miller
- Harriet L. Wilkes Honors College, Florida Atlantic University, 5353 Parkside Drive, Jupiter, FL 33458, USA
| | - Sathyanarayanan V. Puthanveettil
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, 130 Scripps Way, Jupiter, FL 33458, USA
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13
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Maglica M, Kelam N, Perutina I, Racetin A, Rizikalo A, Filipović N, Kuzmić Prusac I, Mišković J, Vukojević K. Immunoexpression Pattern of Autophagy-Related Proteins in Human Congenital Anomalies of the Kidney and Urinary Tract. Int J Mol Sci 2024; 25:6829. [PMID: 38999938 PMCID: PMC11241479 DOI: 10.3390/ijms25136829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/13/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
The purpose of this study was to evaluate the spatiotemporal immunoexpression pattern of microtubule-associated protein 1 light chain 3 beta (LC3B), glucose-regulated protein 78 (GRP78), heat shock protein 70 (HSP70), and lysosomal-associated membrane protein 2A (LAMP2A) in normal human fetal kidney development (CTRL) and kidneys affected with congenital anomalies of the kidney and urinary tract (CAKUT). Human fetal kidneys (control, horseshoe, dysplastic, duplex, and hypoplastic) from the 18th to the 38th developmental week underwent epifluorescence microscopy analysis after being stained with antibodies. Immunoreactivity was quantified in various kidney structures, and expression dynamics were examined using linear and nonlinear regression modeling. The punctate expression of LC3B was observed mainly in tubules and glomerular cells, with dysplastic kidneys displaying distinct staining patterns. In the control group's glomeruli, LAMP2A showed a sporadic, punctate signal; in contrast to other phenotypes, duplex kidneys showed significantly stronger expression in convoluted tubules. GRP78 had a weaker expression in CAKUT kidneys, especially hypoplastic ones, while normal kidneys exhibited punctate staining of convoluted tubules and glomeruli. HSP70 staining varied among phenotypes, with dysplastic and hypoplastic kidneys exhibiting stronger staining compared to controls. Expression dynamics varied among observed autophagy markers and phenotypes, indicating their potential roles in normal and dysfunctional kidney development.
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Affiliation(s)
- Mirko Maglica
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
| | - Nela Kelam
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia
| | - Ilija Perutina
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
| | - Anita Racetin
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia
| | - Azer Rizikalo
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
| | - Natalija Filipović
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia
| | - Ivana Kuzmić Prusac
- Department of Pathology, University Hospital Center Split, 21000 Split, Croatia
| | - Josip Mišković
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
| | - Katarina Vukojević
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia
- Center for Translational Research in Biomedicine, School of Medicine, University of Split, 21000 Split, Croatia
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14
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Li C, Wu Y, Zhu Y, Yan J, Liu S, Xu J, Fa S, Yan T, Zhu D, Yan Y, Liu J. Molecular Motor-Driven Light-Controlled Logic-Gated K + Channel for Cancer Cell Apoptosis. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2312352. [PMID: 38301140 DOI: 10.1002/adma.202312352] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 01/11/2024] [Indexed: 02/03/2024]
Abstract
Developing artificial ion transport systems, which process complicated information and step-wise regulate properties, is essential for deeply comprehending the subtle dynamic behaviors of natural channel proteins (NCPs). Here a photo-controlled logic-gated K+ channel based on single-chain random heteropolymers containing molecular motors, exhibiting multi-core processor-like properties to step-wise control ion transport is reported. Designed with oxygen, deoxygenation, and different wavelengths of light as input signals, complicated logical circuits comprising "YES", "AND", "OR" and "NOT" gate components are established. Implementing these logical circuits with K+ transport efficiencies as output signals, multiple state transitions including "ON", "Partially OFF" and "Totally OFF" in liposomes and cancer cells are realized, further causing step-wise anticancer treatments. Dramatic K+ efflux in the "ON" state (decrease by 50% within 7 min) significantly induces cancer cell apoptosis. This integrated logic-gated strategy will be expanded toward understanding the delicate mechanism underlying NCPs and treating cancer or other diseases is expected.
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Affiliation(s)
- Cong Li
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
- College of Chemistry and Chemical Engineering, Key Laboratory of Special Functional and Smart Polymer Materials of Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, 710129, China
| | - Yaqi Wu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
- College of Chemistry and Chemical Engineering, Key Laboratory of Special Functional and Smart Polymer Materials of Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, 710129, China
| | - Yihang Zhu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Jing Yan
- College of Chemistry and Chemical Engineering, Key Laboratory of Special Functional and Smart Polymer Materials of Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, 710129, China
| | - Shengda Liu
- College of Chemistry and Environmental Engineering, Changchun University of Science and Technology, Changchun, 130022, China
| | - Jiayun Xu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Shixin Fa
- College of Chemistry and Chemical Engineering, Key Laboratory of Special Functional and Smart Polymer Materials of Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, 710129, China
| | - Tengfei Yan
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Dingcheng Zhu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Yi Yan
- College of Chemistry and Chemical Engineering, Key Laboratory of Special Functional and Smart Polymer Materials of Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, 710129, China
| | - Junqiu Liu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, China
- College of Chemistry and Chemical Engineering, Key Laboratory of Special Functional and Smart Polymer Materials of Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, 710129, China
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15
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Chen T, Xiao Z, Liu X, Wang T, Wang Y, Ye F, Su J, Yao X, Xiong L, Yang DH. Natural products for combating multidrug resistance in cancer. Pharmacol Res 2024; 202:107099. [PMID: 38342327 DOI: 10.1016/j.phrs.2024.107099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/22/2024] [Accepted: 02/05/2024] [Indexed: 02/13/2024]
Abstract
Cancer cells frequently develop resistance to chemotherapeutic therapies and targeted drugs, which has been a significant challenge in cancer management. With the growing advances in technologies in isolation and identification of natural products, the potential of natural products in combating cancer multidrug resistance has received substantial attention. Importantly, natural products can impact multiple targets, which can be valuable in overcoming drug resistance from different perspectives. In the current review, we will describe the well-established mechanisms underlying multidrug resistance, and introduce natural products that could target these multidrug resistant mechanisms. Specifically, we will discuss natural compounds such as curcumin, resveratrol, baicalein, chrysin and more, and their potential roles in combating multidrug resistance. This review article aims to provide a systematic summary of recent advances of natural products in combating cancer drug resistance, and will provide rationales for novel drug discovery.
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Affiliation(s)
- Ting Chen
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Zhicheng Xiao
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Xiaoyan Liu
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Tingfang Wang
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Yun Wang
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Fei Ye
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Juan Su
- School of Pharmacy, Naval Medical University, Shanghai 200433, China.
| | - Xuan Yao
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China.
| | - Liyan Xiong
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China.
| | - Dong-Hua Yang
- New York College of Traditional Chinese Medicine, NY 11501, USA.
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16
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Wu C, Du X, Liu H, Chen X, Ge K, Meng R, Zhang Z, Zhang H. Advances in polychlorinated biphenyls-induced female reproductive toxicity. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 918:170543. [PMID: 38309369 DOI: 10.1016/j.scitotenv.2024.170543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/26/2024] [Accepted: 01/27/2024] [Indexed: 02/05/2024]
Abstract
Polychlorinated biphenyls (PCBs) are a class of endocrine-disrupting chemicals (EDCs) widely present in the environment. PCBs have been of concern due to their anti/estrogen-like effects, which make them more toxic to the female reproductive system. However, there is still a lack of systematic reviews on the reproductive toxicity of PCBs in females, so the adverse effects and mechanisms of PCBs on the female reproductive system were summarized in this paper. Our findings showed that PCBs are positively associated with lower pregnancy rate, hormone disruption, miscarriage and various reproductive diseases in women. In animal experiments, PCBs can damage the structure and function of the ovaries, uterus and oviducts. Also, PCBs could produce epigenetic effects and be transferred to the offspring through the maternal placenta, causing development retardation, malformation and death of embryos, and damage to organs of multiple generations. Furthermore, the mechanisms of PCBs-induced female reproductive toxicity mainly include receptor-mediated hormone disorders, oxidative stress, apoptosis, autophagy, and epigenetic modifications. Finally, we also present some directions for future research on the reproductive toxicity of PCBs. This detailed information provided a valuable reference for fully understanding the reproductive toxicity of PCBs.
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Affiliation(s)
- Chunrui Wu
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Xingde Du
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Haohao Liu
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Xinghai Chen
- Department of Chemistry and Biochemistry, St Mary's University, San Antonio, TX, USA
| | - Kangfeng Ge
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Ruiyang Meng
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Zongxin Zhang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China.
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17
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Zhao SF, Leng JF, Xie SS, Zhu LQ, Zhang MY, Kong LY, Yin Y. Design, synthesis and biological evaluation of CDC20 inhibitors for treatment of triple-negative breast cancer. Eur J Med Chem 2024; 268:116204. [PMID: 38364716 DOI: 10.1016/j.ejmech.2024.116204] [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: 12/20/2023] [Revised: 01/24/2024] [Accepted: 01/31/2024] [Indexed: 02/18/2024]
Abstract
The involvement of CDC20 in promoting tumor growth in different types of human cancers and it disturbs the process of cell division and impedes tumor proliferation. In this work, a novel of Apcin derivatives targeting CDC20 were designed and synthesized to evaluate for their biological activities. The inhibitory effect on the proliferation of four human tumor cell lines (MCF-7, MDA-MB-231, MDA-MB-468 and A549) was observed. Among them, compound E1 exhibited the strongest inhibitory effect on the proliferation of MDA-MB-231 cells with an IC50 value of 1.43 μM, which was significantly superior to that of Apcin. Further biological studies demonstrated that compound E1 inhibited cancer cell migration and colony formation. Furthermore, compound E1 specifically targeted CDC20 and exhibited a higher binding affinity to CDC20 compared to that of Apcin, thereby inducing cell cycle arrest in the G2/M phase of cancer cells. Moreover, it has been observed that compound E1 induces autophagy in cancer cells. In 4T1 Xenograft Models compound E1 exhibited the potential antitumor activity without obvious toxicity. These findings suggest that E1 could be regarded as a CDC20 inhibitor deserved further investigation.
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Affiliation(s)
- Shi-Fang Zhao
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Jia-Fu Leng
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Shan-Shan Xie
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Li-Qiao Zhu
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Meng-Yu Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Ling-Yi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Yong Yin
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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18
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Varela YR, Iriondo MN, Goñi FM, Alonso A, Montes LR. Ceramide regulation of autophagy: A biophysical approach. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159444. [PMID: 38056762 DOI: 10.1016/j.bbalip.2023.159444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/29/2023] [Accepted: 11/30/2023] [Indexed: 12/08/2023]
Abstract
Specific membrane lipids play unique roles in (macro)autophagy. Those include phosphatidylethanolamine, to which LC3/GABARAP autophagy proteins become covalently bound in the process, or cardiolipin, an important effector in mitochondrial autophagy (or mitophagy). Ceramide (Cer), or N-acyl sphingosine, is one of the simplest sphingolipids, known as a stress signal in the apoptotic pathway. Moreover, Cer is increasingly being recognized as an autophagy activator, although its mechanism of action is unclear. In the present review, the proposed Cer roles in autophagy are summarized, together with some biophysical properties of Cer in membranes. Possible pathways for Cer activation of autophagy are discussed, including specific protein binding of the lipid, and Cer-dependent perturbation of bilayer properties. Cer generation of lateral inhomogeneities (domain formation) is given special attention. Recent biophysical results, including fluorescence and atomic force microscopy data, show Cer-promoted enhanced binding of LC3/GABARAP to lipid bilayers. These observations could be interpreted in terms of the putative formation of Cer-rich nanodomains.
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Affiliation(s)
- Yaiza R Varela
- Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, 48940 Leioa, Spain
| | - Marina N Iriondo
- Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, 48940 Leioa, Spain
| | - Félix M Goñi
- Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, 48940 Leioa, Spain
| | - Alicia Alonso
- Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, 48940 Leioa, Spain.
| | - L Ruth Montes
- Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, 48940 Leioa, Spain
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19
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Du NH, Ngoc TTB, Cang HQ, Luyen NTT, Thuoc TL, Le Quan T, Thao DTP. KTt-45, a T-type calcium channel blocker, acts as an anticancer agent by inducing apoptosis on HeLa cervical cancer cell line. Sci Rep 2023; 13:22092. [PMID: 38086845 PMCID: PMC10716508 DOI: 10.1038/s41598-023-47199-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 11/10/2023] [Indexed: 12/18/2023] Open
Abstract
The abnormal expression in the T-type calcium channels is involved in various cancer types, thus inhibiting T-type calcium channels is one of approaches in cancer treatment. The fact that KTt-45 acted as a T-type calcium channel inhibitor as well as a pain-relief agent prompts us to address if KTt-45 plays any role against cancer cells. The results showed that KTt-45 caused cytotoxic effects towards HeLa cervical, Raji lymphoma, MCF-7 breast cancer, and A549 lung cancer cell lines with IC50 values less than 100 μM, in which highly selective toxicity was against HeLa cells (IC50 = 37.4 μM, SI > 3.2). Strikingly, the KTt-45 induced an accumulation of cytoplasmic vacuoles after 48 h treatment and mitochondrial-dependent apoptosis activation as evidenced by morphological features, chromatin condensation, nuclear fragmentation, and significant activation of caspase-9 as well as caspase-3. In conclusion, KTt-45 could inhibit cell growth and trigger mitochondrial-dependent apoptosis in HeLa cervical cancer cells. The results, taken together, strongly demonstrated that KTt-45 is a potential agent for further study on anticancer drug development which not only targets cancer cells but also helps to relieve neuropathic pain in cancer patients.
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Affiliation(s)
- Nguyen Huy Du
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Central Laboratory of Analysis, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
| | - Truong Thi Bich Ngoc
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
| | - Huynh Qui Cang
- Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
| | - Nguyen Thi Thuy Luyen
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Central Laboratory of Analysis, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Department of Hydro-Geology-Engineering Geology and Environmental Geology, Faculty of Geology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Department of Medicinal Chemistry, Faculty of Chemistry, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
| | - Tran Linh Thuoc
- Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
| | - Tran Le Quan
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Central Laboratory of Analysis, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Department of Hydro-Geology-Engineering Geology and Environmental Geology, Faculty of Geology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Department of Medicinal Chemistry, Faculty of Chemistry, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
| | - Dang Thi Phuong Thao
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam.
- Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam.
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam.
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20
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Lim DH, Choi MS, Jeon JW, Lee YS. MicroRNA miR-252-5p regulates the Notch signaling pathway by targeting Rab6 in Drosophila wing development. INSECT SCIENCE 2023; 30:1431-1444. [PMID: 36847222 DOI: 10.1111/1744-7917.13188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/06/2023] [Accepted: 02/08/2023] [Indexed: 06/18/2023]
Abstract
The Notch signaling pathway plays a central role in the development of various organisms. However, dysregulation of microRNAs (miRNAs), which are crucial regulators of gene expression, can disrupt signaling pathways at all stages of development. Although Notch signaling is involved in wing development in Drosophila, the mechanism underlying miRNA-based regulation of the Notch signaling pathway is unclear. Here, we report that loss of Drosophila miR-252 increases the size of adult wings, whereas the overexpression of miR-252 in specific compartments of larval wing discs leads to patterning defects in the adult wings. The miR-252 overexpression-induced wing phenotypes were caused by aberrant Notch signaling with intracellular accumulation of the full-length Notch receptor during development, which could be due to defects in intracellular Notch trafficking associated with its recycling to the plasma membrane and autophagy-mediated degradation. Moreover, we identified Rab6 as a direct target of miR-252-5p; Rab6 encodes a small Ras-like GTPase that regulates endosomal trafficking pathways. Consistent with this finding, RNAi-mediated downregulation of Rab6 led to similar defects in both wing patterning and Notch signaling. Notably, co-overexpression of Rab6 completely rescued the wing phenotype associated with miR-252 overexpression, further supporting that Rab6 is a biologically relevant target of miR-252-5p in the context of wing development. Thus, our data indicate that the miR-252-5p-Rab6 regulatory axis is involved in Drosophila wing development by controlling the Notch signaling pathway.
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Affiliation(s)
- Do-Hwan Lim
- School of Systems Biomedical Science, Soongsil University, Seoul, Republic of Korea
| | - Min-Seok Choi
- College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
- Institute of Animal Molecular Biotechnology, Korea University, Seoul, Republic of Korea
| | - Ji Won Jeon
- School of Systems Biomedical Science, Soongsil University, Seoul, Republic of Korea
| | - Young Sik Lee
- College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
- Institute of Animal Molecular Biotechnology, Korea University, Seoul, Republic of Korea
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21
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Ciltas AC, Karabulut S, Sahin B, Filiz AK, Yulak F, Ozkaraca M, Karatas O, Cetin A. FGF-18 alleviates memory impairments and neuropathological changes in a rat model of Alzheimer's disease. Neuropeptides 2023; 101:102367. [PMID: 37506425 DOI: 10.1016/j.npep.2023.102367] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 07/06/2023] [Accepted: 07/22/2023] [Indexed: 07/30/2023]
Abstract
Alzheimer's disease (AD) is a multifactorial pathology marked by amyloid beta (Aβ) accumulation, tau hyperphosphorylation, and progressive cognitive decline. Previous studies show that fibroblast growth factor 18 (FGF18) exerts a neuroprotective effect in experimental models of neurodegeneration; however, how it affects AD pathology remains unknown. This study aimed to ascertain the impact of FGF18 on the behavioral and neuropathological changes in the rat model of sporadic AD induced by intracerebroventricular (ICV) injection of streptozotocin (STZ). The rats were treated with FGF18 (0.94 and 1.88 pmol, ICV) on the 15th day after STZ injection. Their cognitive function was assessed in the Morris water maze and passive avoidance tests for 5 days from the 16th to the 21st days. Aβ levels and histological signs of neurotoxicity were detected using the enzyme-linked immunosorbent assay (ELISA) assay and histopathological analysis of the brain, respectively. FGF18 mildly ameliorated the STZ-induced cognitive impairment; the Aβ accumulation was reduced; and the neuronal damage including pyknosis and apoptosis was alleviated in the rat brain. This study highlights the promising therapeutic potential for FGF18 in managing AD.
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Affiliation(s)
- Arzuhan Cetindag Ciltas
- Department of Medical Services and Techniques, Vocational School of Health Services, Sivas Cumhuriyet University, Sivas, Turkey
| | - Sebahattin Karabulut
- Department of Medical Services and Techniques, Vocational School of Health Services, Sivas Cumhuriyet University, Sivas, Turkey.
| | - Bilal Sahin
- Department of Medical Physiology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
| | - Ahmet Kemal Filiz
- Department of Medical Physiology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
| | - Fatih Yulak
- Department of Medical Physiology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
| | - Mustafa Ozkaraca
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, Sivas Cumhuriyet University, Sivas, Turkey
| | - Ozhan Karatas
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, Sivas Cumhuriyet University, Sivas, Turkey
| | - Ali Cetin
- Department of Obstetrics and Gynecology, Haseki Training and Research Hospital affiliated with the University of Health Sciences, Istanbul, Turkey
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22
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Molinar C, Tannous M, Meloni D, Cavalli R, Scomparin A. Current Status and Trends in Nucleic Acids for Cancer Therapy: A Focus on Polysaccharide-Based Nanomedicines. Macromol Biosci 2023; 23:e2300102. [PMID: 37212473 DOI: 10.1002/mabi.202300102] [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: 03/10/2023] [Revised: 04/28/2023] [Indexed: 05/23/2023]
Abstract
The efficacious delivery of therapeutic nucleic acids to cancer still remains an open issue. Through the years, several strategies are developed for the encapsulation of genetic molecules exploiting different materials, such as viral vectors, lipid nanoparticles (LNPs), and polymeric nanoparticles (NPs). Indeed, the rapid approval by regulatory authorities and the wide use of LNPs complexing the mRNA coding for the spark protein for COVID-19 vaccination paved the way for the initiation of several clinical trials exploiting lipid nanoparticles for cancer therapy. Nevertheless, polymers still represent a valuable alternative to lipid-based formulations, due to the low cost and the chemical flexibility that allows for the conjugation of targeting ligands. This review will analyze the status of the ongoing clinical trials for cancer therapy, including vaccination and immunotherapy approaches, exploiting polymeric materials. Among those nanosized carriers, sugar-based backbones are an interesting category. A cyclodextrin-based carrier (CALAA-01) is the first polymeric material to enter a clinical trial complexed with siRNA for cancer therapy, and chitosan is one of the most characterized non-viral vectors able to complex genetic material. Finally, the recent advances in the use of sugar-based polymers (oligo- and polysaccharides) for the complexation of nucleic acids in advanced preclinical stage will be discussed.
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Affiliation(s)
- Chiara Molinar
- Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, Torino, 10125, Italy
| | - Maria Tannous
- Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, Torino, 10125, Italy
- Department of Chemistry, University of Turin, Via P. Giuria 7, Torino, 10125, Italy
| | - Domitilla Meloni
- Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, Torino, 10125, Italy
| | - Roberta Cavalli
- Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, Torino, 10125, Italy
| | - Anna Scomparin
- Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, Torino, 10125, Italy
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23
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Lee YY, Han JI, Lee KE, Cho S, Suh EC. Neuroprotective effect of dexmedetomidine on autophagy in mice administered intracerebroventricular injections of Aβ 25-35. Front Pharmacol 2023; 14:1184776. [PMID: 37663257 PMCID: PMC10469611 DOI: 10.3389/fphar.2023.1184776] [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: 03/12/2023] [Accepted: 08/08/2023] [Indexed: 09/05/2023] Open
Abstract
Alzheimer's disease (AD), one of the most prevalent neurodegenerative diseases is associated with pathological autophagy-lysosomal pathway dysfunction. Dexmedetomidine (Dex) has been suggested as an adjuvant to general anesthesia with advantages in reducing the incidence of postoperative cognitive dysfunction in Dex-treated patients with AD and older individuals. Several studies reported that Dex improved memory; however, evidence on the effects of Dex on neuronal autophagy dysfunction in the AD model is lacking. We hypothesized that Dex administration would have neuroprotective effects by improving pathological autophagy dysfunction in mice that received an intracerebroventricular (i.c.v.) injection of amyloid β-protein fragment 25-35 (Aβ25-35) and in an autophagy-deficient cellular model. In the Y-maze test, Dex reversed the decreased activity of Aβ25-35 mice. Additionally, it restored the levels of two memory-related proteins, phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII) and postsynaptic density-95 (PSD-95) in Aβ25-35 mice and organotypic hippocampal slice culture (OHSC) with Aβ25-35. Dex administration also resulted in decreased expression of the autophagy-related microtubule-associated proteins light chain 3-II (LC3-II), p62, lysosome-associated membrane protein2 (LAMP2), and cathepsin D in Aβ25-35 mice and OHSC with Aβ25-35. Increased numbers of co-localized puncta of LC3-LAMP2 or LC3-cathepsin D, along with dissociated LC3-p62 immunoreactivity following Dex treatment, were observed. These findings were consistent with the results of western blots and the transformation of double-membrane autophagosomes into single-membraned autolysosomes in ultrastructures. It was evident that Dex treatment alleviated impaired autolysosome formation in Aβ mice. Our study demonstrated the improvement of memory impairment caused by Dex and its neuroprotective mechanism by investigating the role of the autophagy-lysosomal pathway in a murine Aβ25-35 model. These findings suggest that Dex could be used as a potential neuroprotective adjuvant in general anesthesia to prevent cognitive decline.
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Affiliation(s)
- Youn Young Lee
- Department of Anesthesiology and Pain Medicine, Ewha Womans University Seoul Hospital, Seoul, Republic of Korea
- Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Jong In Han
- Department of Anesthesiology and Pain Medicine, Ewha Womans University Seoul Hospital, Seoul, Republic of Korea
- Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Kyung Eun Lee
- Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Sooyoung Cho
- Department of Anesthesiology and Pain Medicine, Ewha Womans University Seoul Hospital, Seoul, Republic of Korea
- Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Eun Cheng Suh
- Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
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24
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McKee CA, Polino AJ, King MW, Musiek ES. Circadian clock protein BMAL1 broadly influences autophagy and endolysosomal function in astrocytes. Proc Natl Acad Sci U S A 2023; 120:e2220551120. [PMID: 37155839 PMCID: PMC10194014 DOI: 10.1073/pnas.2220551120] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 04/12/2023] [Indexed: 05/10/2023] Open
Abstract
An emerging role for the circadian clock in autophagy and lysosome function has opened new avenues for exploration in the field of neurodegeneration. The daily rhythms of circadian clock proteins may coordinate gene expression programs involved not only in daily rhythms but in many cellular processes. In the brain, astrocytes are critical for sensing and responding to extracellular cues to support neurons. The core clock protein BMAL1 serves as the primary positive circadian transcriptional regulator and its depletion in astrocytes not only disrupts circadian function but also leads to a unique cell-autonomous activation phenotype. We report here that astrocyte-specific deletion of Bmal1 influences endolysosome function, autophagy, and protein degradation dynamics. In vitro, Bmal1-deficient astrocytes exhibit increased endocytosis, lysosome-dependent protein cleavage, and accumulation of LAMP1- and RAB7-positive organelles. In vivo, astrocyte-specific Bmal1 knockout (aKO) brains show accumulation of autophagosome-like structures within astrocytes by electron microscopy. Transcriptional analysis of isolated astrocytes from young and aged Bmal1 aKO mice indicates broad dysregulation of pathways involved in lysosome function which occur independently of TFEB activation. Since a clear link has been established between neurodegeneration and endolysosome dysfunction over the course of aging, this work implicates BMAL1 as a key regulator of these crucial astrocyte functions in health and disease.
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Affiliation(s)
- Celia A. McKee
- Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO63110
- Center on Biological Rhythms and Sleep, Washington University School of Medicine in St. Louis, St. Louis, MO63110
| | - Alexander J. Polino
- Department of Cell Biology and Physiology, Washington University School of Medicine in St. Louis, St. Louis, MO63110
| | - Melvin W. King
- Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO63110
- Center on Biological Rhythms and Sleep, Washington University School of Medicine in St. Louis, St. Louis, MO63110
| | - Erik S. Musiek
- Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO63110
- Center on Biological Rhythms and Sleep, Washington University School of Medicine in St. Louis, St. Louis, MO63110
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25
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Long Y, Wang H, Ma Z, Li Y, Ma Z, Yu P, Tang X, Liu R. Combined Epimedii Folium and Ligustri Lucidi Fructus with dexamethasone alleviate the proliferation of airway smooth muscle cells by regulating apoptosis/autophagy. JOURNAL OF ETHNOPHARMACOLOGY 2023; 314:116547. [PMID: 37178983 DOI: 10.1016/j.jep.2023.116547] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/18/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese medicine (TCM) theory believes kidney deficiency is the root cause of chronic refractory asthma with pathological changes of airway remodeling. Our previous experiments confirmed that the combination of Epimedii Folium and Ligustri Lucidi Fructus (ELL) with the effect of nourishing Yin and Yang of the kidney could improve the pathological changes of airway remodeling in asthmatic rats, but the specific mechanism remains unclear. AIM OF THE STUDY This research was designed to reveal the synergy of ELL and dexamethasone (Dex) in the proliferation, apoptosis, and autophagy of airway smooth muscle cells (ASMCs). MATERIALS AND METHODS Primary cultures of ASMCs from rats were prepared and induced with histamine (Hist), Z-DEVD-FMK (ZDF), rapamycin (Rap), or 3-Methyladenine (3-MA) at generation 3-7 for 24 or 48 h. Subsequently, the cells were treated with Dex, ELL, and ELL&Dex for 24 or 48 h. The effect of various concentrations of inducers and drugs on cell viability was detected by Methyl Thiazolyl Tetrazolium (MTT) assay, cell proliferation was tested using immunocytochemistry (ICC) by detecting Ki67 protein, cell apoptosis was measured by Annexin V-FITC/PI assay and Hoechst nuclear staining, cell ultrastructure was observed by transmission electron microscopy (TEM), and immunofluorescence (IF), western blot (WB) combined with quantitative real-time PCR (qPCR) were used for measuring autophagy and apoptosis-related genes including protein 53 (P53), cysteinyl aspartate-specific proteinase (Caspase)-3, microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, mammalian target of rapamycin (mTOR) and p-mTOR. RESULTS In ASMCs, Hist and ZDF promoted cell proliferation, significantly decreased Caspase-3 protein expression, and up-regulated Beclin-1 levels; Dex alone and in combination with ELL promoted Beclin-1, Caspase-3, and P53 expression, enhancing autophagy activity and apoptosis in Hist and ZDF-induced AMSCs. In contrast, Rap inhibited cell viability, increased Caspase-3, P53, Beclin-1, and LC3-II/I and decreased the levels of mTOR and p-mTOR with promoting apoptosis and autophagy; ELL or ELL&Dex reduced P53, Beclin-1, and LC3-II/I to down-regulate apoptosis and the excessive autophagic state of ASMCs induced by Rap. In the 3-MA model, cell viability and autophagy were reduced; ELL&Dex significantly upgraded the expression of Beclin-1, P53, and Caspase-3 and promoted apoptosis and autophagy of ASMCs. CONCLUSIONS These results suggest that ELL combined with Dex may regulate the proliferation of ASMCs by promoting apoptosis and autophagy and be a potential medicine for the treatment of asthma.
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Affiliation(s)
- Yuting Long
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Han Wang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Zitong Ma
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Yuman Li
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Zaina Ma
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Ping Yu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Xiufeng Tang
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250000, China
| | - Renhui Liu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China; Beijing Key Lab of Traditional Chinese Medicine Collateral Disease Theory Research, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069, China.
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26
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Tan Y, Li C, Zhou J, Deng F, Liu Y. Berberine attenuates liver fibrosis by autophagy inhibition triggering apoptosis via the miR-30a-5p/ATG5 axis. Exp Cell Res 2023; 427:113600. [PMID: 37062521 DOI: 10.1016/j.yexcr.2023.113600] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 03/03/2023] [Accepted: 04/09/2023] [Indexed: 04/18/2023]
Abstract
Berberine (BBR) is an effective drug against liver fibrosis (LF). Autophagy is involved in the pathogenesis of LF; however, the mechanism linking BBR to autophagy in LF remains unresolved. To explore the underlying mechanism, we assessed the effects of BBR on autophagy and apoptosis of activated hepatic stellate cells (HSCs) in vitro and in a murine model of fibrosis. The decreased expression of the autophagy activation marker ATG5, autophagosome formation, and autophagy flux in the HSC model confirmed that BBR inhibited autophagy in activated HSCs and in mice with liver fibrosis. Moreover, ATG5 was necessary for inducing autophagy and HSC activation. BBR suppressed ATG5 expression by upregulating miR-30a-5p expression, which affected the stability of ATG5 mRNA by binding to its 3'-untranslated region, an effect that was attenuated by treatment with a miR-30a-5p inhibitor. BBR also markedly induced HSC apoptosis, as indicated by the upregulated expression of the pro-apoptosis markers p53, BAX, and cleaved PARP and the downregulated expression of the anti-apoptosis marker BCL-2, effects that were reversed by ATG5 overexpression. In vivo, BBR improved mouse LF by decreasing collagen deposition, inflammatory cell infiltration, and expression of fibrosis markers hydroxyproline, α-smooth muscle actin, and collagen type 1-A1 and the autophagy marker LC3. BBR had a protective effect on mouse fibrotic livers and reduced serum aspartate aminotransferase and alanine aminotransferase levels. Collectively, these results reveal a novel mechanism of BBR-induced autophagy inhibition triggering apoptosis in HSCs, providing a reliable experimental and theoretical basis for developing BBR-based candidate drugs for LF.
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Affiliation(s)
- Yuehao Tan
- Sichuan Nursing Vocational College, Chengdu, 610100, China
| | - Can Li
- Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China
| | - Jiali Zhou
- Sichuan Nursing Vocational College, Chengdu, 610100, China
| | - Fengmei Deng
- School of Basic Medical Science, Chengdu Medical College, Chengdu, 610500, China.
| | - Yilun Liu
- Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China; People's Hospital of Mingshan District, Ya'an, Sichuan, 625100, China.
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27
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Tamburello M, Abate A, Rossini E, Basnet RM, Zizioli D, Cosentini D, Hantel C, Laganà M, Tiberio GAM, Grisanti S, Memo M, Berruti A, Sigala S. Preclinical Evidence of Progesterone as a New Pharmacological Strategy in Human Adrenocortical Carcinoma Cell Lines. Int J Mol Sci 2023; 24:6829. [PMID: 37047801 PMCID: PMC10095539 DOI: 10.3390/ijms24076829] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND Adrenocortical cancer (ACC) is a rare malignancy with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, and cisplatin). However, new therapeutic approaches for advanced ACC are needed, particularly targeting the metastatic process. Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers. METHODS NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry. RESULTS Progesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells. CONCLUSION Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study.
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Affiliation(s)
- Mariangela Tamburello
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Andrea Abate
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Elisa Rossini
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Ram Manohar Basnet
- Section of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Daniela Zizioli
- Section of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Deborah Cosentini
- Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Constanze Hantel
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), 8091 Zürich, Switzerland
- Medizinische Klinik und Poliklinik III, University Hospital Carl Gustav Carus Dresden, 01307 Dresden, Germany
| | - Marta Laganà
- Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Guido Alberto Massimo Tiberio
- Surgical Clinic, Department of Clinical and Experimental Sciences, University of Brescia at ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Salvatore Grisanti
- Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Maurizio Memo
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Alfredo Berruti
- Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Sandra Sigala
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
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28
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Hydrogel encapsulation as a handling and vitrification tool for zebrafish ovarian tissue. Theriogenology 2023; 198:153-163. [PMID: 36586353 DOI: 10.1016/j.theriogenology.2022.12.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 12/10/2022] [Accepted: 12/11/2022] [Indexed: 12/25/2022]
Abstract
Zebrafish is an important animal model, thousands lines have been developed, thus having a great need for their preservation. However, the cryopreservation of fish oocytes is still limited and needs improvement. The sodium alginate hydrogel, in addition to providing support for the cells, has been shown to be a potential cryoprotectant. Therefore, the aim of this study was to evaluate the sodium alginate hydrogel encapsulation technique efficiency during zebrafish ovarian tissue vitrification. The encapsulation methodology was standardized in the first experiment. In Experiment 2, we evaluated four vitrified groups: standard protocol without encapsulation (VS); encapsulated with cryoprotectants (VS1-A); encapsulated with half the cryoprotectants concentration (VS2-A); encapsulated without cryoprotectants (VA). VS treatment (54.6 ± 12.3%; 23.7 ± 9.9%; 12.6 ± 5.0%) did not differ from the VS1-A and VA showed a lower membrane integrity percentage (1.2 ± 1.4%; 0.3 ± 0.6%; 0.5 ± 1.5%). Mitochondrial activity was significantly greater in non-encapsulated treatment (VS) when compared to the encapsulated treatments. VS1-A and VS obtained the lowest lipid peroxidation (39.4 ± 4.4 and 40.5 ± 3.3 nmol MDA/mg respectively) in which VS was not significantly different from the VS2-A treatment (63.6 ± 3.1 nmol MDA/mg), unlike, VA obtained the highest lipid peroxidation level (124.7 ± 7.9 nmol MDA/mg). The results obtained in this study demonstrate that the sodium alginate hydrogel encapsulation technique did not have a cryoprotective action, but maintained the membrane integrity when used the standard concentration of cryoprotectants. However, halving the cryoprotectant concentration of fragments encapsulated in alginate hydrogel did not cause an increase in lipid peroxidation. In addition, it provided support and prevented the oocytes from loosening from the tissue during the vitrification process, being an interesting alternative for later in vitro maturation.
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Choi JA, Lee EH, Cho H, Kim JH. High-Dose Selenium Induces Ferroptotic Cell Death in Ovarian Cancer. Int J Mol Sci 2023; 24:ijms24031918. [PMID: 36768241 PMCID: PMC9915545 DOI: 10.3390/ijms24031918] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/06/2023] [Accepted: 01/11/2023] [Indexed: 01/21/2023] Open
Abstract
Selenium is a promising multi-target chemotherapeutic agent with controversial clinical results. Hence, reassessing the anticancer effects of Se is necessary to clearly understand the potential of high-dose selenium in cancer treatment. Here, we observed that high-dose sodium selenite (SS) significantly decreased the proliferation and increased the death of ovarian cancer cells, mediated by an increased generation of reactive oxygen species. Notably, high-dose SS decreased the levels of glutathione peroxidase (GPx), a selenoprotein with antioxidant properties, without altering other selenoproteins. Furthermore, high-dose SS triggered lipid peroxidation and ferroptosis, a type of iron-dependent cell death, due to dysregulated GPx4 pathways. We demonstrated that intravenous high-dose SS significantly reduced the tumor growth and weight in SKOV3-bearing mice. Consistent with our in vitro results, mice with SKOV3 cells treated with high-dose SS showed decreased GPx4 expression in tumors. Therefore, we highlight the significance of high-dose SS as a potential chemotherapeutic agent for ovarian cancer. High-dose SS-mediated ferroptotic therapy integrating glutathione depletion and ROS generation is a promising strategy for cancer therapy.
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Monterrubio-Ledezma F, Navarro-García F, Massieu L, Mondragón-Flores R, Soto-Ponce LA, Magaña JJ, Cisneros B. Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1. Cells 2023; 12:275. [PMID: 36672210 PMCID: PMC9856861 DOI: 10.3390/cells12020275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/14/2022] [Accepted: 12/28/2022] [Indexed: 01/12/2023] Open
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by the expression of progerin, a mutant variant of Lamin A. Recently, HGPS studies have gained relevance because unraveling its underlying mechanism would help to understand physiological aging. We previously reported that the CRM1-mediated nuclear protein export pathway is exacerbated in HGPS cells, provoking the mislocalization of numerous protein targets of CRM1. We showed that normalization of this mechanism by pharmacologically inhibiting CRM1 with LMB (specific CRM1 inhibitor), mitigates the senescent phenotype of HGPS cells. Since mitochondrial dysfunction is a hallmark of HGPS, in this study we analyze the effect of LMB on mitochondrial function. Remarkably, LMB treatment induced the recovery of mitochondrial function in HGPS cells, as shown by the improvement in mitochondrial morphology, mitochondrial membrane potential, and ATP levels, which consequently impeded the accumulation of ROS but not mitochondrial superoxide. We provide evidence that the beneficial effect of LMB is mechanistically based on a combinatory effect on mitochondrial biogenesis via upregulation of PGC-1α expression (master transcription cofactor of mitochondrial genes), and mitophagy through the recovery of lysosomal content. The use of exportin CRM1 inhibitors constitutes a promising strategy to treat HGPS and other diseases characterized by mitochondrial impairment.
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Affiliation(s)
- Feliciano Monterrubio-Ledezma
- Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City 07360, Mexico
| | - Fernando Navarro-García
- Department of Cell Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City 07360, Mexico
| | - Lourdes Massieu
- Department of Neuropathology, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico City 04510, Mexico
| | - Ricardo Mondragón-Flores
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City 07360, Mexico
| | - Luz Adriana Soto-Ponce
- Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City 07360, Mexico
| | - Jonathan J. Magaña
- Departament of Bioengineering, Escuela de Ingeniería y Ciencias, Tecnológico de Monterrey-Campus Ciudad de México, Ciudad de Mexico 14380, Mexico
- Laboratory of Genomic Medicine, Department of Genetics, National Rehabilitation Institute-Luis Guillermo Ibarra Ibarra (INR-LGII), Mexico City 14389, Mexico
| | - Bulmaro Cisneros
- Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City 07360, Mexico
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Plini ERG, Melnychuk MC, Harkin A, Dahl MJ, McAuslan M, Kühn S, Boyle RT, Whelan R, Andrews R, Düzel S, Drewelies J, Wagner GG, Lindenberger U, Norman K, Robertson IH, Dockree PM. Dietary Tyrosine Intake (FFQ) Is Associated with Locus Coeruleus, Attention and Grey Matter Maintenance: An MRI Structural Study on 398 Healthy Individuals of the Berlin Aging Study-II. J Nutr Health Aging 2023; 27:1174-1187. [PMID: 38151868 DOI: 10.1007/s12603-023-2005-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/19/2023] [Indexed: 12/29/2023]
Abstract
BACKGROUND AND OBJECTIVE It is documented that low protein and amino-acid dietary intake is related to poorer cognitive health and increased risk of dementia. Degradation of the neuromodulatory pathways, (comprising the cholinergic, dopaminergic, serotoninergic and noradrenergic systems) is observed in neurodegenerative diseases and impairs the proper biosynthesis of key neuromodulators from micro-nutrients and amino acids. How these micro-nutrients are linked to neuromodulatory pathways in healthy adults is less studied. The Locus Coeruleus-Noradrenergic System (LC-NA) is the earliest subcortical structure affected in Alzheimer's disease, showing marked neurodegeneration, but is also sensitive for age-related changes. The LC-NA system is critical for supporting attention and cognitive control, functions that are enhanced both by tyrosine administration and chronic tyrosine intake. The purpose of this study was to 1) investigate whether the dietary intake of tyrosine, the key precursor for noradrenaline (NA), is related to LC signal intensity 2) whether LC mediates the reported association between tyrosine intake and higher cognitive performance (measured with Trail Making Test - TMT), and 3) whether LC signal intensity relates to an objective measure of brain maintenance (BrainPAD). METHODS The analyses included 398 3T MRIs of healthy participants from the Berlin Aging Study II to investigate the relationship between LC signal intensity and habitual dietary tyrosine intake-daily average (HD-Tyr-IDA - measured with Food Frequency Questionnaire - FFQ). As a control procedure, the same analyses were repeated on other main seeds of the neuromodulators' subcortical system (Dorsal and Medial Raphe, Ventral Tegmental Area and Nucleus Basalis of Meynert). In the same way, the relationships between the five nuclei and BrainPAD were tested. RESULTS Results show that HD-Tyr-IDA is positively associated with LC signal intensity. Similarly, LC disproportionally relates to better brain maintenance (BrainPAD). Mediation analyses reveal that only LC, relative to the other nuclei tested, mediates the relationship between HD-Tyr-IDA I and performance in the TMT and between HD-Tyr-IDA and BrainPAD. CONCLUSIONS These findings provide the first evidence linking tyrosine intake with LC-NA system signal intensity and its correlation with neuropsychological performance. This study strengthens the role of diet for maintaining brain and cognitive health and supports the noradrenergic theory of cognitive reserve. Within this framework, adequate tyrosine intake might increase the resilience of LC-NA system functioning, by preventing degeneration and supporting noradrenergic metabolism required for LC function and neuropsychological performance.
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Affiliation(s)
- E R G Plini
- Emanuele RG Plini, Department of Psychology, Trinity College Institute of Neuroscience, Trinity College Dublin, Lloyd Building, 42A Pearse St, 8PVX+GJ Dublin, Ireland,
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Liu C, Li N, Peng M, Huang K, Fan D, Zhao Z, Huang X, Liu Y, Chen S, Li Z. Celastrol directly binds with VAMP7 and RAB7 to inhibit autophagy and induce apoptosis in preadipocytes. Front Pharmacol 2023; 14:1094584. [PMID: 36959859 PMCID: PMC10027750 DOI: 10.3389/fphar.2023.1094584] [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: 11/10/2022] [Accepted: 02/22/2023] [Indexed: 03/09/2023] Open
Abstract
Obesity is one of the most prevalent chronic metabolic diseases, and induction of apoptosis in preadipocytes and adipocytes is a potential strategy to treat obesity. Celastrol represents one of the most robust anti-obesity phytochemicals so far, yet its direct binding target remains elusive. Here, we determined that celastrol could induce apoptosis in preadipocytes via mitochondrial mediated pathway. Further study clarified that celastrol inhibited the fusion of autophagosome and lysosome to prohibit autophagy, leading to cell apoptosis. By conducting virtual screening and genetic manipulation, we verified that overexpression of VAMP7 and RAB7 could block the effects of celastrol on inhibiting autophagy and inducing apoptosis. The Surface Plasmon Resonance study confirmed the direct binding of celastrol with VAMP7 and RAB7. The functional study illustrated the inhibition of RAB7 GTPase activity after celastrol treatment. Moreover, celastrol induced comparable apoptosis in murine epididymal adipose tissue, human preadipocytes and adipocytes, but not in human hepatocytes. An inhibitory effect on differentiation of human primary visceral preadipocytes was also observed. In conclusion, celastrol exhibited inhibitory effect of autophagy via direct binding with VAMP7 and RAB7, leading to an increase in preadipocytes apoptosis. These results advance our understanding in the potential application of celastrol in treating obesity.
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Affiliation(s)
- Chenshu Liu
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Na Li
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Meixiu Peng
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Kan Huang
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Dongxiao Fan
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhengde Zhao
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiuyi Huang
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yunchong Liu
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Sifan Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, China
- *Correspondence: Sifan Chen, ; Zilun Li,
| | - Zilun Li
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- *Correspondence: Sifan Chen, ; Zilun Li,
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Chaudhry N, Sica M, Surabhi S, Hernandez DS, Mesquita A, Selimovic A, Riaz A, Lescat L, Bai H, MacIntosh GC, Jenny A. Lamp1 mediates lipid transport, but is dispensable for autophagy in Drosophila. Autophagy 2022; 18:2443-2458. [PMID: 35266854 PMCID: PMC9542896 DOI: 10.1080/15548627.2022.2038999] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 01/31/2022] [Accepted: 02/03/2022] [Indexed: 01/03/2023] Open
Abstract
The endolysosomal system not only is an integral part of the cellular catabolic machinery that processes and recycles nutrients for synthesis of biomaterials, but also acts as signaling hub to sense and coordinate the energy state of cells with growth and differentiation. Lysosomal dysfunction adversely influences vesicular transport-dependent macromolecular degradation and thus causes serious problems for human health. In mammalian cells, loss of the lysosome associated membrane proteins LAMP1 and LAMP2 strongly affects autophagy and cholesterol trafficking. Here we show that the previously uncharacterized Drosophila Lamp1 is a bona fide ortholog of vertebrate LAMP1 and LAMP2. Surprisingly and in contrast to lamp1 lamp2 double-mutant mice, Drosophila Lamp1 is not required for viability or autophagy, suggesting that fly and vertebrate LAMP proteins acquired distinct functions, or that autophagy defects in lamp1 lamp2 mutants may have indirect causes. However, Lamp1 deficiency results in an increase in the number of acidic organelles in flies. Furthermore, we find that Lamp1 mutant larvae have defects in lipid metabolism as they show elevated levels of sterols and diacylglycerols (DAGs). Because DAGs are the main lipid species used for transport through the hemolymph (blood) in insects, our results indicate broader functions of Lamp1 in lipid transport. Our findings make Drosophila an ideal model to study the role of LAMP proteins in lipid assimilation without the confounding effects of their storage and without interfering with autophagic processes.Abbreviations: aa: amino acid; AL: autolysosome; AP: autophagosome; APGL: autophagolysosome; AV: autophagic vacuole (i.e. AP and APGL/AL); AVi: early/initial autophagic vacuoles; AVd: late/degradative autophagic vacuoles; Atg: autophagy-related; CMA: chaperone-mediated autophagy; Cnx99A: Calnexin 99A; DAG: diacylglycerol; eMI: endosomal microautophagy; ESCRT: endosomal sorting complexes required for transport; FB: fat body; HDL: high-density lipoprotein; Hrs: Hepatocyte growth factor regulated tyrosine kinase substrate; LAMP: lysosomal associated membrane protein; LD: lipid droplet; LDL: low-density lipoprotein; Lpp: lipophorin; LTP: Lipid transfer particle; LTR: LysoTracker Red; MA: macroautophagy; MCC: Manders colocalization coefficient; MEF: mouse embryonic fibroblast MTORC: mechanistic target of rapamycin kinase complex; PV: parasitophorous vacuole; SNARE: soluble N-ethylmaleimide sensitive factor attachment protein receptor; Snap: Synaptosomal-associated protein; st: starved; TAG: triacylglycerol; TEM: transmission electron microscopy; TFEB/Mitf: transcription factor EB; TM: transmembrane domain; tub: tubulin; UTR: untranslated region.
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Affiliation(s)
- Norin Chaudhry
- Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, USA
| | - Margaux Sica
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, USA
| | - Satya Surabhi
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, USA
| | | | - Ana Mesquita
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, USA
| | - Adem Selimovic
- Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, USA
| | - Ayesha Riaz
- Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, USA
| | - Laury Lescat
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, USA
| | - Hua Bai
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, USA
| | - Gustavo C. MacIntosh
- Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, USA
| | - Andreas Jenny
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, USA
- Department of Genetics, Albert Einstein College of MedicineNew York, NY, USA
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Sifaoui I, Díaz-Rodríguez P, Rodríguez-Expósito RL, Reyes-Batlle M, Lopez-Arencibia A, Salazar Villatoro L, Castelan-Ramírez I, Omaña-Molina M, Oliva A, Piñero JE, Lorenzo-Morales J. Pitavastatin loaded nanoparticles: a suitable ophthalmic treatment for Acanthamoeba Keratitis inducing cell death and autophagy in Acanthamoeba polyphaga. Eur J Pharm Biopharm 2022; 180:11-22. [PMID: 36162636 DOI: 10.1016/j.ejpb.2022.09.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 09/14/2022] [Accepted: 09/19/2022] [Indexed: 11/25/2022]
Abstract
Statins are effective sterol lowering agents with high amoebicidal activity. Nevertheless, due to their poor aqueous solubility, they remain underused especially in eye drop formulation. The aim of the present study is to develop Pitavastatin loaded nanoparticles suitable for ophthalmic administration and designed for the management of Acanthamoeba Keratitis. These nanocarriers are aimed to solve both the ophthalmic route-associated problems and the limited aqueous drug solubility issues of Pitavastatin. Nanoparticles were obtained by a nanoprecipitation-solvent displacement method and their amoebicidal activity was evaluated against four strains of Acanthamoeba: A. castellanii Neff, A. polyphaga, A. griffini and A. quina. In Acanthamoeba polyphaga, the effect of the present nanoparticles was investigated with respect to the microtubule distribution and several programmed cell death features. Nanoparticles were able to eliminate all the tested strains and Acanthamoeba polyphaga was determined to be the most resistance strain. Nanoparticles induced chromatin condensation, autophagic vacuoles and mitochondria dysfunction.
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Affiliation(s)
- Ines Sifaoui
- Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), Tenerife, 38206, Spain; Departamento de Obstetricia, Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Universidad De La Laguna, La Laguna, Tenerife, 38203 Islas Canarias, Spain; Red de Investigación Cooperativa en Enfermedades Tropicales (RICET)
| | - Patricia Díaz-Rodríguez
- Institute of Biomedical Technologies (ITB), Universidad de La Laguna, 38320 La Laguna, Spain; Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Rubén L Rodríguez-Expósito
- Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), Tenerife, 38206, Spain; Departamento de Obstetricia, Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Universidad De La Laguna, La Laguna, Tenerife, 38203 Islas Canarias, Spain; Red de Investigación Cooperativa en Enfermedades Tropicales (RICET)
| | - María Reyes-Batlle
- Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), Tenerife, 38206, Spain; Departamento de Obstetricia, Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Universidad De La Laguna, La Laguna, Tenerife, 38203 Islas Canarias, Spain; Red de Investigación Cooperativa en Enfermedades Tropicales (RICET)
| | - Atteneri Lopez-Arencibia
- Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), Tenerife, 38206, Spain; Departamento de Obstetricia, Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Universidad De La Laguna, La Laguna, Tenerife, 38203 Islas Canarias, Spain; Red de Investigación Cooperativa en Enfermedades Tropicales (RICET)
| | - Lizbeth Salazar Villatoro
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del IPN, 07360, Ciudad de México, México
| | - Ismael Castelan-Ramírez
- Facultad de Estudios Superiores Iztacala, Medicina, UNAM, Tlalnepantla, 54090, Estado de México, México
| | - Maritza Omaña-Molina
- Department of Chemical Engineering and Pharmaceutical Technology, Universidad de La Laguna, 38206 La Laguna, Spain
| | - Alexis Oliva
- Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), Tenerife, 38206, Spain; Department of Chemical Engineering and Pharmaceutical Technology, Universidad de La Laguna, 38206 La Laguna, Spain
| | - José E Piñero
- Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), Tenerife, 38206, Spain; Departamento de Obstetricia, Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Universidad De La Laguna, La Laguna, Tenerife, 38203 Islas Canarias, Spain; Red de Investigación Cooperativa en Enfermedades Tropicales (RICET); CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain.
| | - Jacob Lorenzo-Morales
- Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), Tenerife, 38206, Spain; Departamento de Obstetricia, Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Universidad De La Laguna, La Laguna, Tenerife, 38203 Islas Canarias, Spain; Red de Investigación Cooperativa en Enfermedades Tropicales (RICET); CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
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Önder GÖ, Sezer G, Özdamar S, Yay A. Melatonin has an inhibitory effect on MCF‐7 and MDA‐MB‐231 human breast cancer cell lines by inducing autophagy and apoptosis. Fundam Clin Pharmacol 2022; 36:1038-1056. [DOI: 10.1111/fcp.12813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/07/2022] [Accepted: 06/30/2022] [Indexed: 12/19/2022]
Affiliation(s)
- Gözde Özge Önder
- Faculty of Medicine, Department of Histology and Embryology Erciyes University Kayseri Turkey
- Genome and Stem Cell Center Erciyes University Kayseri Turkey
| | - Gülay Sezer
- Genome and Stem Cell Center Erciyes University Kayseri Turkey
- Faculty of Medicine, Department of Pharmacology Erciyes University Kayseri Turkey
| | - Saim Özdamar
- Faculty of Medicine, Department of Histology and Embryology Pamukkale University Denizli Turkey
| | - Arzu Yay
- Faculty of Medicine, Department of Histology and Embryology Erciyes University Kayseri Turkey
- Genome and Stem Cell Center Erciyes University Kayseri Turkey
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Four-octyl itaconate improves osteoarthritis by enhancing autophagy in chondrocytes via PI3K/AKT/mTOR signalling pathway inhibition. Commun Biol 2022; 5:641. [PMID: 35768581 PMCID: PMC9242998 DOI: 10.1038/s42003-022-03592-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 06/15/2022] [Indexed: 12/15/2022] Open
Abstract
Osteoarthritis (OA) is a highly prevalent and chronic disorder that is associated with a substantial social and economic burden. Itaconate, as an important regulator of cellular inflammation, is a metabolite synthesised by an enzyme encoded by immune-responsive gene 1. However, there are few studys regarding the effects of itaconate on OA. Here, we show the effect of the cell-permeable itaconate derivative 4-octyl itaconate (OI) on OA. OI attenuates the chondrocyte apoptosis induced by interleukin 1β (IL-1β) in vitro, indicating that OI protect chondrocytes against apoptosis. Moreover, OI ameliorates the chondrocyte autophagy inhibition induced by IL-1β via the inhibition of PI3K/AKT/mTOR signalling pathway. Finally, OI enhances autophagy and reduces cartilage degradation in a rat model of OA established by destabilization of medial meniscus (DMM). In summary, our findings reveal that OI is involved in regulating the progression of OA. The above results shed light on the treatment of OA. 4-octyl itaconate (OI) attenuates chondrocyte apoptosis and ameliorates cartilage degradation and defection of autophagy induced by IL-1 β via the PI3K/AKT/mTOR pathway. OI improved the autophagy and reduced the inflammation of rat models of osteoarthritis.
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Evaluation of Apoptosis and Autophagy Activities in the Brain of Dogs Naturally Infected with Canine Distemper Virus Based on Changes in Apoptotic and Autophagic Markers. ACTA VET-BEOGRAD 2022. [DOI: 10.2478/acve-2022-0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
This study investig ated the activation of apoptosis and autophagy in CDV infected brain tissues of dogs with acute neurological signs, by determining Cas-3, Cas-8, Cas-9, Bax, Bcl-2, LC3B, and Beclin-1 expression with real-time PCR. The expression levels of Beclin-1 and LC3B, autophagy markers, were significantly up-regulated in comparison with the control group (p < 0.001). The expression levels of apoptotic markers Cas-3, Cas-8, Cas-9 and Bax were slightly up-regulated, but Bcl-2 was slightly down-regulated in contrast to the control group (p < 0.05). Therefore, the autophagy markers were more activated than apoptotic markers in dogs with acute neurological signs. In conclusion, autophagy takes part in the pathogenesis of demyelination in canine distemper. Knowing this may be helpful to create new therapeutic strategies, such as new effective antiviral medicines.
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Diclofenac: A Nonsteroidal Anti-Inflammatory Drug Inducing Cancer Cell Death by Inhibiting Microtubule Polymerization and Autophagy Flux. Antioxidants (Basel) 2022; 11:antiox11051009. [PMID: 35624874 PMCID: PMC9138099 DOI: 10.3390/antiox11051009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 05/15/2022] [Accepted: 05/19/2022] [Indexed: 12/12/2022] Open
Abstract
Diclofenac, a nonsteroidal anti-inflammatory drug (NSAID) used to treat inflammatory diseases induces cellular toxicity by increasing the production of reactive oxygen species (ROS) and impairing autophagic flux. In this study, we investigated whether diclofenac induces cancer cell death and the mechanism by which diclofenac causes cell death. We observed that diclofenac induces mitotic arrest with a half-maximal effective concentration of 170 μM and cell death with a half-maximal lethal dose of 200 µM during 18-h incubation in HeLa cells. Cellular microtubule imaging and in vitro tubulin polymerization assays demonstrated that treatment with diclofenac elicits microtubule destabilization. Autophagy relies on microtubule-mediated transport and the fusion of autophagic vesicles. We observed that diclofenac inhibits both phagophore movement, an early step of autophagy, and the fusion of autophagosomes and lysosomes, a late step of autophagy. Diclofenac also induces the fragmentation of mitochondria and the Golgi during cell death. We found that diclofenac induces cell death further in combination with 5-fuorouracil, a DNA replication inhibitor than in single treatment in cancer cells. Pancreatic cancer cells, which have high basal autophagy, are particularly sensitive to cell death by diclofenac. Our study suggests that microtubule destabilization by diclofenac induces cancer cell death via compromised spindle assembly checkpoints and increased ROS through impaired autophagy flux. Diclofenac may be a candidate therapeutic drug in certain type of cancers by inhibiting microtubule-mediated cellular events in combination with clinically utilized nucleoside metabolic inhibitors, including 5-fluorouracil, to block cancer cell proliferation.
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Carneiro LS, Martinez LC, Oliveira AHD, Cossolin JFS, Resende MTCSD, Gonçalves WG, Medeiros-Santana L, Serrão JE. Acute oral exposure to imidacloprid induces apoptosis and autophagy in the midgut of honey bee Apis mellifera workers. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 815:152847. [PMID: 34995599 DOI: 10.1016/j.scitotenv.2021.152847] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/19/2021] [Accepted: 12/28/2021] [Indexed: 06/14/2023]
Abstract
The honey bee Apis mellifera is an important pollinator that increases the yield and quality of crops. In recent years, honey bee populations have declined in some parts of the world, which has been associated with several causes, including pesticides used in agriculture. Neonicotinoids are neurotoxic insecticides widely used in the world with systemic action mode contaminating nectar and pollen that may be consumed by bees. This study evaluated the side effects of imidacloprid in the midgut of A. mellifera after acute oral exposure. Toxicity, histopathology, cytotoxicity, and expression of autophagy-related gene atg1 were evaluated in honey bee workers orally exposed to imidacloprid. The estimated imidacloprid LC50 was 1.44 mg L-1. The midgut epithelium of bees fed on imidacloprid LC50 has the occurrence of cytoplasm vacuoles, enlarged intercellular spaces, disorganization of the striated border, and nuclear pyknosis, with an organ injury index that increases with time exposure. The midgut digestive cells of treated bees have apical protrusions, damaged mitochondria, and autophagosomes that were characterized for content with organelle debris and high expression of atg1. These features indicate the occurrence of high cell death in the midgut of workers exposed to imidacloprid, which may affect the digestibility the physiology of the insect.
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Affiliation(s)
- Lenise Silva Carneiro
- Departamento de Biologia Geral, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
| | - Luis Carlos Martinez
- Departamento de Biologia Geral, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
| | | | | | | | - Wagner Gonzanga Gonçalves
- Departamento de Biologia Geral, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
| | - Luanda Medeiros-Santana
- Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Viçosa - campus Rio Paranaíba, Rio Paranaíba, Minas Gerais 38810-00, Brazil
| | - José Eduardo Serrão
- Departamento de Biologia Geral, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil.
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Tran PX, Inoue J, Harada H, Inazawa J. Potential for reversing miR-634-mediated cytoprotective processes to improve efficacy of chemotherapy against oral squamous cell carcinoma. Mol Ther Oncolytics 2022; 24:897-908. [PMID: 35571376 PMCID: PMC9073396 DOI: 10.1016/j.omto.2022.02.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 02/11/2022] [Indexed: 01/04/2023] Open
Abstract
For advanced oral squamous cell carcinoma (OSCC), increasing sensitivity to chemotherapy is a major challenge in improving treatment outcomes, and targeting cytoprotective processes that lead to the chemotherapy resistance of cancer cells may be therapeutically promising. Tumor-suppressive microRNAs (miRNAs) can target multiple cancer-promoting genes concurrently and are thus expected to be useful seeds for cancer therapeutics. We revealed that miR-634-mediated targeting of multiple cytoprotective process-related genes, including cellular inhibitor of apoptosis protein 1 (cIAP1), can effectively increase cisplatin (CDDP)-induced cytotoxicity and overcome CDDP resistance in OSCC cells. The combination of topical treatment with miR-634 ointment and administration of CDDP was synergistically effective against OSCC tumor growth in a xenograft mouse model. Furthermore, the expression of miR-634 target genes is frequently upregulated in primary OSCC tumors. Our study suggests that reversing miR-634-mediated cytoprotective processes activated in cancer cells is a potentially useful strategy to improve CDDP efficacy against advanced OSCC.
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Affiliation(s)
- Phuong Xuan Tran
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.,Department of Oral and Maxillofacial Surgery, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Jun Inoue
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hiroyuki Harada
- Department of Oral and Maxillofacial Surgery, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Johji Inazawa
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.,Bioresource Research Center, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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Kanmani P, Kim H. Probiotics counteract the expression of hepatic profibrotic genes via the attenuation of TGF-β/SMAD signaling and autophagy in hepatic stellate cells. PLoS One 2022; 17:e0262767. [PMID: 35051234 PMCID: PMC8775563 DOI: 10.1371/journal.pone.0262767] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 01/04/2022] [Indexed: 12/19/2022] Open
Abstract
Hepatic fibrosis is caused by the increased accumulation and improper degradation of extracellular matrix (ECM) proteins in the liver. Hepatic stellate cells (HSCs) activation is a key process in initiating hepatic fibrosis and can be ameliorated by the administration of probiotic strains. This study hypothesized that LAB strains (Lactiplantibacillus plantarum, Lactobacillus brevis, and Weissella cibaria) might attenuate pro-fibrogenic cytokine TGF-β mediated HSCs activation and induce collagen deposition, expression of other fibrogenic/inflammatory markers, autophagy, and apoptotic processes in vitro. Few studies have evaluated the probiotic effects against fibrogenesis in vitro. In this study, TGF-β exposure increased collagen deposition in LX-2 cells, but this increase was diminished when the cells were pretreated with LAB strains before TGF-β stimulation. TGF-β not only increased collagen deposition, but it also significantly upregulated the mRNA levels of Col1A1, alpha-smooth muscle actin (α-SMA), matrix metalloproteinases-2 (MMP-2), IL-6, CXCL-8, CCL2, and IL-1β in LX-2 cells. Pretreatment of the cells with LAB strains counteracted the TGF-β-induced pro-fibrogenic and inflammatory markers by modulating SMAD-dependent and SMAD-independent TGF-β signaling. In addition, LX-2 cells exposed to TGF-β induced the autophagic and apoptotic associated proteins that were also positively regulated by the LAB strains. These findings suggest that LAB can attenuate TGF-β signaling that is associated with liver fibrogenesis.
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Affiliation(s)
- Paulraj Kanmani
- Department of Korean Medicine, Dongguk University, Goyang, Republic of Korea
- Department of Medicine, University of Illinois, Chicago, Illinois, United States of America
| | - Hojun Kim
- Department of Korean Medicine, Dongguk University, Goyang, Republic of Korea
- * E-mail:
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The Anticancer Ruthenium Compound BOLD-100 Targets Glycolysis and Generates a Metabolic Vulnerability towards Glucose Deprivation. Pharmaceutics 2022; 14:pharmaceutics14020238. [PMID: 35213972 PMCID: PMC8875291 DOI: 10.3390/pharmaceutics14020238] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 12/13/2022] Open
Abstract
Cellular energy metabolism is reprogrammed in cancer to fuel proliferation. In oncological therapy, treatment resistance remains an obstacle and is frequently linked to metabolic perturbations. Identifying metabolic changes as vulnerabilities opens up novel approaches for the prevention or targeting of acquired therapy resistance. Insights into metabolic alterations underlying ruthenium-based chemotherapy resistance remain widely elusive. In this study, colon cancer HCT116 and pancreatic cancer Capan-1 cells were selected for resistance against the clinically evaluated ruthenium complex sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (BOLD-100). Gene expression profiling identified transcriptional deregulation of carbohydrate metabolism as a response to BOLD-100 and in resistance against the drug. Mechanistically, acquired BOLD-100 resistance is linked to elevated glucose uptake and an increased lysosomal compartment, based on a defect in downstream autophagy execution. Congruently, metabolomics suggested stronger glycolytic activity, in agreement with the distinct hypersensitivity of BOLD-100-resistant cells to 2-deoxy-d-glucose (2-DG). In resistant cells, 2-DG induced stronger metabolic perturbations associated with ER stress induction and cytoplasmic lysosome deregulation. The combination with 2-DG enhanced BOLD-100 activity against HCT116 and Capan-1 cells and reverted acquired BOLD-100 resistance by synergistic cell death induction and autophagy disturbance. This newly identified enhanced glycolytic activity as a metabolic vulnerability in BOLD-100 resistance suggests the targeting of glycolysis as a promising strategy to support BOLD-100 anticancer activity.
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Nguyen PL, Lee CH, Lee H, Cho J. Induction of Paraptotic Cell Death in Breast Cancer Cells by a Novel Pyrazolo[3,4-h]quinoline Derivative through ROS Production and Endoplasmic Reticulum Stress. Antioxidants (Basel) 2022; 11:antiox11010117. [PMID: 35052621 PMCID: PMC8773266 DOI: 10.3390/antiox11010117] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/30/2021] [Accepted: 01/01/2022] [Indexed: 12/16/2022] Open
Abstract
Chemotherapy has been a standard intervention for a variety of cancers to impede tumor growth, mainly by inducing apoptosis. However, development of resistance to this regimen has led to a growing interest and demand for drugs targeting alternative cell death modes, such as paraptosis. Here, we designed and synthesized a novel derivative of a pyrazolo[3,4-h]quinoline scaffold (YRL1091), evaluated its cytotoxic effect, and elucidated the underlying molecular mechanisms of cell death in MDA-MB-231 and MCF-7 breast cancer (BC) cells. We found that YRL1091 induced cytotoxicity in these cells with numerous cytoplasmic vacuoles, one of the distinct characteristics of paraptosis. YRL1091-treated BC cells displayed several other distinguishing features of paraptosis, excluding autophagy or apoptosis. Briefly, YRL1091-induced cell death was associated with upregulation of microtubule-associated protein 1 light chain 3B, downregulation of multifunctional adapter protein Alix, and activation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase. Furthermore, the production of reactive oxygen species (ROS) and newly synthesized proteins were also observed, subsequently causing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress. Collectively, these results indicate that YRL1091 induces paraptosis in BC cells through ROS generation and ER stress. Therefore, YRL1091 can serve as a potential candidate for the development of a novel anticancer drug triggering paraptosis, which may provide benefit for the treatment of cancers resistant to conventional chemotherapy.
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Affiliation(s)
- Phuong Linh Nguyen
- Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea; (P.L.N.); (C.H.L.)
| | - Chang Hoon Lee
- Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea; (P.L.N.); (C.H.L.)
| | - Heesoon Lee
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea;
| | - Jungsook Cho
- Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea; (P.L.N.); (C.H.L.)
- Correspondence:
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Dichloromethane extract of Potentilla fulgens wall. Ex. Sims ameliorates alloxan-induced oxidative stress and inflammatory responses in mice. CLINICAL PHYTOSCIENCE 2021. [DOI: 10.1186/s40816-020-00239-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Guillén-Meléndez GA, Villa-Cedillo SA, Pérez-Hernández RA, Castillo-Velázquez U, Salas-Treviño D, Saucedo-Cárdenas O, Montes-de-Oca-Luna R, Gómez-Tristán CA, Garza-Arredondo AJ, Zamora-Ávila DE, de Jesús Loera-Arias M, Soto-Domínguez A. Cytotoxic Effect In Vitro of Acalypha monostachya Extracts over Human Tumor Cell Lines. PLANTS (BASEL, SWITZERLAND) 2021; 10:plants10112326. [PMID: 34834687 PMCID: PMC8617932 DOI: 10.3390/plants10112326] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 06/13/2023]
Abstract
Acalypha monostachya (A. monostachya) is a plant that is used in traditional medicine as a cancer treatment; however, its effect has not been validated. In this study, the potential cytotoxic effects and morphological changes of A. monostachya were evaluated in human tumor cell lines. The aqueous (AE), methanolic (ME), and hexane (HE) extracts were obtained, and flavonoid-type phenolic compounds were detected, which indicates an antineoplastic effect. We observed a time-dependent and concentration-selective toxicity in human tumor cells. Additionally, the ME and HE showed the greatest cytotoxic effect at minimum concentrations compared to the AE, which showed this effect at the highest concentrations. All extracts induced significant morphological changes in tumor cells. The HeLa (cervix carcinoma) cells were more sensitive compared to the MDA-MB-231 (triple-negative breast cancer) cells. In conclusion, we demonstrated a cytotoxic in vitro effect of A. monostachya extracts in tumoral human cell lines. These results show the potential antineoplastic effects of A. monostachya in vitro. Hereafter, our lab team will continue working to usefully isolate and obtain the specific compounds of A. monostachya extracts with cytotoxic effects on tumor cells to find more alternatives for cancer treatment.
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Affiliation(s)
- Gloria A. Guillén-Meléndez
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey C.P. 64460, NL, Mexico; (G.A.G.-M.); (S.A.V.-C.); (D.S.-T.); (O.S.-C.); (R.M.-d.-O.-L.); (C.A.G.-T.)
| | - Sheila A. Villa-Cedillo
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey C.P. 64460, NL, Mexico; (G.A.G.-M.); (S.A.V.-C.); (D.S.-T.); (O.S.-C.); (R.M.-d.-O.-L.); (C.A.G.-T.)
| | - Raymundo A. Pérez-Hernández
- Departamento de Química, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza C.P. 64455, NL, Mexico;
| | - Uziel Castillo-Velázquez
- Departamento de Inmunología, Facultad de Medicina Veterinaria, Universidad Autónoma de Nuevo León, Escobedo C.P. 66050, NL, Mexico;
| | - Daniel Salas-Treviño
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey C.P. 64460, NL, Mexico; (G.A.G.-M.); (S.A.V.-C.); (D.S.-T.); (O.S.-C.); (R.M.-d.-O.-L.); (C.A.G.-T.)
| | - Odila Saucedo-Cárdenas
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey C.P. 64460, NL, Mexico; (G.A.G.-M.); (S.A.V.-C.); (D.S.-T.); (O.S.-C.); (R.M.-d.-O.-L.); (C.A.G.-T.)
- Departamento de Genética Molecular, Centro de Investigación Biomédica del Noreste (CIBIN) del IMSS, Monterrey C.P. 66720, NL, Mexico
| | - Roberto Montes-de-Oca-Luna
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey C.P. 64460, NL, Mexico; (G.A.G.-M.); (S.A.V.-C.); (D.S.-T.); (O.S.-C.); (R.M.-d.-O.-L.); (C.A.G.-T.)
| | - Christian A. Gómez-Tristán
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey C.P. 64460, NL, Mexico; (G.A.G.-M.); (S.A.V.-C.); (D.S.-T.); (O.S.-C.); (R.M.-d.-O.-L.); (C.A.G.-T.)
| | - Aimé Jazmín Garza-Arredondo
- Departamento de Reproducción, Facultad de Medicina Veterinaria, Universidad Autónoma de Nuevo León, Escobedo C.P. 66050, NL, Mexico;
| | - Diana Elisa Zamora-Ávila
- Departamento de Genética, Facultad de Medicina Veterinaria, Universidad Autónoma de Nuevo León, Escobedo C.P. 66050, NL, Mexico;
| | - María de Jesús Loera-Arias
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey C.P. 64460, NL, Mexico; (G.A.G.-M.); (S.A.V.-C.); (D.S.-T.); (O.S.-C.); (R.M.-d.-O.-L.); (C.A.G.-T.)
| | - Adolfo Soto-Domínguez
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey C.P. 64460, NL, Mexico; (G.A.G.-M.); (S.A.V.-C.); (D.S.-T.); (O.S.-C.); (R.M.-d.-O.-L.); (C.A.G.-T.)
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Kakhlon O, Vaknin H, Mishra K, D’Souza J, Marisat M, Sprecher U, Wald‐Altman S, Dukhovny A, Raviv Y, Da’adoosh B, Engel H, Benhamron S, Nitzan K, Sweetat S, Permyakova A, Mordechai A, Akman HO, Rosenmann H, Lossos A, Tam J, Minassian BA, Weil M. Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism. EMBO Mol Med 2021; 13:e14554. [PMID: 34486811 PMCID: PMC8495453 DOI: 10.15252/emmm.202114554] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 11/09/2022] Open
Abstract
This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan-reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbeys/ys ) APBD mouse model. 144DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic polyglucosan. At the cellular level, 144DG11 increased glycolytic, mitochondrial, and total ATP production. The molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. 144DG11 also enhanced mitochondrial activity and modulated lysosomal features as revealed by bioenergetic, image-based phenotyping and proteomics analyses. As an effective lysosomal targeting therapy in a GSD model, 144DG11 could be developed into a safe and efficacious glycogen and lysosomal storage disease therapy.
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Affiliation(s)
- Or Kakhlon
- Department of NeurologyHadassah‐Hebrew University Medical CenterJerusalemIsrael
| | - Hilla Vaknin
- Laboratory for Neurodegenerative Diseases and Personalized MedicineThe Cell Screening Facility for Personalized MedicineThe Shmunis School of Biomedicine and Cancer ResearchThe George S. Wise Faculty for Life SciencesSagol School of NeurosciencesTel Aviv UniversityTel AvivIsrael
| | - Kumudesh Mishra
- Department of NeurologyHadassah‐Hebrew University Medical CenterJerusalemIsrael
| | - Jeevitha D’Souza
- Laboratory for Neurodegenerative Diseases and Personalized MedicineThe Cell Screening Facility for Personalized MedicineThe Shmunis School of Biomedicine and Cancer ResearchThe George S. Wise Faculty for Life SciencesSagol School of NeurosciencesTel Aviv UniversityTel AvivIsrael
| | - Monzer Marisat
- Laboratory for Neurodegenerative Diseases and Personalized MedicineThe Cell Screening Facility for Personalized MedicineThe Shmunis School of Biomedicine and Cancer ResearchThe George S. Wise Faculty for Life SciencesSagol School of NeurosciencesTel Aviv UniversityTel AvivIsrael
| | - Uri Sprecher
- Laboratory for Neurodegenerative Diseases and Personalized MedicineThe Cell Screening Facility for Personalized MedicineThe Shmunis School of Biomedicine and Cancer ResearchThe George S. Wise Faculty for Life SciencesSagol School of NeurosciencesTel Aviv UniversityTel AvivIsrael
| | - Shane Wald‐Altman
- Laboratory for Neurodegenerative Diseases and Personalized MedicineThe Cell Screening Facility for Personalized MedicineThe Shmunis School of Biomedicine and Cancer ResearchThe George S. Wise Faculty for Life SciencesSagol School of NeurosciencesTel Aviv UniversityTel AvivIsrael
| | - Anna Dukhovny
- Laboratory for Neurodegenerative Diseases and Personalized MedicineThe Cell Screening Facility for Personalized MedicineThe Shmunis School of Biomedicine and Cancer ResearchThe George S. Wise Faculty for Life SciencesSagol School of NeurosciencesTel Aviv UniversityTel AvivIsrael
| | - Yuval Raviv
- Laboratory for Neurodegenerative Diseases and Personalized MedicineThe Cell Screening Facility for Personalized MedicineThe Shmunis School of Biomedicine and Cancer ResearchThe George S. Wise Faculty for Life SciencesSagol School of NeurosciencesTel Aviv UniversityTel AvivIsrael
| | - Benny Da’adoosh
- Blavatnik Center for Drug DiscoveryTel Aviv UniversityTel AvivIsrael
| | - Hamutal Engel
- Blavatnik Center for Drug DiscoveryTel Aviv UniversityTel AvivIsrael
| | - Sandrine Benhamron
- Department of NeurologyHadassah‐Hebrew University Medical CenterJerusalemIsrael
- Hadassah BrainLabs – National Knowledge Center for Research on Brain DiseasesHadassah‐Hebrew University Medical CenterJerusalemIsrael
| | - Keren Nitzan
- Department of NeurologyHadassah‐Hebrew University Medical CenterJerusalemIsrael
- Hadassah BrainLabs – National Knowledge Center for Research on Brain DiseasesHadassah‐Hebrew University Medical CenterJerusalemIsrael
| | - Sahar Sweetat
- Department of NeurologyHadassah‐Hebrew University Medical CenterJerusalemIsrael
- Hadassah BrainLabs – National Knowledge Center for Research on Brain DiseasesHadassah‐Hebrew University Medical CenterJerusalemIsrael
| | - Anna Permyakova
- Obesity and Metabolism LaboratoryInstitute for Drug ResearchSchool of PharmacyFaculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael
| | - Anat Mordechai
- Department of NeurologyHadassah‐Hebrew University Medical CenterJerusalemIsrael
| | - Hasan Orhan Akman
- Department of NeurologyColumbia University Medical CenterNew YorkNew YorkUSA
| | - Hanna Rosenmann
- Department of NeurologyHadassah‐Hebrew University Medical CenterJerusalemIsrael
- Hadassah BrainLabs – National Knowledge Center for Research on Brain DiseasesHadassah‐Hebrew University Medical CenterJerusalemIsrael
| | - Alexander Lossos
- Department of NeurologyHadassah‐Hebrew University Medical CenterJerusalemIsrael
| | - Joseph Tam
- Obesity and Metabolism LaboratoryInstitute for Drug ResearchSchool of PharmacyFaculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael
| | - Berge A. Minassian
- Division of NeurologyDepartment of PediatricsUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - Miguel Weil
- Laboratory for Neurodegenerative Diseases and Personalized MedicineThe Cell Screening Facility for Personalized MedicineThe Shmunis School of Biomedicine and Cancer ResearchThe George S. Wise Faculty for Life SciencesSagol School of NeurosciencesTel Aviv UniversityTel AvivIsrael
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Villarejo-Zori B, Jiménez-Loygorri JI, Zapata-Muñoz J, Bell K, Boya P. New insights into the role of autophagy in retinal and eye diseases. Mol Aspects Med 2021; 82:101038. [PMID: 34620506 DOI: 10.1016/j.mam.2021.101038] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/12/2021] [Accepted: 09/27/2021] [Indexed: 02/06/2023]
Abstract
Autophagy is a fundamental homeostatic pathway that mediates the degradation and recycling of intracellular components. It serves as a key quality control mechanism, especially in non-dividing cells such as neurons. Proteins, lipids, and even whole organelles are engulfed in autophagosomes and delivered to the lysosome for elimination. The retina is a light-sensitive tissue located in the back of the eye that detects and processes visual images. Vision is a highly demanding process, making the eye one of the most metabolically active tissues in the body and photoreceptors display glycolytic metabolism, even in the presence of oxygen. The retina and eye are also exposed to other stressors that can impair their function, including genetic mutations and age-associated changes. Autophagy, among other pathways, is therefore a key process for the preservation of retinal homeostasis. Here, we review the roles of both canonical and non-canonical autophagy in normal retinal function. We discuss the most recent studies investigating the participation of autophagy in eye diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy and its role protecting photoreceptors in several forms of retinal degeneration. Finally, we consider the therapeutic potential of strategies that target autophagy pathways to treat prevalent retinal and eye diseases.
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Affiliation(s)
- Beatriz Villarejo-Zori
- Department of Cellular and Molecular Biology, Margarita Salas Center for Biological Research, CSIC, Ramiro de Maetzu, 9, 28040, Madrid, Spain
| | - Juan Ignacio Jiménez-Loygorri
- Department of Cellular and Molecular Biology, Margarita Salas Center for Biological Research, CSIC, Ramiro de Maetzu, 9, 28040, Madrid, Spain
| | - Juan Zapata-Muñoz
- Department of Cellular and Molecular Biology, Margarita Salas Center for Biological Research, CSIC, Ramiro de Maetzu, 9, 28040, Madrid, Spain
| | - Katharina Bell
- Singapore Eye Research Institute, Singapore National Eye Centre, Republic of Singapore
| | - Patricia Boya
- Department of Cellular and Molecular Biology, Margarita Salas Center for Biological Research, CSIC, Ramiro de Maetzu, 9, 28040, Madrid, Spain.
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Das S, Shukla N, Singh SS, Kushwaha S, Shrivastava R. Mechanism of interaction between autophagy and apoptosis in cancer. Apoptosis 2021; 26:512-533. [PMID: 34510317 DOI: 10.1007/s10495-021-01687-9] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2021] [Indexed: 12/13/2022]
Abstract
The mechanisms of two programmed cell death pathways, autophagy, and apoptosis, are extensively focused areas of research in the context of cancer. Both the catabolic pathways play a significant role in maintaining cellular as well as organismal homeostasis. Autophagy facilitates this by degradation and elimination of misfolded proteins and damaged organelles, while apoptosis induces canonical cell death in response to various stimuli. Ideally, both autophagy and apoptosis have a role in tumor suppression, as autophagy helps in eliminating the tumor cells, and apoptosis prevents their survival. However, as cancer proceeds, autophagy exhibits a dual role by enhancing cancer cell survival in response to stress conditions like hypoxia, thereby promoting chemoresistance to the tumor cells. Thus, any inadequacy in either of their levels can lead to tumor progression. A complex array of biomarkers is involved in maintaining coordination between the two by acting as either positive or negative regulators of one or both of these pathways of cell death. The resulting crosstalk between the two and its role in influencing the survival or death of malignant cells makes it quintessential, among other challenges facing chemotherapeutic treatment of cancer. In view of this, the present review aims to highlight some of the factors involved in maintaining their diaphony and stresses the importance of inhibition of cytoprotective autophagy and deletion of the intermediate pathways involved to facilitate tumor cell death. This will pave the way for future prospects in designing drug combinations facilitating the synergistic effect of autophagy and apoptosis in achieving cancer cell death.
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Affiliation(s)
- Shreya Das
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India
| | - Nidhi Shukla
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | | | - Sapana Kushwaha
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, 226025, India
| | - Richa Shrivastava
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India.
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Melatonin Induces Autophagy via Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress Pathway in Colorectal Cancer Cells. Molecules 2021; 26:molecules26165038. [PMID: 34443626 PMCID: PMC8400139 DOI: 10.3390/molecules26165038] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 07/26/2021] [Accepted: 07/29/2021] [Indexed: 01/10/2023] Open
Abstract
Even though an increasing number of anticancer treatments have been discovered, the mortality rates of colorectal cancer (CRC) have still been high in the past few years. It has been discovered that melatonin has pro-apoptotic properties and counteracts inflammation, proliferation, angiogenesis, cell invasion, and cell migration. In previous studies, melatonin has been shown to have an anticancer effect in multiple tumors, including CRC, but the underlying mechanisms of melatonin action on CRC have not been fully explored. Thus, in this study, we investigated the role of autophagy pathways in CRC cells treated with melatonin. In vitro CRC cell models, HT-29, SW48, and Caco-2, were treated with melatonin. CRC cell death, oxidative stress, and autophagic vacuoles formation were induced by melatonin in a dose-dependent manner. Several autophagy pathways were examined, including the endoplasmic reticulum (ER) stress, 5′–adenosine monophosphate-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K), serine/threonine-specific protein kinase (Akt), and mammalian target of rapamycin (mTOR) signaling pathways. Our results showed that melatonin significantly induced autophagy via the ER stress pathway in CRC cells. In conclusion, melatonin demonstrated a potential as an anticancer drug for CRC.
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Trybus W, Król T, Trybus E, Stachurska A. Physcion Induces Potential Anticancer Effects in Cervical Cancer Cells. Cells 2021; 10:cells10082029. [PMID: 34440797 PMCID: PMC8392222 DOI: 10.3390/cells10082029] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/03/2021] [Accepted: 08/06/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The extent of morphological and ultrastructural changes in HeLa cells was assessed by optical, fluorescence and electron microscopy after exposure to various concentrations of physcion, taking into account the biological properties of the test compound. METHODS Cell viability was assessed by MTT assay, while the cell cycle, LC3 expression, apoptosis, change of mitochondrial potential, Bcl-2 protein expression level and the level of reactive oxygen species were analyzed by flow cytometry. RESULTS As a result of physcion encumbrance, concentration-dependent inhibition of HeLa cell viability and the G0/G1 phase of the cell cycle was observed. Activation of the lysosomal system was also revealed, which was expressed by an increased number of lysosomes, autophage vacuoles and increased expression of the LC3 protein, a marker of the autophagy process. Transmission electron microscopy and fluorescence microscopy showed that physcion induced clear changes in cervical cancer cells, especially in the structure of the nucleus and mitochondria, which correlated with the production of reactive oxygen species by the test compound and indicated the induction of the oxidative process. At the same time, the pro-apoptotic effect of physcion was demonstrated, and this mechanism was dependent on the activation of caspases 3/7 and the reduction in Bcl-2 protein expression. CONCLUSION The obtained results indicate an antitumor mechanism of action of physcion, based on the induction of oxidative stress, autophagy and apoptosis.
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Affiliation(s)
- Wojciech Trybus
- Laboratory of Medical Biology, Institute of Biology, The Jan Kochanowski University, Uniwersytecka 7, 25-406 Kielce, Poland;
- Correspondence: (W.T.); (T.K.)
| | - Teodora Król
- Laboratory of Medical Biology, Institute of Biology, The Jan Kochanowski University, Uniwersytecka 7, 25-406 Kielce, Poland;
- Correspondence: (W.T.); (T.K.)
| | - Ewa Trybus
- Laboratory of Medical Biology, Institute of Biology, The Jan Kochanowski University, Uniwersytecka 7, 25-406 Kielce, Poland;
| | - Anna Stachurska
- Department of Immunohematology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland;
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