Vol. 27 (2022)
| No. 01 | DOI: 10.1186/s11658-021-00301-9 Volume 27 (2022) - 27:01 | |
| Title | THE ROLE OF POLYPHENOLS IN OVERCOMING CANCER DRUG RESISTANCE: A COMPREHENSIVE REVIEW | |
| Authors | Parisa Maleki Dana1, Fatemeh Sadoughi1, Zatollah Asemi1* and Bahman Yousef2,3* | |
| Abstract | Chemotherapeutic drugs are used to treat advanced stages of cancer or following surgery. However, cancers often develop resistance against drugs, leading to failure of treatment and recurrence of the disease. Polyphenols are a family of organic compounds with more than 10,000 members which have a three-membered favan ring system in common. These natural compounds are known for their benefcial properties, such as free radical scavenging, decreasing oxidative stress, and modulating infammation. Herein, we discuss the role of polyphenols (mainly curcumin, resveratrol, and epigallocatechin gallate [EGCG]) in diferent aspects of cancer drug resistance. Increasing drug uptake by tumor cells, decreasing drug metabolism by enzymes (e.g. cytochromes and glutathione-S-transferases), and reducing drug efux are some of the mechanisms by which polyphenols increase the sensitivity of cancer cells to chemotherapeutic agents. Polyphenols also afect other targets for overcoming chemoresistance in cancer cells, including cell death (i.e. autophagy and apoptosis), EMT, ROS, DNA repair processes, cancer stem cells, and epigenetics (e.g. miRNAs). | |
| Keywords | Polyphenols, Curcumin, Resveratrol, Epigallocatechin gallate, Chemoresistance | |
| Address and Contact Information |
1 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran 2 Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 3 Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. *Corresponding author: asemi_z@Kaums.ac.ir; bahmanusef@gmail.com |
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| No. 02 | DOI: 10.1186/s11658-021-00302-8 Volume 27 (2022) - 27:02 | |
| Title | THE FUNCTIONS AND ROLES OF SESTRINS IN REGULATING HUMAN DISEASES | |
| Authors | Yitong Chen1†, Tingben Huang2†, Zhou Yu2, Qiong Yu2, Ying Wang3, Ji’an Hu4*, Jiejun Shi1* and Guoli Yang2* | |
| Abstract | Sestrins (Sesns), highly conserved stress-inducible metabolic proteins, are known to protect organisms against various noxious stimuli including DNA damage, oxidative stress, starvation, endoplasmic reticulum (ER) stress, and hypoxia. Sesns regulate metabolism mainly through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Sesns also play pivotal roles in autophagy activation and apoptosis inhibition in normal cells, while conversely promoting apoptosis in cancer cells. The functions of Sesns in diseases such as metabolic disorders, neurodegenerative diseases, cardiovascular diseases, and cancer have been broadly investigated in the past decades. However, there is a limited number of reviews that have summarized the functions of Sesns in the pathophysiological processes of human diseases, especially musculoskeletal system diseases. One aim of this review is to discuss the biological functions of Sesns in the pathophysiological process and phenotype of diseases. More signifcantly, we include some new evidence about the musculoskeletal system. Another purpose is to explore whether Sesns could be potential biomarkers or targets in the future diagnostic and therapeutic process. | |
| Keywords | Sestrins, Biological functions, Human diseases, Musculoskeletal system disease, Biomarker, Therapeutic target | |
| Address and Contact Information |
1 Department of Orthodontics, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, Zhejiang, China 2 Department of Implantology, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, Zhejiang, China 3 Department of Oral Medicine, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, Zhejiang,China. 4 Department of Oral Pathology, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, Zhejiang, China *Corresponding author: hja@zju.edu.cn; sjiejun@zju.edu.cn; 7308037@zju.edu.cn † Yitong Chen and Tingben Huang contributed equally to this work |
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| No. 03 | DOI: 10.1186/s11658-021-00299-0 Volume 27 (2022) - 27:03 | |
| Title | MITOCHONDRIAL POTASSIUM CHANNELS: A NOVEL CALCITRIOL TARGET | |
| Authors | Anna M. Olszewska1, Adam K. Sieradzan2, Piotr Bednarczyk3, Adam Szewczyk4 and Michał A. Żmijewski1* | |
| Abstract | Background: Calcitriol (an active metabolite of vitamin D) modulates the expression of hundreds of human genes by activation of the vitamin D nuclear receptor (VDR). However, VDR-mediated transcriptional modulation does not fully explain various phenotypic efects of calcitriol. Recently a fast non-genomic response to vitamin D has been described, and it seems that mitochondria are one of the targets of calcitriol. These non-classical calcitriol targets open up a new area of research with potential clinical applications. The goal of our study was to ascertain whether calcitriol can modulate mitochondrial function through regulation of the potassium channels present in the inner mitochondrial membrane. Methods: The efects of calcitriol on the potassium ion current were measured using the patch-clamp method modifed for the inner mitochondrial membrane. Molecular docking experiments were conducted in the Autodock4 program. Additionally, changes in gene expression were investigated by qPCR, and transcription factor binding sites were analyzed in the CiiiDER program. Results: For the frst time, our results indicate that calcitriol directly afects the activity of the mitochondrial large-conductance Ca2+-regulated potassium channel (mitoBKCa) from the human astrocytoma (U-87 MG) cell line but not the mitochondrial calciumindependent two-pore domain potassium channel (mitoTASK-3) from human keratinocytes (HaCaT). The open probability of the mitoBKCa channel in high calcium conditions decreased after calcitriol treatment and the opposite efect was observed in low calcium conditions. Moreover, using the AutoDock4 program we predicted the binding poses of calcitriol to the calcium-bound BKCa channel and identifed amino acids interacting with the calcitriol molecule. Additionally, we found that calcitriol infuences the expression of genes encoding potassium channels. Such a dual, genomic and nongenomic action explains the pleiotropic activity of calcitriol. Conclusions: Calcitriol can regulate the mitochondrial large-conductance calcium regulated potassium channel. Our data open a new chapter in the study of nongenomic responses to vitamin D with potential implications for mitochondrial bioenergetics and cytoprotective mechanisms. | |
| Keywords | Calcitriol, Large-conductance calcium-regulated potassium channel, Mitochondria, Patch-clamp | |
| Address and Contact Information |
1 Department of Histology, Medical University of Gdańsk, 1a Dębinki, 80-211 Gdańsk, Poland 2 Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland. 3 Department of Physics and Biophysics, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland. 4 Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland. *Corresponding author: mzmijewski@gumed.edu.pl |
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| No. 04 | DOI: 10.1186/s11658-021-00300-w Volume 27 (2022) - 27:04 | |
| Title | Specifcity of H2O2 signaling in leaf senescence: is the ratio of H2O2 contents in diferent cellular compartments sensed in Arabidopsis plants? | |
| Authors | Ulrike Zentgraf*, Ana Gabriela Andrade‐Galan and Stefan Bieker | |
| Abstract | Leaf senescence is an integral part of plant development and is driven by endogenous cues such as leaf or plant age. Developmental senescence aims to maximize the usage of carbon, nitrogen and mineral resources for growth and/or for the sake of the next generation. This requires efcient reallocation of the resources out of the senescing tissue into developing parts of the plant such as new leaves, fruits and seeds. However, premature senescence can be induced by severe and long-lasting biotic or abiotic stress conditions. It serves as an exit strategy to guarantee ofspring in an unfavorable environment but is often combined with a trade-of in seed number and quality. In order to coordinate the very complex process of developmental senescence with environmental signals, highly organized networks and regulatory cues have to be in place. Reactive oxygen species, especially hydrogen peroxide (H2O2), are involved in senescence as well as in stress signaling. Here, we want to summarize the role of H2O2 as a signaling molecule in leaf senescence and shed more light on how specifcity in signaling might be achieved. Altered hydrogen peroxide contents in specifc compartments revealed a diferential impact of H2O2 produced in diferent compartments. Arabidopsis lines with lower H2O2 levels in chloroplasts and cytoplasm point to the possibility that not the actual contents but the ratio between the two diferent compartments is sensed by the plant cells. | |
| Keywords | Leaf senescence, Free oxygen radicals, ROS, Hydrogen peroxide, Stromules, Senescence regulation, Intracellular compartments | |
| Address and Contact Information |
ZMBP (Centre of Plant Molecular Biology), University of Tübingen, Auf der Morgenstelle 32, 72076 Tübingen, Germany *Corresponding author: ulrike.zentgraf@zmbp.uni-tuebingen.de |
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| No. 05 | DOI: 10.1186/s11658-021-00304-6 Volume 27 (2022) - 27:05 | |
| Title | LncRNA HCG18 PROMOTES OSTEOSARCOMA GROWTH BY ENHANCED AEROBIC GLYCOLYSIS VIA THE miR‐365a‐3p/PGK1 AXIS | |
| Authors | Xiaohui Pan1, Jin Guo3, Canjun Liu4, Zhanpeng Pan1, Zhicheng Yang2*, Xiang Yao1* and Jishan Yuan1* | |
| Abstract | Background: Osteosarcoma (OS) is a common primary bone malignancy. Long non-coding RNA HCG18 is known to play an important role in a variety of cancers. However, its role in OS and relevant molecular mechanisms are unclear. Methods: Real-time quantitative PCR was performed to determine the expression of target genes. Function experiments showed the efects of HCG18 and miR-365a-3p on OS cell growth. Results: HCG18 expression was increased in OS cell lines. Moreover, in vitro and in vivo experiments demonstrated that HCG18 knockdown inhibited OS cell proliferation. Mechanistically, HCG18 was defned as a competing endogenous RNA by sponging miR-365a-3p, thus elevating phosphoglycerate kinase 1 (PGK1) expression by directly targeting its 3ʹUTR to increase aerobic glycolysis. Conclusion: HCG18 promoted OS cell proliferation via enhancing aerobic glycolysis by regulating the miR-365a-3p/PGK1 axis. Therefore, HCG18 may be a potential target for OS treatment. | |
| Keywords | HCG18, miR-365a-3p, PGK1, Osteosarcoma, Aerobic glycolysis | |
| Address and Contact Information |
1 Department of Orthopedics, The Afliated People’s Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu, China 2 Department of Orthopedics, Changzhou No. 2 People’s Hospital, The Afliated Hospital of Nanjing Medical University, Changzhou, China 3 Department of Orthopedics, Zhenjiang First People’s Hospital Branch, Zhenjiang, People’s Republic of China. 4 Department of Respiratory Therapy, The Afliated People’s Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu, China. *Corresponding author: 727633793yzc@sina.com; yaoxiang6266@163.com; yuanjs2022@163.com |
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| No. 06 | DOI: 10.1186/s11658-022-00308-w Volume 27 (2022) - 27:06 | |
| Title | THE PROBABLE ROLE AND THERAPEUTIC POTENTIAL OF THE PI3K/AKT SIGNALING PATHWAY IN SARS‐CoV‐2 INDUCED COAGULOPATHY | |
| Authors | Mohammad Raf Khezri1*, Reza Varzandeh1 and Morteza Ghasemnejad‐Berenji1,2* | |
| Abstract | Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is associated with a high mortality rate. The majority of deaths in this disease are caused by ARDS (acute respiratory distress syndrome) followed by cytokine storm and coagulation complications. Although alterations in the level of the number of coagulation factors have been detected in samples from COVID-19 patients, the direct molecular mechanism which has been involved in this pathologic process has not been explored yet. The PI3K/AKT signaling pathway is an intracellular pathway which plays a central role in cell survival. Also, in recent years the association between this pathway and coagulopathies has been well clarifed. Therefore, based on the evidence on over-activity of the PI3K/AKT signaling pathway in SARS-CoV-2 infection, in the current review, the probable role of this cellular pathway as a therapeutic target for the prevention of coagulation complications in patients with COVID-19 is discussed. | |
| Keywords | SARS-CoV-2, Coagulation, COVID-19, PI3K/AKT | |
| Address and Contact Information |
1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Sero Road, 5715799313 Urmia, Iran 2 Research Center for Experimental and Applied Pharmaceutical Sciences, Urmia University of Medical Sciences, Urmia, Iran. *Corresponding author: Drmnkh76@gmail.com; ghasemnejad.m@umsu.ac.ir |
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| No. 07 | DOI: 10.1186/s11658-021-00305-5 Volume 27 (2022) - 27:07 | |
| Title | THE INTERACTION OF CANONICAL Wnt/β‐CATENIN SIGNALING WITH PROTEIN LYSINE ACETYLATION | |
| Authors | Hongjuan You1†, Qi Li1,2†, Delong Kong1, Xiangye Liu1, Fanyun Kong1*, Kuiyang Zheng1,3 and Renxian Tang1,3* | |
| Abstract | Canonical Wnt/β-catenin signaling is a complex cell-communication mechanism that has a central role in the progression of various cancers. The cellular factors that participate in the regulation of this signaling are still not fully elucidated. Lysine acetylation is a signifcant protein modifcation which facilitates reversible regulation of the target protein function dependent on the activity of lysine acetyltransferases (KATs) and the catalytic function of lysine deacetylases (KDACs). Protein lysine acetylation has been classifed into histone acetylation and non-histone protein acetylation. Histone acetylation is a kind of epigenetic modifcation, and it can modulate the transcription of important biological molecules in Wnt/β-catenin signaling. Additionally, as a type of post-translational modifcation, non-histone acetylation directly alters the function of the core molecules in Wnt/β-catenin signaling. Conversely, this signaling can regulate the expression and function of target molecules based on histone or non-histone protein acetylation. To date, various inhibitors targeting KATs and KDACs have been discovered, and some of these inhibitors exert their anti-tumor activity via blocking Wnt/β-catenin signaling. Here, we discuss the available evidence in understanding the complicated interaction of protein lysine acetylation with Wnt/β-catenin signaling, and lysine acetylation as a new target for cancer therapy via controlling this signaling. | |
| Keywords | Protein lysine acetylation, Canonical Wnt/β-catenin signaling, Interaction, Therapy, Molecular mechanisms | |
| Address and Contact Information |
1 Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China. 2 Laboratory Department, The People’s Hospital of Funing, Yancheng, Jiangsu, China. 3 National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China. *Corresponding author: kong.fanyun@163.com; tangrenxian-t@163.com † Hongjuan You and Qi Li contributed equally to this work |
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| No. 08 | DOI: 10.1186/s11658-022-00306-y Volume 27 (2022) - 27:08 | |
| Title | CONSTRUCTION AND INVESTIGATION OF β3GNT2‐ASSOCIATED REGULATORY NETWORK IN ESOPHAGEAL CARCINOMA | |
| Authors | Zhiguo Luo1†, Qing Hu2†, Yuanhui Tang1, Yahui Leng2, Tian Tian2, Shuangyue Tian2, Chengyang Huang2, Ao Liu2, Xinzhou Deng1* and Li Shen1,2* | |
| Abstract | Background: Glycosyltransferases play a crucial role in various cancers. β1, 3-N-acetyl-glucosaminyltransferase 2, a polylactosamine synthase, is an important member of the glycosyltransferase family. However, the biological function and regulatory mechanism of β3GNT2 in esophageal carcinoma (ESCA) is still poorly understood. Methods: The Cancer Genome Atlas and Genotype-Tissue Expression databases were used for gene expression and prognosis analysis. Quantitative real-time PCR, Western blot, and immunohistochemistry were performed to detect the expression of β3GNT2 in ESCA cell lines and tissues. In vitro assays and xenograft tumor models were utilized to evaluate the impact of β3GNT2 on ESCA progression. The downstream efectors and upstream regulators of β3GNT2 were predicted by online software and verifed by functional experiments. Results: We found that β3GNT2 was highly expressed in ESCA tissues and positively correlated with poor prognosis in ESCA patients. β3GNT2 expression was closely associated with the tumor size, TNM stage, and overall survival of ESCA patients. Functionally, β3GNT2 promoted ESCA cell growth, migration, and invasion in vitro, as well as tumorigenesis in vivo. Mechanistically, β3GNT2 knockdown decreased the expression of the polylactosamine on EGFR. Knockdown of β3GNT2 also inhibited the JAK/STAT signaling pathway. Meanwhile, the JAK/STAT inhibitor could partly reverse the biological efects caused by β3GNT2 overexpression. Moreover, β3GNT2 expression was positively regulated by CREB1 and negatively regulated by miR-133b. Both CREB1 and miR-133b was involved in the β3GNT2-mediated ESCA progression. Conclusions: Our study, for the frst time, reveals the importance of β3GNT2 in ESCA progression and ofers a potential therapeutic target for ESCA. | |
| Keywords | Esophageal carcinoma, Progression, Glycosyltransferase, β3GNT2 | |
| Address and Contact Information |
1 Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, 30 South Renmin Road, Shiyan 442000, Hubei, China 2 Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China. *Corresponding author: 576700586@qq.com; 20101061@hbmu.edu.cn † Zhiguo Luo and Qing Hu contributed equally to this article |
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| No. 09 | DOI: 10.1186/s11658-022-00307-x Volume 27 (2022) - 27:09 | |
| Title | RAMAN SPECTROSCOPY BIOCHEMICAL CHARACTERISATION OF BLADDER CANCER CISPLATIN RESISTANCE REGULATED BY FDFT1: A REVIEW | |
| Authors | M. Kanmalar1, Siti Fairus Abdul Sani1*, Nur Izzahtul Nabilla B. Kamri1, Nur Akmarina B. M. Said2, Amirah Hajirah B. A. Jamil2, S. Kuppusamy3, K. S. Mun4 and D. A. Bradley5,6 | |
| Abstract | Bladder cancer is the fourth most common malignancy in males. It can present across the whole continuum of severity, from mild through well-diferentiated disease to extremely malignant tumours with poor survival rates. As with other vital organ malignancies, proper clinical management involves accurate diagnosis and staging. Chemotherapy consisting of a cisplatin-based regimen is the mainstay in the management of muscle-invasive bladder cancers. Control via cisplatin-based chemotherapy is threatened by the development of chemoresistance. Intracellular cholesterol biosynthesis in bladder cancer cells is considered a contributory factor in determining the chemotherapy response. Farnesyl-diphosphate farnesyltransferase 1 (FDFT1), one of the main regulatory components in cholesterol biosynthesis, may play a role in determining sensitivity towards chemotherapy compounds in bladder cancer. FDFT1-associated molecular identifcation might serve as an alternative or appendage strategy for early prediction of potentially chemoresistant muscle-invasive bladder cancer tissues. This can be accomplished using Raman spectroscopy. Developments in the instrumentation have led to it becoming one of the most convenient forms of analysis, and there is a highly realistic chance that it will become an efective tool in the pathology lab. Chemosensitive bladder cancer tissues tend to have a higher lipid content, more protein genes and more cholesterol metabolites. These are believed to be associated with resistance towards bladder cancer chemotherapy. Herein, Raman peak assignments have been tabulated as an aid to indicating metabolic changes in bladder cancer tissues that are potentially correlated with FDFT1 expression. | |
| Keywords | Bladder cancer, Diagnostic, FDFT1, Cisplatin chemoresistance, Raman spectroscopy | |
| Address and Contact Information |
1 Department of Physics, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia 2 Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, University of Malaya, 50603 Kuala Lumpur, Malaysia. 3 Department of Surgery, University of Malaya, 50603 Kuala Lumpur, Malaysia. 4 Department of Pathology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. 5 Centre for Applied Physics and Radiation Technologies, Sunway University, Jalan University, 46150 Petaling Jaya, Malaysia. 6 Department of Physics, University of Surrey, Guildford GU2 7XH, UK. *Corresponding author: s.fairus@um.edu.my |
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| No. 10 | DOI: 10.1186/s11658-022-00311-1 Volume 27 (2022) - 27:10 | |
| Title | THE ROLES OF Eph RECEPTORS, NEUROPILIN‐1, P2X7, AND CD147 IN COVID‐19‐ASSOCIATED NEURODEGENERATIVE DISEASES: INFAMMASOME AND JaK INHIBITORS AS POTENTIAL PROMISING THERAPIES | |
| Authors | Hamidreza Zalpoor1,2,3†, Abdullatif Akbari4†, Azam Samei5, Razieh Forghaniesfdvajani4, Monireh Kamali6, Azadeh Afzalnia6, Shirin Manshouri6, Fatemeh Heidari7, Majid Pornour8, Majid Khoshmirsafa9, Hossein Aazami10 and Farhad Seif2,11* | |
| Abstract | The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and fnding a safe therapeutic strategy and efective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinfammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest infammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases. | |
| Keywords | COVID-19, CNS, Ephrin, Neuropilin-1, P2X7, CD147, Cytokine, Jak, Infammasome, Neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease | |
| Address and Contact Information |
1 American Association of Kidney Patients, Tampa, FL, USA. 2 Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran. 3 Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. 4 Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientifc Education and Research Network (USERN), Tehran, Iran. 5 Department of Laboratory Sciences, School of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran. 6 Rajaei Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran. 7 Immunology Department, Faculty of Medicine, Tarbiat Modares University, Tehran, Iran. 8 Department of Oncology, School of Medicine, University of Maryland, Maryland, USA. 9 Department of Immunology, School of Medicine, Iran University of Medical Sciences, Iran, Iran. 10 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. 11 Department of Immunology and Allergy, Academic Center for Education, Culture, and Research (ACECR), Enghelab St., Aboureyhan St., Vahid Nazari Crossroad, P17, 1315795613 Tehran, Iran *Corresponding author: farhad.seif@outlook.com † Hamidreza Zalpoor and Abdullatif Akbari contributed equally as the first authors |
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| No. 11 | DOI: 10.1186/s11658-022-00314-y Volume 27 (2022) - 27:11 | |
| Title | Slc25a5 REGULATES ADIPOGENESIS BY MODULATING ERK SIGNALING IN OP9 CELLS | |
| Authors | Shenglong Zhu1,2†, Wei Wang1†, Jingwei Zhang3, Siyu Ji1, Zhe Jing1 and Yong Q. Chen1,2,3* | |
| Abstract | Background: A comprehensive understanding of the molecular mechanisms of adipogenesis is a critically important strategy for identifying new targets for obesity intervention. Methods: Transcriptomic and lipidomic approaches were used to explore the functional genes regulating adipogenic diferentiation and their potential mechanism of action in OP9 cells and adipose-derived stem cells. Oil Red O staining was used to detect oil droplets in adipocytes. Results: RNA sequencing (RNA-seq) showed that Slc25a5 expression was signifcantly upregulated in adipogenic diferentiation. Depletion of Slc25a5 led to the suppressed expression of adipogenesis-related genes, reduced the accumulation of triglycerides, and inhibited PPARγ protein expression. Moreover, the knockdown of Slc25a5 resulted in signifcant reduction of oxidative phosphorylation (OXPHOS) protein expression (ATP5A1, CQCRC2, and MTCO1) and ATP production. The RNA-seq and real-time quantitative polymerase chain reaction (RT–qPCR) results suggested that adipogenic diferentiation is possibly mediated by ERK1/2 phosphorylation, and this hypothesis was confrmed by intervention with PD98059 (an ERK 1/2 inhibitor). Conclusions: This study indicates that Slc25a5 inhibits adipogenesis and might be a new therapeutic target for the treatment of obesity. | |
| Keywords | Obesity, Adipogenic diferentiation, Slc25a5, ERK, Transcriptome, Metabolome | |
| Address and Contact Information |
1 Wuxi School of Medicine, Jiangnan University, 1800 Lihu Road, Wuxi 214122, Jiangsu, China 2 Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch, Wuxi, China. 3 School of Food Science and Technology, Jiangnan University, Wuxi, China. *Corresponding author: yqc_lab@126.com; yqchen@jiangnan.edu.cn † Shenglong Zhu and Wei Wang contributed equally to this work |
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| No. 12 | DOI: 10.1186/s11658-022-00315-x Volume 27 (2022) - 27:12 | |
| Title | ERp57/PDIA3: NEW INSIGHT | |
| Authors | Silvia Chichiarelli1*, Fabio Altieri1, Giuliano Paglia1, Elisabetta Rubini1,2, Marco Minacori1 and Margherita Eufemi1 | |
| Abstract | The ERp57/PDIA3 protein is a pleiotropic member of the PDIs family and, although predominantly located in the endoplasmic reticulum (ER), has indeed been found in other cellular compartments, such as the nucleus or the cell membrane. ERp57/PDIA3 is an important research target considering it can be found in various subcellular locations. This protein is involved in many diferent physiological and pathological processes, and our review describes new data on its functions and summarizes some ligands identifed as PDIA3-specifc inhibitors. | |
| Keywords | ERp57, PDIA3, PDI inhibitors, Punicalagin, Vitamin D3, Cancer, Infections, Nervous system, Cardiovascular system, Fertility | |
| Address and Contact Information |
1 Department of Biochemical Sciences “A.Rossi-Fanelli”, Sapienza University of Rome, P.le A.Moro 5, 00185 Rome, Italy 2 Enrico Ed Enrica Sovena” Foundation, Rome, Italy. *Corresponding author: silvia.chichiarelli@uniroma1.it |
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| No. 13 | DOI: 10.1186/s11658-022-00313-z Volume 27 (2022) - 27: | |
| Title | SNHG3 COULD PROMOTE PROSTATE CANCER PROGRESSION THROUGH REDUCING METHIONINE DEPENDENCE OF PCa CELLS | |
| Authors | Xiaotian Wang, Yongsheng Song, Yaxing Shi, Da Yang, Jiaxing Li and Bo Yin* | |
| Abstract | In recent years, morbidity and mortality of prostate cancer (PCa) have increased dramatically, while mechanistic understanding of its onset and progression remains unmet. LncRNA SNHG3 has been proved to stimulate malignant progression of multiple cancers, whereas its functional mechanism in PCa needs to be deciphered. In this study, our analysis in the TCGA database revealed high SNHG3 expression in PCa tissue. Further analysis in starBase, TargetScan, and mirDIP databases identifed the SNHG3/miR-152-3p/SLC7A11 regulatory axis. FISH was conducted to assess the distribution of SNHG3 in PCa tissue. Dual-luciferase reporter gene and RIP assays confrmed the relationship among the three objects. Next, qRT-PCR and western blot were conducted to measure expression levels of SNHG3, miR-152-3p, and SLC7A11. CCK-8, colony formation, Transwell, and fow cytometry were carried out to assess proliferation, migration, invasion, methionine dependence, apoptosis, and the cell cycle. It was noted that SNHG3 as a molecular sponge of miR-152-3p stimulated proliferation, migration, and invasion, restrained methionine dependence and apoptosis, and afected the cell cycle of PCa cells via targeting SLC7A11. Additionally, we constructed xenograft tumor models in nude mice and confrmed that knockdown of SNHG3 could restrain PCa tumor growth and elevate methionine dependence in vivo. In conclusion, our investigation improved understanding of the molecular mechanism of SNHG3 modulating PCa progression, thereby generating novel insights into clinical therapy for PCa. | |
| Keywords | Prostate cancer, SNHG3, miR-152-3p, SLC7A11, Methionine dependence | |
| Address and Contact Information |
Department of Urology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang 110001, Liaoning, China *Corresponding author: yinbo19751003@hotmail.com |
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| No. 14 | DOI: 10.1186/s11658-022-00317-9 Volume 27 (2022) - 27:14 | |
| Title | MicroRNA let‐7 AND VIRAL INFECTIONS: FOCUS ON MECHANISMS OF ACTION | |
| Authors | Arash Letafati1, Sajad Najaf2, Mehran Mottahedi3, Mohammad Karimzadeh4, Ali Shahini3, Setareh Garousi3, Mohammad Abbasi‐Kolli5, Javid Sadri Nahand6, Seyed Saeed Tamehri Zadeh7, Michael R. Hamblin8, Neda Rahimian9,10*, Mohammad Taghizadieh11* and Hamed Mirzaei12,13* | |
| Abstract | MicroRNAs (miRNAs) are fundamental post-transcriptional modulators of several critical cellular processes, a number of which are involved in host defense mechanisms. In particular, miRNA let-7 functions as an essential regulator of the function and diferentiation of both innate and adaptive immune cells. Let-7 is involved in several human diseases, including cancer and viral infections. Several viral infections have found ways to dysregulate the expression of miRNAs. Extracellular vesicles (EV) are membrane-bound lipid structures released from many types of human cells that can transport proteins, lipids, mRNAs, and miRNAs, including let-7. After their release, EVs are taken up by the recipient cells and their contents released into the cytoplasm. Let-7-loaded EVs have been suggested to afect cellular pathways and biological targets in the recipient cells, and can modulate viral replication, the host antiviral response, and the action of cancer-related viruses. In the present review, we summarize the available knowledge concerning the expression of let-7 family members, functions, target genes, and mechanistic involvement in viral pathogenesis and host defense. This may provide insight into the development of new therapeutic strategies to manage viral infections. | |
| Keywords | MicroRNAs, Let-7, Viral infections, Regulatory role | |
| Address and Contact Information |
1 Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. 2 Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3 Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 4 Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. 5 Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. 6 Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 7 School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 8 Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa. 9 Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran. 10 Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran. 11 Department of Pathology, School of Medicine, Center for Women’s Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran. 12 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran. 13Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran. *Corresponding author: rahimian.n@iums.ac.ir; MohammadTaghizadieh@gmail.com; mirzaei-h@kaums.ac.ir; h.mirzaei2002@gmail.com |
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| No. 15 | DOI: 10.1186/s11658-022-00310-2 Volume 27 (2022) - 27:15 | |
| Title | THE lncRNA DANCR PROMOTES DEVELOPMENT OF ATHEROSCLEROSIS BY REGULATING THE miR‐214‐5p/COX20 SIGNALING PATHWAY | |
| Authors | Ruolan Zhang1*, Yuming Hao2 and Jinrong Zhang1 | |
| Abstract | Background: Although long non-coding RNA diferentiation antagonizing non-protein coding RNA (DANCR) has been reported to be involved in atherosclerosis (AS) development, its specifc mechanism remains unclear. Methods: DANCR expression levels in blood samples of AS patients and oxidized low-density lipoprotein (ox-LDL) treated vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The small interfering RNA targeting DANCR (si-DANCR) was used to silence DANCR expression. Cell viability was assessed by CCK-8 assay. Cell apoptosis was evaluated by fow cytometry. Levels of infammatory cytokines, anti-oxidative enzyme superoxide dismutase (SOD) activity, and malonaldehyde (MDA) were detected by specifc commercial kits. An animal AS model was established to confrm the role of DANCR/microR-214-5p/COX20 (the chaperone of cytochrome c oxidase subunit II COX2) in AS development. Results: DANCR was signifcantly increased in the blood samples of AS patients and ox-LDL treated VSMCs and HUVECs. DANCR downregulation obviously increased viability and reduced apoptosis of ox-LDL-treated VSMCs and HUVECs. Meanwhile, DANCR downregulation reduced the levels of infammatory cytokines, including interleukin (IL)-6 (IL-6), IL-1beta (IL-1β), IL-6 and tumor necrosis factor (TNF)-alpha (TNF-α) and MDA while increasing the SOD level in ox-LDL-treated VSMCs and HUVECs. DANCR regulated COX20 expression by acting as a competing endogenous RNA (ceRNA) of miR-214-5p. Rescue experiments demonstrated that miR-214-5p downregulation obviously attenuated si-DANCR-induced protective efects on ox-LDL-caused endothelial injury. Conclusions: Our results revealed that DANCR promoted AS progression by targeting the miR-214-5p/COX20 axis, suggesting that DANCR might be a potential therapeutic target for AS. | |
| Keywords | Atherosclerosis, DANCR, miR-214-5p, COX20 | |
| Address and Contact Information |
1 Department of Cardiology, Harrison International Peace Hospital, No. 180 Renmin Road, Hengshui City 053000, Hebei Province, People’s Republic of China 2 Department of Cardiology, Second Afliated Hospital of Hebei Medical University, Shijiazhuang City 05000, Hebei Province, People’s Republic of China. *Corresponding author: ruolanzhangharriso@163.com |
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| No. 16 | DOI: 10.1186/s11658-022-00316-w Volume 27 (2022) - 27:16 | |
| Title | EXPLORING NEURONAL MECHANISMS INVOLVED IN THE SCRATCHING BEHAVIOR OF A MOUSE MODEL OF ALLERGIC CONTACT DERMATITIS BY TRANSCRIPTOMICS | |
| Authors | Boyu Liu1†, Ruixiang Chen1,2†, Jie Wang1†, Yuanyuan Li1†, Chengyu Yin1, Yan Tai3, Huimin Nie1, Danyi Zeng1, Junfan Fang1, Junying Du1, Yi Liang1, Xiaomei Shao1, Jianqiao Fang1* and Boyi Liu1* | |
| Abstract | Background: Allergic contact dermatitis (ACD) is a common skin condition characterized by contact hypersensitivity to allergens, accompanied with skin infammation and a mixed itch and pain sensation. The itch and pain dramatically afects patients’ quality of life. However, still little is known about the mechanisms triggering pain and itch sensations in ACD. Methods: We established a mouse model of ACD by sensitization and repetitive challenge with the hapten oxazolone. Skin pathological analysis, transcriptome RNA sequencing (RNA-seq), qPCR, Ca2+ imaging, immunostaining, and behavioral assay were used for identifying gene expression changes in dorsal root ganglion innervating the infamed skin of ACD model mice and for further functional validations. Results: The model mice developed typical ACD symptoms, including skin dryness, erythema, excoriation, edema, epidermal hyperplasia, infammatory cell infltration, and scratching behavior, accompanied with development of eczematous lesions. Transcriptome RNA-seq revealed a number of diferentially expressed genes (DEGs), including 1436-DEG mRNAs and 374-DEG-long noncoding RNAs (lncRNAs). We identifed a number of DEGs specifcally related to sensory neuron signal transduction, pain, itch, and neuroinfammation. Comparison of our dataset with another published dataset of atopic dermatitis mouse model identifed a core set of genes in peripheral sensory neurons that are exclusively afected by local skin infammation. We further found that the expression of the pain and itch receptor MrgprD was functionally upregulated in dorsal root ganglia (DRG) neurons innervating the infamed skin of ACD model mice. MrgprD activation induced by its agonist β-alanine resulted in exaggerated scratching responses in ACD model mice compared with naïve mice. Conclusions: We identifed the molecular changes and cellular pathways in peripheral sensory ganglia during ACD that might participate in neurogenic infammation, pain, and itch. We further revealed that the pain and itch receptor MrgprD is functionally upregulated in DRG neurons, which might contribute to peripheral pain and itch sensitization during ACD. Thus, targeting MrgprD may be an efective method for alleviating itch and pain in ACD. | |
| Keywords | Itch, Pain, Sensory neurons, Allergic contact dermatitis, RNA-seq | |
| Address and Contact Information |
1 Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou 310053, China. 2 The First Department of Acupuncture, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an, Shaanxi, China. 3 Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China. *Corresponding author: fangjianqiao7532@163.com; boyi.liu@foxmail.com † Boyu Liu, Ruixiang Chen, Jie Wang and Yuanyuan Li contributed equally to this work |
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| No. 17 | DOI: 10.1186/s11658-022-00309-9 Volume 27 (2022) - 27:17 | |
| Title | EXOSOMAL lncRNA TUG1 FROM CANCER‐ASSOCIATED FBROBLASTS PROMOTES LIVER CANCER CELL MIGRATION, INVASION, AND GLYCOLYSIS BY REGULATING THE miR‐524‐5p/SIX1 AXIS | |
| Authors | Le Lu, Jingjing Huang, Jiantao Mo, Xuanbo Da, Qiaoxin Li, Meng Fan and Hongwei Lu* | |
| Abstract | Background: Increasing evidence suggests that taurine upregulated gene 1 (TUG1) is crucial for tumor progression; however, its role in hepatocellular carcinoma (HCC) and the underlying mechanisms are not well characterized. Methods: The expression levels of TUG1, miR-524-5p, and sine oculis homeobox homolog 1 (SIX1) were determined using quantitative real-time PCR. The regulatory relationships were confrmed by dual-luciferase reporter assay. Cell proliferation and invasion were assessed using Cell Counting Kit 8 and transwell assays. Glucose uptake, cellular levels of lactate, lactate dehydrogenase (LDH), and adenosine triphosphate (ATP) were detected using commercially available kits. Silencing of TUG1 or SIX1 was performed by lentivirus transduction. Protein levels were measured by immunoblotting. Results: Cancer-associated fbroblasts (CAFs)-secreted exosomes promoted migration, invasion, and glycolysis in HepG2 cells by releasing TUG1. The promotive efects of CAFs-secreted exosomes were attenuated by silencing of TUG1. TUG1 and SIX1 are targets of miR-524-5p. SIX1 knockdown inhibited the promotive efects of miR-524-5p inhibitor. Silencing of TUG1 suppressed tumor growth and lung metastasis and therefore increased survival of xenograft model mice. We also found that TUG1 and SIX1 were increased in HCC patients with metastasis while miR-524-5p was decreased in HCC patients with metastasis. Conclusions: CAFs-derived exosomal TUG1 promoted migration, invasion, and glycolysis in HCC cells via the miR-524-5p/SIX1 axis. These fndings may help establish the foundation for the development of therapeutics strategies and clinical management for HCC in future. | |
| Keywords | Long noncoding RNA, Taurine upregulated gene 1, Hepatocellular carcinoma, microRNA, Sine oculis homeobox homolog 1, Exosomes | |
| Address and Contact Information |
Department of General Surgery, The Second Afliated Hospital of Xi’an Jiaotong University, No.157, West 5th Road, Xi’an 710004, China *Corresponding author: lhwdoc@163.com; lhwlhw135@163.com |
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| No. 18 | DOI: 10.1186/s11658-022-00323-x Volume 27 (2022) - 27:18 | |
| Title | IDENTIFYING PATHWAYS REGULATING THE ONCOGENIC p53 FAMILY MEMBER ΔNp63 PROVIDES THERAPEUTIC AVENUES FOR SQUAMOUS CELL CARCINOMA | |
| Authors | Zuzana Pokorna, Jan Vyslouzil, Borivoj Vojtesek and Philip J. Coates* | |
| Abstract | Background: ΔNp63 overexpression is a common event in squamous cell carcinoma (SCC) that contributes to tumorigenesis, making ΔNp63 a potential target for therapy. Methods: We created inducible TP63-shRNA cells to study the efects of p63-depletion in SCC cell lines and non-malignant HaCaT keratinocytes. DNA damaging agents, growth factors, signaling pathway inhibitors, histone deacetylase inhibitors, and metabolism-modifying drugs were also investigated for their ability to infuence ΔNp63 protein and mRNA levels. Results: HaCaT keratinocytes, FaDu and SCC-25 cells express high levels of ΔNp63. HaCaT and FaDu inducible TP63-shRNA cells showed reduced proliferation after p63 depletion, with greater efects on FaDu than HaCaT cells, compatible with oncogene addiction in SCC. Genotoxic insults and histone deacetylase inhibitors variably reduced ΔNp63 levels in keratinocytes and SCC cells. Growth factors that regulate proliferation/survival of squamous cells (IGF-1, EGF, amphiregulin, KGF, and HGF) and PI3K, mTOR, MAPK/ERK or EGFR inhibitors showed lesser and inconsistent efects, with dual inhibition of PI3K and mTOR or EGFR inhibition selectively reducing ΔNp63 levels in HaCaT cells. In contrast, the antihyperlipidemic drug lovastatin selectively increased ΔNp63 in HaCaT cells. Conclusions: These data confrm that ΔNp63-positive SCC cells require p63 for continued growth and provide proof of concept that p63 reduction is a therapeutic option for these tumors. Investigations of ΔNp63 regulation identifed agent-specifc and cell-specifc pathways. In particular, dual inhibition of the PI3K and mTOR pathways reduced ΔNp63 more efectively than single pathway inhibition, and broad-spectrum histone deacetylase inhibitors showed a time-dependent biphasic response, with high level downregulation at the transcriptional level within 24 h. In addition to furthering our understanding of ΔNp63 regulation in squamous cells, these data identify novel drug combinations that may be useful for p63-based therapy of SCC. | |
| Keywords | ΔNp63, Oncogene addiction, Squamous cell carcinoma, DNA damage, Histone deacetylase inhibitors, Growth factor signaling | |
| Address and Contact Information |
Research Center of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic *Corresponding author: philip.coates@mou.cz |
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| No. 19 | DOI: 10.1186/s11658-022-00312-0 Volume 27 (2022) - 27:19 | |
| Title | PEPTIDYLARGININE DEIMINASE 2 PROMOTES T HELPER 17‐LIKE T CELL ACTIVATION AND ACTIVATED T CELL‐AUTONOMOUS DEATH (ACAD) THROUGH AN ENDOPLASMIC RETICULUM STRESS AND AUTOPHAGY COUPLING MECHANISM | |
| Authors | Yi‐Fang Yang1,2†, Chuang‐Ming Wang3†, I.‐Hsin Hsiao1, Yi‐Liang Liu1,4, Wen‐Hao Lin1,4, Chih‐Li Lin4, Hui‐Chih Hung1,6,7* and Guang‐Yaw Liu4,5* | |
| Abstract | Peptididylarginine deiminase type 2 (PADI2) catalyzes the conversion of arginine residues to citrulline residues on proteins. We demonstrate that PADI2 induces T cell activation and investigate how PADI2 promotes activated T cell autonomous death (ACAD). In activated Jurkat T cells, overexpression of PADI2 signifcantly increases citrullinated proteins and induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling, ultimately resulting in the expression of autophagy-related proteins and autophagy. PADI2 promoted autophagy and resulted in the early degradation of p62 and the light chain 3B (LC3B)-II accumulation. In Jurkat T cells, silencing the autophagy-related gene (Atg) 12 protein inhibits PADI2-mediated autophagy and promotes ER stress and apoptosis, whereas overexpression of Atg12 decreased ER stress and prolonged autophagy to promote cell survival. Additionally, PADI2 regulates T cell activation and the production of Th17 cytokines in Jurkat T cells (interleukins 6, IL-17A, IL-17F, IL-21, and IL-22). In Jurkat T cells, silencing IL-6 promotes autophagy mediated by PADI2 and inhibits PADI2-induced apoptosis, whereas silencing Beclin-1 increases the activation and survival of Th17-like T cells while decreasing autophagy and apoptosis. PADI2 silencing alleviates ER stress caused by PADI2 and decreases cytokine expression associated with Th17-like T cell activation and ACAD. We propose that PADI2 was involved in Th17 lymphocyte ACAD via a mechanism involving ER stress and autophagy that was tightly regulated by PADI2-mediated citrullination. These fndings suggest that inhibiting Th17 T cell activation and the development of severe autoimmune diseases may be possible through the use of novel antagonists that specifcally target PADI2. | |
| Keywords | Peptidylarginine deiminase 2, Cytokines, Activated T cell-autonomous death, Endoplasmic reticulum stress, Autophagy | |
| Address and Contact Information |
1 Department of Life Sciences, National Chung Hsing University (NCHU), Taichung 40227, Taiwan 2 Ph.D. Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung 40227, Taiwan. 3 Department of Pediatrics, Ditmanson Medical Foundation Chia-Yi Christian Hospital (CYCH), Chia‐Yi 60002, Taiwan. 4 Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. 5 Department of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan. 6 Institute of Genomics and Bioinformatics, National Chung Hsing University (NCHU), Taichung 40227, Taiwan. 7 iEGG and Animal Biotechnology Center, NCHU, Taichung 40227, Taiwan. *Corresponding author: hchung@dragon.nchu.edu.tw; liugy@csmu.edu.tw † Yi-Fang Yang and Chuang Ming Wang contributed equally to this work |
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| No. 20 | DOI: 10.1186/s11658-022-00319-7 Volume 27 (2022) - 27:20 | |
| Title | SENESCENCE‐ASSOCIATED REPROGRAMMING INDUCED BY INTERLEUKIN‐1 IMPAIRS RESPONSE TO EGFR NEUTRALIZATION | |
| Authors | Donatella Romaniello1,2†, Valerio Gelfo1,2†, Federica Pagano1, Enea Ferlizza1, Michela Sgarzi1,2, Martina Mazzeschi1,2, Alessandra Morselli1, Carmen Miano3, Gabriele D’Uva1,3 and Mattia Lauriola1,2* | |
| Abstract | Background: EGFR targeting is currently the main treatment strategy for metastatic colorectal cancer (mCRC). Results of diferent clinical trials show that patients with wild-type KRAS and BRAF beneft from anti-EGFR monoclonal antibodies (moAbs) cetuximab (CTX) or panitumumab. Unfortunately, despite initial response, patients soon became refractory. Tumor heterogeneity and multiple escaping routes have been addressed as the main culprit, and, behind genomic alterations already described, changes in signaling pathways induced by drug pressure are emerging as mechanisms of acquired resistance. We previously reported an association between reduced sensitivity to CTX and increased expression of IL-1. However, how IL-1 mediates CTX resistance in mCRC is still unclear. Methods: Under CTX treatment, the upregulation of IL-1R1 expression and a senescence program in sensitive colorectal cancer (CRC) cell lines is examined over time using qPCR, immunoblotting, and immunofuorescence. Results: In sensitive CRC cells, IL-1 appeared responsible for a CTX-mediated G0 phase arrest. On the contrary, CTX-resistant CRC cells (CXR) maintained high mRNA levels of IL-1R1 and a post-senescence reprogramming, as indicated by increased SNAIL expression. Interestingly, treatment of CXR cells with a recombinant decoy, able to sequester the soluble form of IL-1, pushed CTX-resistant CRC cells back into a stage of senescence, thus blocking their proliferation. Our model suggests a trans-regulatory mechanism mediated by IL-1 on EGFR signaling. By establishing senescence and regulating EGFR activity and expression, IL-1 exposure ultimately bestows resistance. Conclusions: To sum up, our fndings point to the combined blockage of IL-1R and EGFR as a promising therapeutical approach to restore sensitivity to EGFR-targeting monoclonal antibodies. | |
| Keywords | EGFR, Pseudo-senescence, IL-1, Cell plasticity, Colon cancer, Cetuximab, Resistance | |
| Address and Contact Information |
1 Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy 2 Centre for Applied Biomedical Research (CRBA), Bologna University Hospital Authority St. Orsola-Malpighi Polyclinic, 40138 Bologna, Italy. 3 National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), Bologna, Italy. *Corresponding author: mattia.lauriola2@unibo.it † Donatella Romaniello and Valerio Gelfo contributed equally to this work. |
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| No. 21 | DOI: 10.1186/s11658-022-00320-0 Volume 27 (2022) - 27:21 | |
| Title | POTENTIAL ANTICANCER PROPERTIES AND MECHANISMS OF THYMOQUINONE IN OSTEOSARCOMA AND BONE METASTASIS | |
| Authors | Mina Homayoonfal1, Zatollah Asemi1* and Bahman Yousef2,3* | |
| Abstract | Despite great advances, therapeutic approaches of osteosarcoma, the most prevalent class of preliminary pediatric bone tumors, as well as bone-related malignancies, continue to demonstrate insufcient adequacy. In recent years, a growing trend toward applying natural bioactive compounds, particularly phytochemicals, as novel agents for cancer treatment has been observed. Bioactive phytochemicals exert their anticancer features through two main ways: they induce cytotoxic efects against cancerous cells without having any detrimental impact on normal cell macromolecules such as DNA and enzymes, while at the same time combating the oncogenic signaling axis activated in tumor cells. Thymoquinone (TQ), the most abundant bioactive compound of Nigella sativa, has received considerable attention in cancer treatment owing to its distinctive properties, including apoptosis induction, cell cycle arrest, angiogenesis and metastasis inhibition, and reactive oxygen species (ROS) generation, along with inducing immune system responses and reducing side efects of traditional chemotherapeutic drugs. The present review is focused on the characteristics and mechanisms by which TQ exerts its cytotoxic efects on bone malignancies. | |
| Keywords | Osteosarcoma, Bone metastasis, Thymoquinone, Signaling pathway, Apoptosis, Angiogenesis, Chemotherapy resistance | |
| Address and Contact Information |
1 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran. 2 Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 3 Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. *Corresponding author: Asemi_r@yahoo.com; bahmanusef@gmail.com |
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| No. 22 | DOI: 10.1186/s11658-022-00322-y Volume 27 (2022) - 27:22 | |
| Title | miR‐152‐3p IMPEDES THE MALIGNANT PHENOTYPES OF HEPATOCELLULAR CARCINOMA BY REPRESSING ROUNDABOUT GUIDANCE RECEPTOR 1 | |
| Authors | Tao Yin* and Haonan Zhao | |
| Abstract | Background: miR-152-3p functions as a tumour suppressor in the progression of hepatic tumorigenesis. Herein, we further discussed the prognostic signifcance and immune infltration of miR-152-3p and its potential gene target in hepatocellular carcinoma (HCC). Methods: The Cancer Genome Atlas (TCGA), Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), Human Protein Atlas (HPA) and Kaplan–Meier Plotter databases were used to evaluate miR-152-3p and roundabout guidance receptor 1 (ROBO1) expression, prognosis and immune infltration. In vitro cell experiments, including cell proliferation and apoptosis, were evaluated using Cell Counting Kit 8 (CCK8) and terminal-deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) assays. Results: Up-regulation of ROBO1 functioned as an oncogene associated with poor prognosis, immune cell enrichment and cell proliferation in HCC. ROBO1 was signifcantly positively correlated with the enrichment of multiple immune cells and their biomarkers. Enrichment of type-2 T-helper (Th2) cells is an unfavourable biomarker of HCC prognosis. GSEA revealed that ROBO1 correlated with apoptosis, mitosis and carcinogenic signalling pathways. Suppression of cell proliferation and the enhancement of cell apoptosis by miR-152-3p mimics were counteracted by overexpression of ROBO1 in HCC cells. Conclusion: ROBO1 expression is positively correlated with multiple immune checkpoint molecules, suggesting that ROBO1 may be a potential drug target to enhance the potency of immunotherapy. The miR-152-3p/ROBO1 signalling axis contributes to malignant progression and provides a prospective immunotherapeutic target for HCC. | |
| Keywords | Roundabout guidance receptor 1, Prognosis, miR-152-3p, Immunotherapy, Hepatic tumorigenesis | |
| Address and Contact Information |
Department of General Surgery, Afliated Hospital of Chifeng University, No. 42 Wangfu Street, Songshan, Chifeng 024005, China *Correspondeing author: tao_y717@163.com |
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| No. 23 | DOI: 10.1186/s11658-022-00327-7 Volume 27 (2022) - 27:23 | |
| Title | ROR2 increases the chemoresistance of melanoma by regulating p53 and Bcl2‐family proteins via ERK hyperactivation | |
| Authors | María Victoria Castro1,2, Gastón Alexis Barbero1,2, Paula Máscolo1, Rocío Ramos1, María Josefna Quezada1,2 and Pablo Lopez‐Bergami1,2* | |
| Abstract | Background: ROR2 is a tyrosine-kinase receptor whose expression is dysregulated in many human diseases. In cancer, ROR2 stimulates proliferation, survival, migration, and metastasis, and is associated with more aggressive tumor stages. The purpose of this work is to study the role of ROR2 in the chemoresistance of melanoma. Methods: Gain- and loss-of-function experiments were used to study the biological function of ROR2 in melanoma. Cell death induced by chemotherapeutic drugs and BH-3 mimetics was evaluated using crystal violet cytotoxicity assays and annexin V/propidium iodide staining. Western blots were used to evaluate the expression of proteins implicated in cell death. The diferences observed between cells with manipulation of ROR2 levels and control cells were evaluated using both Student’s t-test and ANOVA. Results: We describe that ROR2 contributes to tumor progression by enhancing the resistance of melanoma cells to both chemotherapeutic drugs and BH-3 mimetics. We demonstrate that ROR2 reduced cell death upon treatment with cisplatin, dacarbazine, lomustine, camptothecin, paclitaxel, ABT-737, TW-37, and venetoclax. This efect was mediated by the inhibition of apoptosis. In addition, we investigated the molecular mechanisms implicated in this role of ROR2. We identifed the MDM2/p53 pathway as a novel target of ROR2 since ROR2 positively regulates MDM2 levels, thus leading to p53 downregulation. We also showed that ROR2 also upregulates Mcl-1 and Bcl2-xL while it negatively regulates Bax and Bid expression. The efect of ROR2 on the expression of these proteins is mediated by the hyperactivation of ERK. Conclusions: These results demonstrate that ROR2 contributes to melanoma progression by inhibiting apoptosis and increasing chemoresistance. These results not only position ROR2 as a marker of chemoresistance but also support its use as a novel therapeutic target in cancer. | |
| Keywords | ROR2, ERK, Melanoma, Chemoresistance, Apoptosis | |
| Address and Contact Information |
1 Centro de Estudios Biomédicos, Básicos, Biotecnológicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, Hidalgo 775, 6th Floor, Lab 602, 1405 Buenos Aires, Argentina 2 Consejo Nacional de Investigaciones Científcas y Técnicas (CONICET), 1425 Buenos Aires, Argentina. *Corresponding author: lopezbergami.pablo@maimonides.edu |
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| No. 24 | DOI: 10.1186/s11658-022-00321-z Volume 27 (2022) - 27:24 | |
| Title | ||
| Authors | Junqiang Li1†, Yang Song1†, Chao Zhang1†, Ronglin Wang1, Lei Hua1, Yongdong Guo1, Dongxue Gan1, Liaoliao Zhu1, Shanshan Li1, Peixiang Ma1, Cheng Yang1, Hong Li1, Jing Yang1, Jingjie Shi1, Xiaonan Liu2* and Haichuan Su1* | |
| Abstract | Background: Transmembrane protein 43 (TMEM43), a member of the transmembrane protein subfamily, plays a critical role in the initiation and development of cancers. However, little is known concerning the biological function and molecular mechanisms of TMEM43 in pancreatic cancer. Methods: In this study, TMEM43 expression levels were analyzed in pancreatic cancer samples compared with control samples. The relationship of TMEM43 expression and disease-free survival (DFS) and overall survival (OS) were assessed in pancreatic cancer patients. In vitro and in vivo assays were performed to explore the function and role of TMEM43 in pancreatic cancer. Coimmunoprecipitation (co-IP) followed by protein mass spectrometry was applied to analyze the molecular mechanisms of TMEM43 in pancreatic cancer. Results: We demonstrated that TMEM43 expression level is elevated in pancreatic cancer samples compared with control group, and is correlated with poor DFS and OS in pancreatic cancer patients. Knockdown of TMEM43 inhibited pancreatic cancer progression in vitro, decreased the percentage of S phase, and inhibited the tumorigenicity of pancreatic cancer in vivo. Moreover, we demonstrated that TMEM43 promoted pancreatic cancer progression by stabilizing PRPF3 and regulating the RAP2B/ERK axis. Conclusions: The present study suggests that TMEM43 contributes to pancreatic cancer progression through the PRPF3/RAP2B/ERK axis, and might be a novel therapeutic target for pancreatic cancer. | |
| Keywords | Pancreatic cancer, Progression, TMEM43, PRPF3, RAP2B | |
| Address and Contact Information |
1 Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an 710038, Shaanxi, China 2 Ambulatory Surgery Center, Xijing Hospital, Air Force Medical University, Xi’an 710032, Shaanxi, China *Correspondence: 15353589999@163.com;suhc@fmmu.edu.cn † Junqiang Li, Yang Song and Chao Zhang contributed equally to this work |
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| No. 25 | DOI: 10.1186/s11658-022-00326-8 Volume 27 (2022) - 27:25 | |
| Title | MiR‐5195‐3p FUNCTIONS AS A TUMOR SUPPRESSOR IN PROSTATE CANCER VIA TARGETING CCNL1 | |
| Authors | Xing Zeng, Zhiquan Hu, Yuanqing Shen, Xian Wei, Jiahua Gan and Zheng Liu* | |
| Abstract | Background: Accumulating evidence indicates that miR-5195-3p exerts tumor-suppressive roles in several tumors. However, the clinical signifcance and biological function of miR-5195-3p in prostate cancer (PCa) have not been reported yet. Methods: The expression levels of miR-5195-3p and Cyclin L1 (CCNL1) were determined using quantitative real-time PCR in clinical specimens and cell lines. The clinical signifcance of miR-5195-3p in patients with PCa was evaluated using Kaplan–Meier survival analysis and Cox regression models. Cell proliferation and cell cycle distribution were measured by CCK-8 assay and fow cytometry, respectively. The association between miR-5195-3p and CCNL1 was analyzed by luciferase reporter assay. Results: MiR-5195-3p expression levels were signifcantly downregulated in 69 paired PCa tissues compared with matched adjacent normal tissues. The decreased miR-5195-3p expression was associated with Gleason score and TNM stage, as well as worse survival prognosis. The in vitro experiments showed that miR-5195-3p overexpression suppressed the proliferation and cell cycle G1/S transition in PC-3 and DU145 cells. Elevated miR-5195-3p abundance obviously impaired tumor formation in vivo using PC-3 xenografts. Mechanistically, CCNL1 was a direct target of miR-5195-3p in PCa cells, which was inversely correlated with miR-5195-3p in PCa tissues. Importantly, CCNL1 knockdown imitated, while overexpression reversed, the efects of miR-5195-3p overexpression on PCa cell proliferation and cell cycle G1/S transition. Conclusions: Our data suggest that miR-5195-3p functions as a tumor suppressor by targeting CCNL1 in PCa. | |
| Keywords | Prostate cancer, miR-5195-3p, CCNL1, Proliferation | |
| Address and Contact Information |
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Ave, Wuhan 430030, Hubei, China *Corresponding author: liu_zheng0205@126.com |
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| No. 26 | DOI: 10.1186/s11658-022-00329-5 Volume 27 (2022) - 27:26 | |
| Title | ALKBH5 PROMOTES LUNG FBROBLAST ACTIVATION AND SILICA‐INDUCED PULMONARY FBROSIS THROUGH miR‐320a‐3p AND FOXM1 | |
| Authors | Wenqing Sun1†, Yan Li1†, Dongyu Ma1†, Yi Liu2, Qi Xu1, Demin Cheng1, Guanru Li1 and Chunhui Ni1* | |
| Abstract | Background: N6-methyladenosine (m6A) is the most common and abundant internal modifcation of RNA. Its critical functions in multiple physiological and pathological processes have been reported. However, the role of m6A in silica-induced pulmonary fbrosis has not been fully elucidated. AlkB homolog 5 (ALKBH5), a well-known m6A demethylase, is upregulated in the silica-induced mouse pulmonary fbrosis model. Here, we sought to investigate the function of ALKBH5 in pulmonary fbrosis triggered by silica inhalation. Methods: We performed studies with fbroblast cell lines and silica-induced mouse pulmonary fbrosis models. The expression of ALKBH5, miR-320a-3p, and forkhead box protein M1 (FOXM1) was determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RNA immunoprecipitation (RIP) assays and m6 A RNA immuno-precipitation assays (MeRIP), western bolt, immunofuorescence assays, and 5-ethynyl-2’-deoxyuridine (EdU) fuorescence staining were performed to explore the roles of ALKBH5, miR-320a-3p, and FOXM1 in fibroblast activation. Results: ALKBH5 expression was increased in silica-inhaled mouse lung tissues and transforming growth factor (TGF)-β1-stimulated fbroblasts. Moreover, ALKBH5 knockdown exerted antifbrotic efects in vitro. Simultaneously, downregulation of ALKBH5 elevated miR-320a-3p but decreased pri-miR-320a-3p. Mechanically, ALKBH5 demethylated pri-miR-320a-3p, thus blocking the microprocessor protein DGCR8 from interacting with pri-miR-320a-3p and leading to mature process blockage of pri-miR-320a-3p. We further demonstrated that miR-320a-3p could regulate fbrosis by targeting FOXM1 messenger RNA (mRNA) 3′-untranslated region (UTR). Notably, our study also verifed that ALKBH5 could also directly regulate FOXM1 in an m6A-dependent manner. Conclusions: Our fndings suggest that ALKBH5 promotes silica-induced lung fbrosis via the miR-320a-3p/FOXM1 axis or targeting FOXM1 directly. Approaches aimed at ALKBH5 may be efcacious in treating lung fbrosis. | |
| Keywords | Silicosis, ALKBH5, miR-320a-3p, FOXM1, m6A | |
| Address and Contact Information |
1 Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China 2 Gusu School, Nanjing Medical University, Nanjing 211166, China. *Corresponding author: chni@njmu.edu.cn; chninjmu@126.com † Wenqing Sun, Yan Li, and Dongyu Ma contributed equally to this work and should be considered co-frst authors |
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| No. 27 | DOI: 10.1186/s11658-022-00325-9 Volume 27 (2022) - 27:27 | |
| Title | INTERLEUKIN‐10 GENETICALLY MODIFED CLINICAL‐GRADE MESENCHYMAL STROMAL CELLS MARKEDLY REINFORCED FUNCTIONAL RECOVERY AFTER SPINAL CORD INJURY VIA DIRECTING ALTERNATIVE ACTIVATION OF MACROPHAGES | |
| Authors | Tianyun Gao†, Feifei Huang†, Wenqing Wang, Yuanyuan Xie and Bin Wang* | |
| Abstract | Background: After spinal cord injury (SCI), dysregulated or nonresolving infammatory processes can severely disturb neuronal homeostasis and drive neurodegeneration. Although mesenchymal stromal cell (MSC)-based therapies have showed certain therapeutic efcacy, no MSC therapy has reached its full clinical goal. In this study, we examine interleukin-10 (IL10) genetically modifed clinical-grade MSCs (IL10-MSCs) and evaluate their clinical safety, efectiveness, and therapeutic mechanism in a completely transected SCI mouse model. Methods: We established stable IL10-overexpressing human umbilical-cord-derived MSCs through electric transduction and screened out clinical-grade IL10-MSCs according to the criteria of cell-based therapeutic products, which were applied to mice with completely transected SCI by repeated tail intravenous injections. Then we comprehensively investigated the motor function, histological structure, and nerve regeneration in SCI mice, and further explored the potential therapeutic mechanism after IL10-MSC treatment. Results: IL10-MSC treatment markedly reinforced locomotor improvement, accompanied with decreased lesion volume, regeneration of axons, and preservation of neurons, compared with naïve unmodifed MSCs. Further, IL10-MSC transplantation increased the ratio of microglia to infltrated alternatively activated macrophages (M2), and reduced the ratio of classically activated macrophages (M1) at the injured spinal cord, meanwhile increasing the percentage of Treg and Th2 cells, and reducing the percentage of Th1 cells in the peripheral circulatory system. In addition, IL10-MSC administration could prevent apoptosis and promote neuron diferentiation of neural stem cells (NSCs) under infammatory conditions in vitro. Conclusions: IL10-MSCs exhibited a reliable safety profle and demonstrated promising therapeutic efcacy in SCI compared with naïve MSCs, providing solid support for future clinical application of genetically engineered MSCs. | |
| Keywords | MSCs, Interleukin 10, Gene modifcation, Spinal cord injury, Cell-based therapy, Cell quality assessment | |
| Address and Contact Information |
Center for Clinic Stem Cell Research, the Afliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China *Corresponding author: wangbin022800@126.com † Tianyun Gao and Feifei Huang contributed equally to this study |
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| No. 28 | DOI: 10.1186/s11658-022-00324-w Volume 27 (2022) - 27:28 | |
| Title | PARECOXIB INHIBITS ESOPHAGEAL SQUAMOUS CELL CARCINOMA PROGRESSION VIA THE PDK1–AKT PATHWAY | |
| Authors | Han‐Ming Huang1, Xiao‐Yu Huang1, Shao‐Ping Wu1, Can‐Keng Chen1, Xin‐Hua He2* and Yong‐Fa Zhang1* | |
| Abstract | Background: Parecoxib plays an important role in inhibition of human cancer. However, the efect of parecoxib on esophageal squamous cell carcinoma (ESCC) is still not well known. The purpose of this study was to investigate the efect of parecoxib on ESCC and its underlying mechanism. Methods: RNA-sequence analysis was performed to identify functional alterations and mechanisms. Cell cycle, proliferation, invasion, and migration were assessed using fow cytometry, CCK-8 assay, colony formation, transwell, and wound healing assays. Extracellular matrix (ECM) degradation was detected by substrate gel zymography and 3D cell culture assay. Western blotting was used to detect parecoxib-dependent mechanisms involving cell cycle, proliferation, invasion, and migration. Tumor formation in vivo was detected by mouse assay. Results: Functional experiments indicated that parecoxib induced ESCC cell cycle arrest in G2 phase, and inhibited cell proliferation, invasion, and migration in vitro. Western blotting revealed that parecoxib downregulated the phosphorylation levels of AKT and PDK1, as well as the expression of the mutant p53, cyclin B1, and CDK1, while upregulating p21waf1. Parecoxib inhibited matrix metalloproteinase-2 (MMP2) secretion and invadopodia formation, which were related to ECM degradation. Furthermore, we found that parecoxib suppressed ESCC growth in heterotopic tumor models. Conclusion: Parecoxib inhibits ESCC progression, including cell cycle, proliferation, invasion, and migration, via the PDK1–AKT signaling pathway. | |
| Keywords | Parecoxib, Mutant p53, PDK1–AKT, ESCC | |
| Address and Contact Information |
1 Department of Anesthesiology, Second Afliated Hospital of Shantou University Medical College, Shantou 515041, People’s Republic of China 2 Department of Physiology, Shantou University Medical College, Shantou 515041, People’s Republic of China *Corresponding author: Hexh@stu.edu.cn; 10yfzhang1@stu.edu.cn |
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| No. 29 | DOI: 10.1186/s11658-022-00318-8 Volume 27 (2022) - 27:29 | |
| Title | OBACUNONE ALLEVIATES FERROPTOSIS DURING LIPOPOLYSACCHARIDE‐INDUCED ACUTE LUNG INJURY BY UPREGULATING Nrf2‐DEPENDENT ANTIOXIDANT RESPONSES | |
| Authors | Jin Li1,2†, Shi‐hua Deng1,2†, Jing Li1,2†, Li Li1,2, Feng Zhang1,2, Ye Zou1,2, Dong‐ming Wu1,2* and Ying Xu1,2* | |
| Abstract | Background: Acute lung injury (ALI) has received considerable attention in the feld of intensive care as it is associated with a high mortality rate. Obacunone (OB), widely found in citrus fruits, is a natural bioactive compound with anti-infammatory and antioxidant activities. However, it is not clear whether OB protects against lipopolysaccharide (LPS)-induced ALI. Therefore, in this study, we aimed to evaluate the protective efects of OB and the potential mechanisms against LPS-induced ALI and BEAS-2B cell injury. Methods: We established a model of BEAS-2B cell injury and a mouse model of ALI by treating with LPS. Samples of in vitro model were subjected to cell death, Cell Counting Kit-8, and lactate dehydrogenase (LDH) release assays. The total number of cells and neutrophils, protein content, and levels of IL-6, TNF-α, and IL-1β were determined in bronchoalveolar lavage fuid (BALF). Glutathione, reactive oxygen species, and malondialdehyde levels were determined in lung tissue. Additionally, immunohistochemical analysis, immunofuorescence, western blot, quantitative real-time PCR, and enzymelinked immunosorbent assay were conducted to examine the efects of OB. Furthermore, mice were treated with an Nrf2 inhibitor (ML385) to verify its role in ferroptosis. Data were analyzed using one-way analysis of variance or paired t-tests. Results: Compared with the LPS group, OB efectively alleviated LPS-induced ALI by decreasing lung wet/dry weight ratio, reactive oxygen species and malondialdehyde production, and superoxide dismutase and glutathione consumption in vivo. In addition, OB signifcantly alleviated lung histopathological injury, reduced infammatory cytokine secretion and Fe2+ and 4-HNE levels, and upregulated GPX4, SLC7A11, and Nrf2 expression. Mechanistically, OB activated Nrf2 by inhibiting Nrf2 ubiquitinated proteasome degradation. ML385 reversed the protective efects of OB against LPS-induced ALI. Conclusion: Overall, OB alleviates LPS-induced ALI, making it a potential novel protective agent against LPS-induced ALI. | |
| Keywords | Obacunone, Nrf2, Ferroptosis, Acute lung injury, Lipopolysaccharide | |
| Address and Contact Information |
1 The First Afliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, People’s Republic of China. 2 School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan 610500, People’s Republic of China. *Corresponding author: harvey1989@126.com; yingxu825@126.com † Jin Li, Shi-hua Deng, and Jing Li contributed equally to this work and share first authorship |
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| No. 30 | DOI: 10.1186/s11658-022-00328-6 Volume 27 (2022) - 27:30 | |
| Title | SETD8 COOPERATES WITH MZF1 TO PARTICIPATE IN HYPERGLYCEMIA‐INDUCED ENDOTHELIAL INFAMMATION VIA ELEVATION OF WNT5A LEVELS IN DIABETIC NEPHROPATHY | |
| Authors | Fei Wang1†, Wenting Hou1†, Xue Li1, Lihong Lu1, Ting Huang1, Minmin Zhu1,2* and Changhong Miao3* | |
| Abstract | Objective: Diabetic nephropathy (DN) is regarded as the main vascular complication of diabetes mellitus, directly afecting the outcome of diabetic patients. Infammatory factors were reported to participate in the progress of DN. Wingless-type family member 5 (WNT5A), myeloid zinc fnger 1 (MZF1), and lysine methyltransferase 8 (SETD8) have also been reported to elevate infammatory factor levels and activate the nuclear factor kappa B (NF-κB) pathway to induce endothelial dysfunction. In the current study, it was assumed that MZF1 associates with SETD8 to regulate WNT5A transcription, thus resulting in hyperglycemia-induced glomerular endothelial infammation in DN. Methods: The present study recruited 25 diagnosed DN patients (type 2 diabetes) and 25 control participants (nondiabetic renal cancer patients with normal renal function, stage I–II) consecutively. Moreover, a DN rat and cellular model was constructed in the present study. Immunohistochemistry, Western blot, and quantitative polymerase chain reaction (qPCR) were implemented to determine protein and messenger RNA (mRNA) levels. Coimmunoprecipitation (CoIP) and immunofuorescence were implemented in human glomerular endothelial cells (HGECs). Chromatin immunoprecipitation assays and dual luciferase assays were implemented to determine transcriptional activity. Results: The results of this study indicated that levels of WNT5A expression, p65 phosphorylation (p-p65), and infammatory factors were all elevated in DN patients and rats. In vitro, levels of p-p65 and infammatory factors increased along with the increase of WNT5A expression in hyperglycemic HGECs. Moreover, high glucose increased MZF1 expression and decreased SETD8 expression. MZF1 and SETD8 inhibit each other under the stimulus of high glucose, but cooperate to regulate WNT5A expression, thus infuencing p-p65 and endothelial infammatory factors levels. Overexpression of MZF1 and silencing of SETD8 induced endothelial p-p65 and infammatory factors levels, which can be reversed by si-WNT5A. Mechanistic research indicated that MZF1, SETD8, and its downstream target histone H4 lysine 20 methylation (H4K20me1) all occupied the WNT5A promoter region. sh-SETD8 expanded the enrichment of MZF1 on WNT5A promoter. Our in vivo study proved that SETD8 overexpression inhibited levels of WNT5A, p-p65 expression, and infammatory factors in DN rats. Conclusions: MZF1 links with SETD8 to regulate WNT5A expression in HGECs, thus elevating levels of hyperglycemia-mediated infammatory factors in glomerular endothelium of DN patients and rats. | |
| Keywords | Diabetic nephropathy, SETD8, Endothelial | |
| Address and Contact Information |
1 Department of Anesthesiology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. 2 Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, People’s Republic of China. 3 Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. *Corresponding author: zhu_mm@126.com; miao_chh@126.com † Fei Wang and Wenting Hou contributed equally to this work |
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| No. 31 | DOI: 10.1186/s11658-022-00330-y Volume 27 (2022) - 27:31 | |
| Title | CircRbms1 KNOCKDOWN ALLEVIATES HYPOXIA‐INDUCED CARDIOMYOCYTE INJURY VIA REGULATING THE miR‐742‐3p/FOXO1 AXIS | |
| Authors | Bo Liu and Kai Guo* | |
| Abstract | Background: Circular RNA (circRNA) has been shown to play an important role in a variety of cardiovascular diseases, including myocardial infarction (MI). However, the role of circRbms1 in MI progression remains unclear. Methods: An MI mouse model was constructed in vivo, and cardiomyocytes were cultured under hypoxia condition to induce a cardiomyocyte injury model in vitro. The expression levels of circRbms1, microRNA (miR)-742-3p, and forkhead box O1 (FOXO1) were determined by quantitative real-time PCR. Cell viability, migration, invasion, and apoptosis were measured using Cell Counting Kit-8 assay, transwell assay, and flow cytometry. Meanwhile, western blot analysis was used to examine the protein levels of apoptosis markers and FOXO1. Additionally, dual-luciferase reporter assay, RNA pull-down assay, and RIP assay were employed to verify the interactions between miR-742-3p and circRbms1 or FOXO1. Results: CircRbms1 was upregulated in the heart tissues of MI mice and hypoxia-induced cardiomyocytes. Hypoxia induced cardiomyocyte injury by suppressing cell viability, migration, and invasion, and promoting apoptosis. Function experiments showed that circRbms1 overexpression aggravated hypoxia-induced cardiomyocyte injury, while its silencing relieved cardiomyocyte injury induced by hypoxia. Furthermore, circRbms1 sponged miR-742-3p. MiR-742-3p overexpression alleviated hypoxia-induced cardiomyocyte injury, and its inhibitor reversed the suppressive efect of circRbms1 silencing on hypoxia-induced cardiomyocyte injury. Further experiments showed that FOXO1 was a target of miR-742-3p, and its expression was positively regulated by circRbms1. The inhibitory efect of miR-742-3p on hypoxia-induced cardiomyocyte injury was reversed by FOXO1 overexpression. Conclusion: CircRbms1 regulated the miR-742-3p/FOXO1 axis to mediate hypoxia-induced cardiomyocyte injury, suggesting that circRbms1 might be an efective target for MI treatment. | |
| Keywords | Myocardial infarction, Hypoxia, CircRbms1, MiR-742-3p, FOXO1 | |
| Address and Contact Information |
Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665 Kongjiang Road, 20092 Shanghai, China *Corresponding: guokai@xinhuamed.com.cn |
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| No. 32 | DOI: 10.1186/s11658-022-00334-8 Volume 27 (2022) - 27:32 | |
| Title | TIGHT ASSOCIATION OF AUTOPHAGY AND CELL CYCLE IN LEUKEMIA CELLS | |
| Authors | Alena Gschwind1,2†, Christian Marx3†, Marie D. Just1,2, Paula Severin1,2, Hannah Behring1,2, Lisa Marx‐Blümel1,2, Sabine Becker1,2, Linda Rothenburger3, Martin Förster4, James F. Beck1 and Jürgen Sonnemann1,2,5* | |
| Abstract | Background: Autophagy plays an essential role in maintaining cellular homeostasis and in the response to cellular stress. Autophagy is also involved in cell cycle progression, yet the relationship between these processes is not clearly defned. Results: In exploring this relationship, we observed that the inhibition of autophagy impaired the G2/M phase-arresting activity of etoposide but enhanced the G1 phase-arresting activity of palbociclib. We further investigated the connection of basal autophagy and cell cycle by utilizing the autophagosome tracer dye Cyto-ID in two ways. First, we established a double-labeling fow-cytometric procedure with Cyto-ID and the DNA probe DRAQ5, permitting the cell cycle phase-specifc determination of autophagy in live cells. This approach demonstrated that diferent cell cycle phases were associated with diferent autophagy levels: G1-phase cells had the lowest level, and G2/M-phase cells had the highest one. Second, we developed a fow-cytometric cell-sorting procedure based on Cyto-ID that separates cell populations into fractions with low, medium, and high autophagy. Cell cycle analysis of Cyto-ID-sorted cells confrmed that the high-autophagy fraction contained a much higher percentage of G2/M-phase cells than the low-autophagy fraction. In addition, Cyto-ID-based cell sorting also proved to be useful for assessing other autophagy-related processes: extracellular fux analysis revealed metabolic diferences between the cell populations, with higher autophagy being associated with higher respiration, higher mitochondrial ATP production, and higher glycolysis. Conclusion: This work provides clear evidence of high autophagy in G2/M-phase cells by establishing a novel cell sorting technique based on Cyto-ID. | |
| Keywords | Autophagy, Cell cycle, Cell sorting, Cyto-ID, DRAQ5, Metabolic analysis | |
| Address and Contact Information |
1 Department of Pediatric Hematology and Oncology, Children’s Clinic, Jena University Hospital, Jena, Germany. 2 Research Center Lobeda, Jena University Hospital, 07747 Jena, Germany. 3 Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), 07747 Jena, Germany. 4 Clinic of Internal Medicine I, Jena University Hospital, 07747 Jena, Germany. 5 Klinik für Kinder und Jugendmedizin, Universitätsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany. *Corresponding author: juergen.sonnemann@med.uni-jena.de † Alena Gschwind and Christian Marx have contributed equally to this work |
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