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Costantini C, Brancorsini S, Grignani F, Romani L, Bellet MM. Circadian metabolic adaptations to infections. Philos Trans R Soc Lond B Biol Sci 2025; 380:20230473. [PMID: 39842481 PMCID: PMC11753887 DOI: 10.1098/rstb.2023.0473] [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: 01/04/2024] [Revised: 04/22/2024] [Accepted: 05/16/2024] [Indexed: 01/24/2025] Open
Abstract
Circadian clocks are biological oscillators that evolved to coordinate rhythms in behaviour and physiology around the 24-hour day. In mammalian tissues, circadian rhythms and metabolism are highly intertwined. The clock machinery controls rhythmic levels of circulating hormones and metabolites, as well as rate-limiting enzymes catalysing biosynthesis or degradation of macromolecules in metabolic tissues, such control being exerted both at the transcriptional and post-transcriptional level. During infections, major metabolic adaptation occurs in mammalian hosts, at the level of both the single immune cell and the whole organism. Under these circumstances, the rhythmic metabolic needs of the host intersect with those of two other players: the pathogen and the microbiota. These three components cooperate or compete to meet their own metabolic demands across the 24 hours. Here, we review findings describing the circadian regulation of the host response to infection, the circadian metabolic adaptations occurring during host-microbiota-pathogen interactions and how such regulation can influence the immune response of the host and, ultimately, its own survival.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.
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Affiliation(s)
- Claudio Costantini
- Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, Perugia06132, Italy
| | - Stefano Brancorsini
- Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, Perugia06132, Italy
| | - Francesco Grignani
- Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, Perugia06132, Italy
| | - Luigina Romani
- Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, Perugia06132, Italy
| | - Marina Maria Bellet
- Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, Perugia06132, Italy
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2
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Givonetti A, Galantin C, Fiorilla I, Todesco AM, Braghin M, Uga E, Cosi G, Audrito V, Cavaletto M. Impact of holder pasteurization on protein and eNAMPT/Visfatin content in human breast milk. Sci Rep 2024; 14:29246. [PMID: 39587277 PMCID: PMC11589111 DOI: 10.1038/s41598-024-80706-6] [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: 07/31/2024] [Accepted: 11/21/2024] [Indexed: 11/27/2024] Open
Abstract
Human milk proteins, a mixture of whey proteins including caseins, milk fat globule membrane (MFGM) proteins, various peptides, and their amino acids, play a crucial role in infant growth and development, as do non-nutritional bioactive components. The extracellular nicotinamide phosphoribosyltransferase (eNAMPT) or visfatin is a conserved cytokine/enzyme released by many mammalian cells, related to multiple metabolic and immune processes. Few investigations have been reported about detecting visfatin in skimmed milk and the hypothesis of its potential role in regulating infant adiposity through breast milk. Milk samples from a donated human milk bank were analyzed. After milk fractionation by centrifugation, skimmed milk and MFGM were analyzed by SDS-PAGE, MALDI-TOF mass spectrometry ELISA and/or Western blot. The ELISA assay showed a higher visfatin content in raw skimmed milk than in pasteurized samples. Meanwhile, MFGMs revealed higher visfatin levels in pasteurized samples. This is the first time visfatin has been identified associated with MFGM, and these results could suggest an affinity of this molecule for a lipidic environment.
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Affiliation(s)
- Annalisa Givonetti
- Department of Sustainable Development and Ecological Transition (DiSSTE), University of Piemonte Orientale, Piazza S. Eusebio 5, Vercelli, 13100, Italy.
| | - Chiara Galantin
- Department of Sustainable Development and Ecological Transition (DiSSTE), University of Piemonte Orientale, Piazza S. Eusebio 5, Vercelli, 13100, Italy
| | - Irene Fiorilla
- Department of Science and Technological Innovation (DISIT), University of Piemonte Orientale, Viale Teresa Michel 11, Alessandria, 15121, Italy
| | - Alberto Maria Todesco
- Department of Science and Technological Innovation (DISIT), University of Piemonte Orientale, Viale Teresa Michel 11, Alessandria, 15121, Italy
| | - Michela Braghin
- Complex facility of pediatrics, St. Andrea Hospital Pole, Corso Mario Abbiate 21, Vercelli, VC, 13100, Italy
| | - Elena Uga
- Complex facility of pediatrics, St. Andrea Hospital Pole, Corso Mario Abbiate 21, Vercelli, VC, 13100, Italy
| | - Gianluca Cosi
- Complex facility of pediatrics, St. Andrea Hospital Pole, Corso Mario Abbiate 21, Vercelli, VC, 13100, Italy
| | - Valentina Audrito
- Department of Science and Technological Innovation (DISIT), University of Piemonte Orientale, Viale Teresa Michel 11, Alessandria, 15121, Italy
| | - Maria Cavaletto
- Department of Sustainable Development and Ecological Transition (DiSSTE), University of Piemonte Orientale, Piazza S. Eusebio 5, Vercelli, 13100, Italy
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3
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Peng A, Li J, Xing J, Yao Y, Niu X, Zhang K. The function of nicotinamide phosphoribosyl transferase (NAMPT) and its role in diseases. Front Mol Biosci 2024; 11:1480617. [PMID: 39513038 PMCID: PMC11540786 DOI: 10.3389/fmolb.2024.1480617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 10/11/2024] [Indexed: 11/15/2024] Open
Abstract
Nicotinamide phosphoribosyl transferase (NAMPT) is a rate-limiting enzyme in the mammalian nicotinamide adenine dinucleotide (NAD) salvage pathway, and plays a vital role in the regulation of cell metabolic activity, reprogramming, aging and apoptosis. NAMPT synthesizes nicotinamide mononucleotide (NMN) through enzymatic action, which is a key protein involved in host defense mechanism and plays an important role in metabolic homeostasis and cell survival. NAMPT is involved in NAD metabolism and maintains intracellular NAD levels. Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases (HDACs), the members are capable of sensing cellular NAD+ levels. NAMPT-NAD and SIRT constitute a powerful anti-stress defense system. In this paper, the structure, biological function and correlation with diseases of NAMPT are introduced, aiming to provide new ideas for the targeted therapy of related diseases.
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Affiliation(s)
| | | | | | | | | | - Kaiming Zhang
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Center Hospital, Taiyuan, China
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Machado-Junior PA, Dias MSS, de Souza ABF, Lopes LSE, Menezes TP, Talvani A, Brochard L, Bezerra FS. A short duration of mechanical ventilation alters redox status in the diaphragm and aggravates inflammation in septic mice. Respir Physiol Neurobiol 2024; 331:104361. [PMID: 39433197 DOI: 10.1016/j.resp.2024.104361] [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: 09/04/2024] [Revised: 10/07/2024] [Accepted: 10/13/2024] [Indexed: 10/23/2024]
Abstract
BACKGROUND Mechanical ventilation (MV) is a life support method used to treat patients with respiratory failure. High tidal volumes during MV can cause ventilator-induced lung injury (VILI), but also affect other organs, such as the diaphragm (Dia) causing ventilator-induced diaphragmatic dysfunction (VIDD). VIDD is often associated with a complicated course on MV. Sepsis can induce inflammation and oxidative stress, contributing to the impairment of the Dia and worsening of the prognosis. This study evaluated the additive or synergistic effects of a short course of mechanical ventilation on Dia in healthy and septic adult mice. METHODS 32 adult male C57BL/6 mice were randomly into four groups: Control (CG), non-ventilated animals instilled with saline solution (PBS1x); Lipopolysaccharide (LPS), non-ventilated animals instilled with PBS solution containing lipopolysaccharide; Mechanical Ventilation (MV) for 1 h, ventilated animals instilled with PBS solution; and Mechanical Ventilation and LPS (MV+LPS), ventilated animals instilled with PBS solution containing LPS. At the end of the experimental protocol, the animals were euthanized, then blood and diaphragm tissue samples were collected. RESULTS Evaluation of leukocyte/blood parameters and diaphragm muscle showed that MV, LPS and the combination of both were able to increase neutrophil count, creatine kinase, inflammatory mediators and oxidative stress in all groups compared to the control. MV and sepsis combined had additive effects on inflammation and lipid peroxidation. CONCLUSIONS A short course of Mechanical ventilation promotes inflammation and oxidative stress and, its combination with sepsis further increases local and systemic inflammation.
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Affiliation(s)
- Pedro Alves Machado-Junior
- Laboratory of Experimental Pathophysiology (LAFEx), Department of Biological Sciences and Center of Research in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, MG 35400-000, Brazil
| | - Marcelo Santiago Soares Dias
- Laboratory of Experimental Pathophysiology (LAFEx), Department of Biological Sciences and Center of Research in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, MG 35400-000, Brazil
| | - Ana Beatriz Farias de Souza
- Laboratory of Experimental Pathophysiology (LAFEx), Department of Biological Sciences and Center of Research in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, MG 35400-000, Brazil
| | - Leonardo Spinelli Estevão Lopes
- Laboratory of Experimental Pathophysiology (LAFEx), Department of Biological Sciences and Center of Research in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, MG 35400-000, Brazil
| | - Tatiana Prata Menezes
- Laboratory of Immunobiology of Inflammation (LABIIN), Department of Biological Sciences (DECBI), Institute of Exact and Biological Sciences (ICEB), Federal University of Ouro Preto (UFOP), Ouro Preto, MG 35400-000, Brazil
| | - André Talvani
- Laboratory of Immunobiology of Inflammation (LABIIN), Department of Biological Sciences (DECBI), Institute of Exact and Biological Sciences (ICEB), Federal University of Ouro Preto (UFOP), Ouro Preto, MG 35400-000, Brazil
| | - Laurent Brochard
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
| | - Frank Silva Bezerra
- Laboratory of Experimental Pathophysiology (LAFEx), Department of Biological Sciences and Center of Research in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, MG 35400-000, Brazil; Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.
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Dawid M, Kurowska P, Pawlicki P, Kotula-Balak M, Milewicz T, Dupont J, Rak A. Visfatin (NAMPT) expression in human placenta cells in normal and pathological conditions and its hormonal regulation in trophoblast JEG-3 cells. PLoS One 2024; 19:e0310389. [PMID: 39292698 PMCID: PMC11410215 DOI: 10.1371/journal.pone.0310389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 08/30/2024] [Indexed: 09/20/2024] Open
Abstract
Visfatin is an adipokine involved in energy metabolism, insulin resistance, inflammation, and female reproduction. Due to limited data about its action in the human placenta, the aims of our studies included the analysis of visfatin expression and immunolocalization in trophoblast cell lines JEG-3 and BeWo as well as in human placentas from normal and pathological pregnancies. Moreover, we also checked the hormonal regulation of visfatin levels and the molecular mechanism of observed changes in JEG-3 cells. Cell culture and placental fragments collection along with statistical analysis were performed using standard laboratory procedures also described in our previous papers. We demonstrated an increased gene and protein expression of visfatin in JEG-3, BeWo cells, while variable expression in maternal and fetal parts of normal/ pathological pregnancy placentas. In addition, the immunolocalization of visfatin was observed in the cytoplasm of both cell lines, the capillary epithelium of the maternal part and syncytiotrophoblasts of the placental fetal part; in all tested pathologies, the signal was also detected in decidual cells. Furthermore, we demonstrated that hormones: progesterone, estradiol, human chorionic gonadotropin, and insulin increased the visfatin levels in JEG-3 cells with the involvement of specific signaling pathways. Taken together, differences in the expression and localization of visfatin between normal and pathological placentas suggested that visfatin may be a potential marker for the diagnosis of pregnancy disorders. In addition, we found that placental levels of visfatin can be regulated by hormones known to modulate the function of placental cells.
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Affiliation(s)
- Monika Dawid
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Kraków, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University in Kraków, Kraków, Poland
| | - Patrycja Kurowska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Kraków, Poland
| | - Piotr Pawlicki
- Department of Animal Anatomy and Preclinical Sciences, University Centre of Veterinary Medicine JU-UA, University of Agriculture in Krakow, Kraków, Poland
| | - Małgorzata Kotula-Balak
- Center of Experimental and Innovative Medicine, University of Agriculture in Krakow, Kraków, Poland
| | - Tomasz Milewicz
- Department of Gynecological Endocrinology, Jagiellonian University Medical College, Kraków, Poland
| | - Joelle Dupont
- INRAE, UMR0085, Unité Physiologie de la Reproduction et des Comportements, Nouzilly, France
| | - Agnieszka Rak
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Kraków, Poland
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Wu F, Han Y, Xiong Q, Tang H, Shi J, Yang Q, Li X, Jia H, Qian J, Dong Y, Li T, Gao Y, Qian Z, Wang H, Wang T. Cerebral Endothelial CXCR2 Promotes Neutrophil Transmigration into Central Nervous System in LPS-Induced Septic Encephalopathy. Biomedicines 2024; 12:1536. [PMID: 39062109 PMCID: PMC11274668 DOI: 10.3390/biomedicines12071536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/21/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
Septic encephalopathy (SE) represents a severe inflammatory syndrome linked to elevated septic mortality rates, lacking specific therapeutic interventions, and often resulting in enduring neurological sequelae. The present investigation endeavors to elucidate the involvement of C-X-C Motif Chemokine Receptor 2 (CXCR2) in the pathogenesis of SE and to explore the potential of CXCR2 modulation as a therapeutic avenue for SE. Employing a murine SE model induced by lipopolysaccharide (LPS) administration, CXCR2 knockout mice and the CXCR2 inhibitor SB225002 were utilized to assess neutrophil recruitment, endothelial integrity, and transendothelial migration. Our findings substantiate that either CXCR2 deficiency or its inhibition curtails neutrophil recruitment without impacting their adhesion to cerebral endothelial cells. This phenomenon is contingent upon endothelial CXCR2 expression rather than CXCR2's presence on neutrophils. Furthermore, the CXCR2 blockade preserves the integrity of tight junction protein ZO-1 and mitigates F-actin stress fiber formation in cerebral endothelial cells following septic challenge. Mechanistically, CXCL1-mediated CXCR2 activation triggers cerebral endothelial actin contraction via Rho signaling, thereby facilitating neutrophil transmigration in SE. These observations advocate for the potential therapeutic efficacy of CXCR2 inhibition in managing SE.
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Affiliation(s)
- Fengjiao Wu
- Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Anhui Provincial Key Laboratory of Infection and Immunology, Department of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, China
| | - Yuhong Han
- Department of Clinical Laboratory, The Second People’s Hospital of Fuyang City, Fuyang 236015, China
| | - Qianqian Xiong
- Department of Clinical Laboratory, Nanjing Meishan Hospital, Nanjing 210041, China
| | - Haitao Tang
- Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Anhui Provincial Key Laboratory of Infection and Immunology, Department of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, China
| | - Jing Shi
- Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Anhui Provincial Key Laboratory of Infection and Immunology, Department of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, China
| | - Qingqing Yang
- Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Anhui Provincial Key Laboratory of Infection and Immunology, Department of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, China
| | - Xuemeng Li
- Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Anhui Provincial Key Laboratory of Infection and Immunology, Department of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, China
| | - Haoxuan Jia
- Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Anhui Provincial Key Laboratory of Infection and Immunology, Department of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, China
| | - Jun Qian
- Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Anhui Provincial Key Laboratory of Infection and Immunology, Department of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, China
| | - Yishu Dong
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
| | - Tuantuan Li
- Department of Clinical Laboratory, The Second People’s Hospital of Fuyang City, Fuyang 236015, China
| | - Yong Gao
- Department of Clinical Laboratory, The Second People’s Hospital of Fuyang City, Fuyang 236015, China
| | - Zhongqing Qian
- Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Anhui Provincial Key Laboratory of Infection and Immunology, Department of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, China
| | - Hongtao Wang
- Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Anhui Provincial Key Laboratory of Infection and Immunology, Department of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, China
| | - Ting Wang
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
- Department of Internal Medicine, University of Arizona, Phoenix, AZ 85004, USA
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7
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Dobrzyn K, Kopij G, Kiezun M, Zaobidna E, Gudelska M, Zarzecka B, Paukszto L, Rak A, Smolinska N, Kaminski T. Visfatin (NAMPT) affects global gene expression in porcine anterior pituitary cells during the mid-luteal phase of the oestrous cycle. J Anim Sci Biotechnol 2024; 15:96. [PMID: 38978053 PMCID: PMC11232246 DOI: 10.1186/s40104-024-01054-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 05/23/2024] [Indexed: 07/10/2024] Open
Abstract
BACKGROUND The pituitary belongs to the most important endocrine glands involved in regulating reproductive functions. The proper functioning of this gland ensures the undisturbed course of the oestrous cycle and affects the female's reproductive potential. It is believed that visfatin, a hormone belonging to the adipokine family, may regulate reproductive functions in response to the female's metabolic state. Herein we verified the hypothesis that suggests a modulatory effect of visfatin on the anterior pituitary transcriptome during the mid-luteal phase of the oestrous cycle. RESULTS RNA-seq analysis of the porcine anterior pituitary cells revealed changes in the expression of 202 genes (95 up-regulated and 107 down-regulated in the presence of visfatin, when compared to the non-treated controls), assigned to 318 gene ontology terms. We revealed changes in the frequency of alternative splicing events (235 cases), as well as long noncoding RNA expression (79 cases) in the presence of the adipokine. The identified genes were associated, among others, with reproductive system development, epithelial cell proliferation, positive regulation of cell development, gland morphogenesis and cell chemotaxis. CONCLUSIONS The obtained results indicate a modulatory influence of visfatin on the regulation of the porcine transcriptome and, in consequence, pituitary physiology during the mid-luteal phase of the oestrous cycle.
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Affiliation(s)
- Kamil Dobrzyn
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.
| | - Grzegorz Kopij
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Marta Kiezun
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Ewa Zaobidna
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Marlena Gudelska
- School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Barbara Zarzecka
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Lukasz Paukszto
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Agnieszka Rak
- Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland
| | - Nina Smolinska
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Tadeusz Kaminski
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
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8
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Kopij G, Kiezun M, Gudelska M, Dobrzyn K, Zarzecka B, Rytelewska E, Zaobidna E, Swiderska B, Malinowska A, Rak A, Kaminski T, Smolinska N. Visfatin impact on the proteome of porcine luteal cells during implantation. Sci Rep 2024; 14:14625. [PMID: 38918475 PMCID: PMC11199572 DOI: 10.1038/s41598-024-65577-1] [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: 02/08/2024] [Accepted: 06/21/2024] [Indexed: 06/27/2024] Open
Abstract
Visfatin (VIS) is a hormone belonging to the adipokines' group secreted mainly by the adipose tissue. VIS plays a crucial role in the control of energy homeostasis, inflammation, cell differentiation, and angiogenesis. VIS expression was confirmed in the hypothalamic-pituitary-gonadal (HPG) axis structures, as well as in the uterus, placenta, and conceptuses. We hypothesised that VIS may affect the abundance of proteins involved in the regulation of key processes occurring in the corpus luteum (CL) during the implantation process in pigs. In the present study, we performed the high-throughput proteomic analysis (liquid chromatography with tandem mass spectrometry, LC-MS/MS) to examine the in vitro influence of VIS (100 ng/mL) on differentially regulated proteins (DRPs) in the porcine luteal cells (LCs) on days 15-16 of pregnancy (implantation period). We have identified 511 DRPs, 276 of them were up-regulated, and 235 down-regulated in the presence of VIS. Revealed DRPs were assigned to 162 gene ontology terms. Western blot analysis of five chosen DRPs, ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1), lanosterol 14-α demethylase (CYP51A1), inhibin subunit beta A (INHBA), notch receptor 3 (NOTCH3), and prostaglandin E synthase 2 (mPGES2) confirmed the veracity and accuracy of LC-MS/MS method. We indicated that VIS modulates the expression of proteins connected with the regulation of lipogenesis and cholesterologenesis, and, in consequence, may be involved in the synthesis of steroid hormones, as well as prostaglandins' metabolism. Moreover, we revealed that VIS affects the abundance of protein associated with ovarian cell proliferation, differentiation, and apoptosis, as well as CL new vessel formation and tissue remodelling. Our results suggest important roles for VIS in the regulation of ovarian functions during the peri-implantation period.
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Affiliation(s)
- Grzegorz Kopij
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Marta Kiezun
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Marlena Gudelska
- School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Kamil Dobrzyn
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Barbara Zarzecka
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Edyta Rytelewska
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Ewa Zaobidna
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Bianka Swiderska
- Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics PAS in Warsaw, Warsaw, Poland
| | - Agata Malinowska
- Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics PAS in Warsaw, Warsaw, Poland
| | - Agnieszka Rak
- Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Kraków, Poland
| | - Tadeusz Kaminski
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Nina Smolinska
- Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.
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9
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de Jong MME, Fokkema C, Papazian N, Czeti Á, Appelman MK, Vermeulen M, van Heusden T, Hoogenboezem RM, van Beek G, Tahri S, Sanders MA, van de Woestijne PC, Gay F, Moreau P, Büttner-Herold M, Bruns H, van Duin M, Broijl A, Sonneveld P, Cupedo T. An IL-1β-driven neutrophil-stromal cell axis fosters a BAFF-rich protumor microenvironment in individuals with multiple myeloma. Nat Immunol 2024; 25:820-833. [PMID: 38600356 DOI: 10.1038/s41590-024-01808-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 03/11/2024] [Indexed: 04/12/2024]
Abstract
Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner, and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting antimyeloma treatment, human bone marrow retains residual stromal inflammation, and newly formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.
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Affiliation(s)
- Madelon M E de Jong
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Cathelijne Fokkema
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Natalie Papazian
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Ágnes Czeti
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Marjolein K Appelman
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Michael Vermeulen
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Teddie van Heusden
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Remco M Hoogenboezem
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Gregory van Beek
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Sabrin Tahri
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Mathijs A Sanders
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | | | - Francesca Gay
- Clinical Trial Unit, Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy
| | - Philippe Moreau
- Department of Hematology, Nantes University Hospital Hotel-Dieu, Nantes, France
| | - Maike Büttner-Herold
- Department of Internal Medicine 5, Hematology and Oncology, Friedrich Alexander University Erlangen-Nuremberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Heiko Bruns
- Department of Internal Medicine 5, Hematology and Oncology, Friedrich Alexander University Erlangen-Nuremberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Mark van Duin
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Annemiek Broijl
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Pieter Sonneveld
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
| | - Tom Cupedo
- Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
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10
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Shankar-Hari M, Calandra T, Soares MP, Bauer M, Wiersinga WJ, Prescott HC, Knight JC, Baillie KJ, Bos LDJ, Derde LPG, Finfer S, Hotchkiss RS, Marshall J, Openshaw PJM, Seymour CW, Venet F, Vincent JL, Le Tourneau C, Maitland-van der Zee AH, McInnes IB, van der Poll T. Reframing sepsis immunobiology for translation: towards informative subtyping and targeted immunomodulatory therapies. THE LANCET. RESPIRATORY MEDICINE 2024; 12:323-336. [PMID: 38408467 PMCID: PMC11025021 DOI: 10.1016/s2213-2600(23)00468-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 11/27/2023] [Accepted: 12/07/2023] [Indexed: 02/28/2024]
Abstract
Sepsis is a common and deadly condition. Within the current model of sepsis immunobiology, the framing of dysregulated host immune responses into proinflammatory and immunosuppressive responses for the testing of novel treatments has not resulted in successful immunomodulatory therapies. Thus, the recent focus has been to parse observable heterogeneity into subtypes of sepsis to enable personalised immunomodulation. In this Personal View, we highlight that many fundamental immunological concepts such as resistance, disease tolerance, resilience, resolution, and repair are not incorporated into the current sepsis immunobiology model. The focus for addressing heterogeneity in sepsis should be broadened beyond subtyping to encompass the identification of deterministic molecular networks or dominant mechanisms. We explicitly reframe the dysregulated host immune responses in sepsis as altered homoeostasis with pathological disruption of immune-driven resistance, disease tolerance, resilience, and resolution mechanisms. Our proposal highlights opportunities to identify novel treatment targets and could enable successful immunomodulation in the future.
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Affiliation(s)
- Manu Shankar-Hari
- Institute for Regeneration and Repair, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK.
| | - Thierry Calandra
- Service of Immunology and Allergy, Center of Human Immunology Lausanne, Department of Medicine and Department of Laboratory Medicine and Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | | | - Michael Bauer
- Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - W Joost Wiersinga
- Center for Experimental and Molecular Medicine and Division of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Hallie C Prescott
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Julian C Knight
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Kenneth J Baillie
- Institute for Regeneration and Repair, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK
| | - Lieuwe D J Bos
- Department of Intensive Care, Academic Medical Center, Amsterdam, Netherlands
| | - Lennie P G Derde
- Intensive Care Center, University Medical Center Utrecht, Utrecht, Netherlands
| | - Simon Finfer
- Critical Care Division, The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia
| | - Richard S Hotchkiss
- Department of Anesthesiology and Critical Care Medicine, Washington University School of Medicine in St Louis, St Louis, MO, USA
| | - John Marshall
- Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada
| | | | - Christopher W Seymour
- Department of Critical Care Medicine, The Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Fabienne Venet
- Immunology Laboratory, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | | | - Christophe Le Tourneau
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris-Saclay University, Paris, France
| | - Anke H Maitland-van der Zee
- Department of Pulmonary Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Iain B McInnes
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Tom van der Poll
- Center for Experimental and Molecular Medicine and Division of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
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11
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Russjan E. The Role of Peptides in Asthma-Obesity Phenotype. Int J Mol Sci 2024; 25:3213. [PMID: 38542187 PMCID: PMC10970696 DOI: 10.3390/ijms25063213] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/08/2024] [Accepted: 03/10/2024] [Indexed: 01/04/2025] Open
Abstract
The co-occurrence of asthma and obesity is becoming an increasingly common health problem. It became clear that both diseases are closely related, since overweight/obesity are associated with an increased risk of asthma development, and more than half of the subjects with severe or difficult-to-treat asthma are obese. Currently, there are no specific guidelines for the treatment of this group of patients. The mechanisms involved in the asthma-obesity phenotype include low-grade chronic inflammation and changes in pulmonary physiology. However, genetic predispositions, gender differences, comorbid conditions, and gut microbiota also seem to be important. Regulatory peptides affect many processes related to the functioning of the respiratory tract and adipose tissue. Adipokines such as leptin, adiponectin, resistin, and the less studied omentin, chemerin, and visfatin, as well as the gastrointestinal hormones ghrelin, cholecystokinin, glucagon-like peptide-1, and neuropeptides, including substance P or neuropeptide Y, can play a significant role in asthma with obesity. The aim of this article is to provide a concise review of the contribution of particular peptides in inflammatory reactions, obesity, asthma, and a combination of both diseases, as well as emphasize their potential role in the effective treatment of the asthma-obesity phenotype in the future.
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Affiliation(s)
- Ewelina Russjan
- Department of Respiration Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5 St., 02-106 Warsaw, Poland
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12
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Rizo-Téllez SA, Filep JG. Beyond host defense and tissue injury: the emerging role of neutrophils in tissue repair. Am J Physiol Cell Physiol 2024; 326:C661-C683. [PMID: 38189129 PMCID: PMC11193466 DOI: 10.1152/ajpcell.00652.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/31/2023] [Accepted: 12/31/2023] [Indexed: 01/09/2024]
Abstract
Neutrophils, the most abundant immune cells in human blood, play a fundamental role in host defense against invading pathogens and tissue injury. Neutrophils carry potentially lethal weaponry to the affected site. Inadvertent and perpetual neutrophil activation could lead to nonresolving inflammation and tissue damage, a unifying mechanism of many common diseases. The prevailing view emphasizes the dichotomy of their function, host defense versus tissue damage. However, tissue injury may also persist during neutropenia, which is associated with disease severity and poor outcome. Numerous studies highlight neutrophil phenotypic heterogeneity and functional versatility, indicating that neutrophils play more complex roles than previously thought. Emerging evidence indicates that neutrophils actively orchestrate resolution of inflammation and tissue repair and facilitate return to homeostasis. Thus, neutrophils mobilize multiple mechanisms to limit the inflammatory reaction, assure debris removal, matrix remodeling, cytokine scavenging, macrophage reprogramming, and angiogenesis. In this review, we will summarize the homeostatic and tissue-reparative functions and mechanisms of neutrophils across organs. We will also discuss how the healing power of neutrophils might be harnessed to develop novel resolution and repair-promoting therapies while maintaining their defense functions.
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Affiliation(s)
- Salma A Rizo-Téllez
- Department of Pathology and Cell Biology, University of Montreal and Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada
| | - János G Filep
- Department of Pathology and Cell Biology, University of Montreal and Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada
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13
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Sok C, Sandhu S, Shah H, Ajay PS, Russell MC, Cardona K, Maegawa F, Maithel SK, Sarmiento J, Goyal S, Kooby DA, Shah MM. Simple Preoperative Imaging Measurements Predict Postoperative Pancreatic Fistula After Pancreatoduodenectomy. Ann Surg Oncol 2024; 31:1898-1905. [PMID: 37968411 PMCID: PMC10922305 DOI: 10.1245/s10434-023-14564-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 10/22/2023] [Indexed: 11/17/2023]
Abstract
OBJECTIVE Postoperative pancreatic fistula is a potentially devastating complication after pancreatoduodenectomy (PD). The purpose of this study was to identify features on preoperative computed tomography (CT) imaging that correlate with an increased risk of postoperative pancreatic fistula (POPF). METHODS Patients who underwent PD at our high-volume pancreatic surgery center from 2019 to 2021 were included if CT imaging was available within 8 weeks of surgical intervention. Pancreatic neck thickness (PNT), abdominal wall thickness (AWT), and intra-abdominal distance from pancreas to peritoneum (PTP) were measured by two board-certified radiologists who were blinded to the clinical outcomes. Radiographic measurements, as well as preoperative patient characteristics and intraoperative data, were assessed with univariate and multivariable analysis (MVA) to determine risk for clinically relevant POPF (CR-POPF, grades B and C). RESULTS A total of 204 patients met inclusion criteria. Median PTP was 5.8 cm, AWT 1.9 cm, and PNT 1.3 cm. CR-POPF occurred in 33 of 204 (16.2%) patients. MVA revealed PTP > 5.8 cm (odds ratio [OR] 2.86, p = 0.023), PNT > 1.3 cm (OR 2.43, p = 0.047), soft pancreas consistency (OR 3.47, p = 0.012), and pancreatic duct size ≤ 3.0 mm (OR 4.55, p = 0.01) as independent risk factors for CR-POPF after PD. AWT and obesity were not associated with increased risk of CR-POPF. Patients with PTP > 5.8 cm or PNT > 1.3 cm were significantly more likely to suffer a major complication after PD (39.6% vs. 22.3% and 40% vs. 22.1%, p < 0.008). CONCLUSIONS Patients with a thick pancreatic neck and increased intra-abdominal girth have a heightened risk of CR-POPF after pancreatoduodenectomy, and they experience more serious postoperative complications. We defined a simple CT scan-based measurement tool to identify patients at increased risk of CR-POPF.
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Affiliation(s)
- Caitlin Sok
- Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine/Winship Cancer Institute, Atlanta, GA, USA
| | - Sameer Sandhu
- Department of Radiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Hardik Shah
- Department of Radiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Pranay S Ajay
- Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine/Winship Cancer Institute, Atlanta, GA, USA
| | - Maria C Russell
- Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine/Winship Cancer Institute, Atlanta, GA, USA
| | - Kenneth Cardona
- Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine/Winship Cancer Institute, Atlanta, GA, USA
| | - Felipe Maegawa
- Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine/Winship Cancer Institute, Atlanta, GA, USA
| | - Shishir K Maithel
- Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine/Winship Cancer Institute, Atlanta, GA, USA
| | - Juan Sarmiento
- Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine/Winship Cancer Institute, Atlanta, GA, USA
| | - Subir Goyal
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health of Emory University, Atlanta, GA, USA
| | - David A Kooby
- Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine/Winship Cancer Institute, Atlanta, GA, USA
| | - Mihir M Shah
- Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine/Winship Cancer Institute, Atlanta, GA, USA.
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14
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Wang Y, Chen X, Xu X, Yang J, Liu X, Sun G, Li Z. Weighted Gene Co-Expression Network Analysis Based on Stimulation by Lipopolysaccharides and Polyinosinic:polycytidylic Acid Provides a Core Set of Genes for Understanding Hemolymph Immune Response Mechanisms of Amphioctopus fangsiao. Animals (Basel) 2023; 14:80. [PMID: 38200810 PMCID: PMC10778463 DOI: 10.3390/ani14010080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 12/05/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
The primary influencer of aquaculture quality in Amphioctopus fangsiao is pathogen infection. Both lipopolysaccharides (LPS) and polyinosinic:polycytidylic acid (Poly I:C) are recognized by the pattern recognition receptor (PRR) within immune cells, a system that frequently serves to emulate pathogen invasion. Hemolymph, which functions as a transport mechanism for immune cells, offers vital transcriptome information when A. fangsiao is exposed to pathogens, thereby contributing to our comprehension of the species' immune biological mechanisms. In this study, we conducted analyses of transcript profiles under the influence of LPS and Poly I:C within a 24 h period. Concurrently, we developed a Weighted Gene Co-expression Network Analysis (WGCNA) to identify key modules and genes. Further, we carried out Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to investigate the primary modular functions. Co-expression network analyses unveiled a series of immune response processes following pathogen stress, identifying several key modules and hub genes, including PKMYT1 and NAMPT. The invaluable genetic resources provided by our results aid our understanding of the immune response in A. fangsiao hemolymph and will further our exploration of the molecular mechanisms of pathogen infection in mollusks.
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Affiliation(s)
- Yongjie Wang
- School of Agriculture, Ludong University, Yantai 264025, China
| | - Xipan Chen
- School of Agriculture, Ludong University, Yantai 264025, China
| | - Xiaohui Xu
- School of Agriculture, Ludong University, Yantai 264025, China
| | - Jianmin Yang
- School of Agriculture, Ludong University, Yantai 264025, China
| | - Xiumei Liu
- College of Life Sciences, Yantai University, Yantai 264005, China;
| | - Guohua Sun
- School of Agriculture, Ludong University, Yantai 264025, China
| | - Zan Li
- School of Agriculture, Ludong University, Yantai 264025, China
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15
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Stangret A, Dykacz W, Jabłoński K, Wesołowska A, Klimczak-Tomaniak D, Kochman J, Tomaniak M. The cytokine trio - visfatin, placental growth factor and fractalkine - and their role in myocardial infarction with non-obstructive coronary arteries (MINOCA). Cytokine Growth Factor Rev 2023; 74:76-85. [PMID: 37679252 DOI: 10.1016/j.cytogfr.2023.08.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/18/2023] [Accepted: 08/22/2023] [Indexed: 09/09/2023]
Abstract
Myocardial infarction with nonobstructive coronary arteries (MINOCA) remains a puzzling clinical entity. It is characterized by clinical evidence of myocardial infarction (MI) with normal or near-normal coronary arteries in angiography. Given the complex etiology including multiple possible scenarios with varied pathogenetic mechanisms, profound investigation of the plausible biomarkers of MINOCA may bring further pathophysiological insights and novel diagnostic opportunities. Cytokines have a great diagnostic potential and are used as biomarkers for many diseases. An unusual trio of visfatin, placental growth factor (PlGF) and fractalkine (CX3CL1) can directly promote vascular dysfunction, inflammation and angiogenesis through the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. They are redundant in physiological processes and become overexpressed in the pathomechanisms underlying MINOCA. The knowledge about their concentration might serve as a valuable diagnostic and/or therapeutic tool for assessing vascular endothelial function. Here we analyze the current knowledge on visfatin, PlGF and CX3CL1 in the context of MINOCA and present the novel clinical implications of their combined expression as predictors or indicators of this condition.
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Affiliation(s)
- Aleksandra Stangret
- Department of Human Physiology and Pathophysiology, Faculty of Medicine, Collegium Medicum Cardinal Stefan Wyszynski University in Warsaw, Wóycickiego 1/3, 01-938 Warsaw, Poland; College of Medical Sciences, Nicolaus Copernicus Superior School, Nowogrodzka 47a, 00-695 Warsaw, Poland
| | - Weronika Dykacz
- First Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland
| | - Konrad Jabłoński
- First Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland
| | - Aleksandra Wesołowska
- First Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland
| | - Dominika Klimczak-Tomaniak
- Department of Cardiology, Hypertension and Internal Medicine, Medical University of Warsaw, Warsaw, Poland; Department of Immunology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Janusz Kochman
- First Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland
| | - Mariusz Tomaniak
- First Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
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16
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Koka S, Surineni S, Singh GB, Boini KM. Contribution of membrane raft redox signalling to visfatin-induced inflammasome activation and podocyte injury. Aging (Albany NY) 2023; 15:12738-12748. [PMID: 38032896 DOI: 10.18632/aging.205243] [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: 09/15/2021] [Accepted: 10/24/2023] [Indexed: 12/02/2023]
Abstract
Recently we have shown that adipokine visfatin-induced NLRP3 inflammasome activation contributes to podocyte injury. However, the molecular mechanisms of how visfatin-induces the Nlrp3 inflammasome activation and podocyte damage is still unknown. The present study tested whether membrane raft (MR) redox signalling pathway plays a central role in visfatin-induced NLRP3 inflammasomes formation and activation in podocytes. Upon visfatin stimulation an aggregation of NADPH oxidase subunits, gp91phox and p47phox was observed in the membrane raft (MR) clusters, forming a MR redox signalling platform in podocytes. The formation of this signalling platform was blocked by prior treatment with MR disruptor MCD or NADPH oxidase inhibitor DPI. In addition, visfatin stimulation significantly increased the colocalization of Nlrp3 with Asc or Nlrp3 with caspase-1, IL-β production, cell permeability in podocytes compared to control cells. Pretreatment with MCD, DPI, WEHD significantly abolished the visfatin-induced colocalization of NLRP3 with Asc or NLRP3 with caspase-1, IL-1β production and cell permeability in podocytes. Furthermore, Immunofluorescence analysis demonstrated that visfatin treatment significantly decreased the podocin and nephrin expression (podocyte damage) and prior treatments with DPI, WEHD, MCD attenuated this visfatin-induced podocin and nephrin reduction. In conclusion, our results suggest that visfatin stimulates membrane raft clustering in the membrane of podocytes to form redox signaling platforms by aggregation and activation of NADPH oxidase subunits enhancing O2·- production and leading to NLRP3 inflammasome activation in podocytes and ultimate podocyte injury.
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Affiliation(s)
- Saisudha Koka
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
- Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
| | - Sreenidhi Surineni
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
- Division of Biomedical Sciences, University of California, Riverside, CA 92130, USA
| | - Gurinder Bir Singh
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Krishna M Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
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17
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Jahanbani S, Khaksari M, Bitaraf FS, Rahmati M, Foroughi K, Shayannia A. Effectiveness of Nicotinamide Phosphoribosyltransferase/Pre-B Cell Colony-enhancing Factor/Visfatin in preventing High Glucose-induced Neurotoxicity in an In-vitro Model of Diabetic Neuropathy. Basic Clin Neurosci 2023; 14:867-878. [PMID: 39070193 PMCID: PMC11273206 DOI: 10.32598/bcn.2021.2870.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 05/26/2021] [Accepted: 07/26/2021] [Indexed: 07/30/2024] Open
Abstract
Introduction Diabetic neuropathy is a well-known complication of diabetes. Recently, hyperglycemia-induced toxicity has been confirmed to participates in multiple cellular pathways typical for neural deterioration. Nicotinamide phosphoribosyltransferase/pre-b cell colony-enhancing factor (Nampt/PBEF)/visfatin is a novel endogenous ligand that some studies have shown its neuroprotective effects on neurodegenerative disease. Therefore, we hypothesized that visfatin may prevent high glucose (HG)-induced neurotoxicity by inhibiting apoptosis, autophagy, and reactive oxygen species (ROS) responses properly. Methods In this study, pheochromocytoma cell line 12 (PC12) cells were exposed to both HG concentrations (50, 75, 100, 125, 150 mM) and visfatin (50, 100, 150 ng/mL) at different time -points to determine the optimum time and dose of glucose and visfatin. To investigate the effects of visfatin on HG-induced damage in the PC12 diabetic neuropathy model, we examined ROS response, apoptosis, and autophagy using ROS detection kit, flow cytometry, and real-time PCR/Western blot, respectively. Results We determined that HG concentration significantly increased the ROS level and apoptosis of diabetic PC12 cells. However, visfatin treatment significantly decreased the ROS production (P<0.05) and apoptosis of diabetic PC12 cells (P<0.0001). Beclin-1 messenger ribonucleic acid (mRNA) level (P<0.05) and light chain 3 (Lc3)-II protein level (P<0.05) showed that the autophagy pathway is impaired by HG concentrations. Conclusion We concluded that visfatin can sufficiently decrease neural damage caused by ROS production and apoptosis under HG-induced toxicity. Highlights High glucose significantly increased the ROS level and apoptosis of diabetic PC12 cells;The autophagy pathway is impaired by high glucose;Nampt/PBEF/visfatin can significantly reduce neural damage caused by ROS production and apoptosis of diabetic PC12 cells. Plain Language Summary Diabetes mellitus is a metabolic disorder characterized by hyperglycemia resulting from a failure in insulin secretion, insulin action, or both. Visfatin (Nampt/PBEF) has insulin-mimetic effects. So far, no study has assessed its effects on diabetic neuropathy. Therefore, we examined the neuroprotective effects of visfatin on cell line 12 (PC12) against glucose-induced neurotoxicity. Based on the results, it was concluded that the Nampt/PBEF/visfatin can significantly reduce neural damage caused by production of reactive oxygen species and apoptosis of diabetic PC12 cell.
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Affiliation(s)
- Sarvin Jahanbani
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mehdi Khaksari
- Addiction Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Fatemeh Sadat Bitaraf
- Department of Medical Biotechnology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Majid Rahmati
- Cancer Prevention Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Kobra Foroughi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Asghar Shayannia
- Department of Medical Biotechnology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
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18
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Zhu X, Li J, Wang H, Gasior FM, Lee C, Lin S, Justice CN, O’Donnell JM, Vanden Hoek TL. Nicotinamide restores tissue NAD+ and improves survival in rodent models of cardiac arrest. PLoS One 2023; 18:e0291598. [PMID: 37713442 PMCID: PMC10503771 DOI: 10.1371/journal.pone.0291598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 09/04/2023] [Indexed: 09/17/2023] Open
Abstract
Metabolic suppression in the ischemic heart is characterized by reduced levels of NAD+ and ATP. Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts, and enhances survival in a mouse model of cardiac arrest. Mouse cardiomyocytes were exposed to 30 min simulated ischemia and 90 min reperfusion. NAD+ content dropped 40% by the end of ischemia compared to pre-ischemia. Treatment with 100 μM nicotinamide (NAM) at the start of reperfusion completely restored the cellular level of NAD+ at 15 min of reperfusion. This rescue of NAD+ depletion was associated with improved contractile recovery as early as 10 min post-reperfusion. In a mouse model of cardiac arrest, 100 mg/kg NAM administered IV immediately after cardiopulmonary resuscitation resulted in 100% survival at 4 h as compared to 50% in the saline group. In an isolated rat heart model, the effect of NAM on cardiac function was measured for 20 min following 18 min global ischemia. Rate pressure product was reduced by 26% in the control group following arrest. Cardiac contractile function was completely recovered with NAM treatment given at the start of reperfusion. NAM restored tissue NAD+ and enhanced production of lactate and ATP, while reducing glucose diversion to sorbitol in the heart. We conclude that NAM can rapidly restore cardiac NAD+ following ischemia and enhance glycolysis and contractile recovery, with improved survival in a mouse model of cardiac arrest.
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Affiliation(s)
- Xiangdong Zhu
- Center for Advanced Resuscitation Medicine and Department of Emergency Medicine, Center for Cardiovascular Research, University of Illinois Hospital & Health Sciences System, Chicago, Illinois, United States of America
| | - Jing Li
- Center for Advanced Resuscitation Medicine and Department of Emergency Medicine, Center for Cardiovascular Research, University of Illinois Hospital & Health Sciences System, Chicago, Illinois, United States of America
| | - Huashan Wang
- Center for Advanced Resuscitation Medicine and Department of Emergency Medicine, Center for Cardiovascular Research, University of Illinois Hospital & Health Sciences System, Chicago, Illinois, United States of America
| | - Filip M. Gasior
- Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois Hospital & Health Sciences System, Chicago, Illinois, United States of America
| | - Chunpei Lee
- Center for Advanced Resuscitation Medicine and Department of Emergency Medicine, Center for Cardiovascular Research, University of Illinois Hospital & Health Sciences System, Chicago, Illinois, United States of America
| | - Shaoxia Lin
- Center for Advanced Resuscitation Medicine and Department of Emergency Medicine, Center for Cardiovascular Research, University of Illinois Hospital & Health Sciences System, Chicago, Illinois, United States of America
| | - Cody N. Justice
- Center for Advanced Resuscitation Medicine and Department of Emergency Medicine, Center for Cardiovascular Research, University of Illinois Hospital & Health Sciences System, Chicago, Illinois, United States of America
- Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois Hospital & Health Sciences System, Chicago, Illinois, United States of America
| | - J. Michael O’Donnell
- Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois Hospital & Health Sciences System, Chicago, Illinois, United States of America
| | - Terry L. Vanden Hoek
- Center for Advanced Resuscitation Medicine and Department of Emergency Medicine, Center for Cardiovascular Research, University of Illinois Hospital & Health Sciences System, Chicago, Illinois, United States of America
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19
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Shimizu J, Murao A, Aziz M, Wang P. EXTRACELLULAR CIRP INHIBITS NEUTROPHIL APOPTOSIS TO PROMOTE ITS AGING BY UPREGULATING SERPINB2 IN SEPSIS. Shock 2023; 60:450-460. [PMID: 37548626 PMCID: PMC10529402 DOI: 10.1097/shk.0000000000002187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
ABSTRACT Background: Sepsis reduces neutrophil apoptosis. As the result, neutrophils may become aged, exacerbating inflammation and tissue injury. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a damage-associated molecular pattern to promote inflammation and tissue injury in sepsis. SerpinB2, a serine protease inhibitor, has been shown to inhibit apoptosis. We hypothesize that eCIRP upregulates SerpinB2 to promote aged neutrophil subset by inhibiting apoptosis in sepsis. Methods: We stimulated bone marrow-derived neutrophils (BMDNs) of wild-type (WT) mice with 1 μg/mL of recombinant mouse CIRP (i.e., eCIRP) and assessed cleaved caspase-3 and SerpinB2 by western blotting. Apoptotic neutrophils were assessed by Annexin V/PI. Bone marrow-derived neutrophils were stimulated with 1 μg/mL eCIRP and treated with or without PAC-1 (caspase-3 activator) and aged neutrophils (CXCR4 hi CD62L lo ) were assessed by flow cytometry. To induce sepsis, we performed cecal ligation and puncture in WT or CIRP -/- mice. We determined the percentage of aged neutrophils and SerpinB2 + neutrophils in blood and spleen by flow cytometry. Results: We found that cleaved caspase-3 levels were increased at 4 h of PBS treatment compared with 0 h but decreased by eCIRP treatment. Extracellular cold-inducible RNA-binding protein reduced apoptotic cells after 20 h of treatment. Extracellular cold-inducible RNA-binding protein also increased the frequencies of aged neutrophils compared with PBS after 20 h, while PAC-1 treatment reduced aging in eCIRP-treated BMDNs. Extracellular cold-inducible RNA-binding protein significantly increased the expression of SerpinB2 at protein levels in BMDNs at 20 h. In WT mice, the frequencies of aged and SerpinB2 + neutrophils in blood and spleen were increased after 20 h of cecal ligation and puncture, while in CIRP -/- mice, aged and SerpinB2 + neutrophils were significantly decreased compared with WT mice. We also found that aged neutrophils expressed significantly higher levels of SerpinB2 compared with non-aged neutrophils. Conclusions: eCIRP inhibits neutrophil apoptosis to increase aged phenotype by increasing SerpinB2 expression in sepsis. Thus, targeting eCIRP could be a new therapeutic strategy to ameliorate inflammation caused by neutrophil aging in sepsis.
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Affiliation(s)
- Junji Shimizu
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York
| | - Atsushi Murao
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York
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20
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Chen C, Yan W, Tao M, Fu Y. NAD + Metabolism and Immune Regulation: New Approaches to Inflammatory Bowel Disease Therapies. Antioxidants (Basel) 2023; 12:1230. [PMID: 37371959 DOI: 10.3390/antiox12061230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a multifactorial systemic inflammatory immune response. Nicotinamide adenine dinucleotide (NAD+) is a co-enzyme involved in cell signaling and energy metabolism. Calcium homeostasis, gene transcription, DNA repair, and cell communication involve NAD+ and its degradation products. There is a growing recognition of the intricate relationship between inflammatory diseases and NAD+ metabolism. In the case of IBD, the maintenance of intestinal homeostasis relies on a delicate balance between NAD+ biosynthesis and consumption. Consequently, therapeutics designed to target the NAD+ pathway are promising for the management of IBD. This review discusses the metabolic and immunoregulatory processes of NAD+ in IBD to examine the molecular biology and pathophysiology of the immune regulation of IBD and to provide evidence and theoretical support for the clinical use of NAD+ in IBD.
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Affiliation(s)
- Chaoyue Chen
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Meihui Tao
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yu Fu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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21
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Bhayana S, Zhao Y, Merchant M, Cummins T, Dougherty JA, Kamigaki Y, Pathmasiri W, McRitchie S, Mariani LH, Sumner S, Klein JB, Li L, Smoyer WE. Multiomics Analysis of Plasma Proteomics and Metabolomics of Steroid Resistance in Childhood Nephrotic Syndrome Using a "Patient-Specific" Approach. Kidney Int Rep 2023; 8:1239-1254. [PMID: 37284673 PMCID: PMC10239920 DOI: 10.1016/j.ekir.2023.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 03/20/2023] [Indexed: 06/08/2023] Open
Abstract
Introduction Nephrotic syndrome (NS) occurs commonly in children with glomerular disease and glucocorticoids (GCs) are the mainstay treatment. Steroid resistant NS (SRNS) develops in 15% to 20% of children, increasing the risk of chronic kidney disease compared to steroid sensitive NS (SSNS). NS pathogenesis is unclear in most children, and no biomarkers exist that predict the development of pediatric SRNS. Methods We studied a unique patient cohort with plasma specimens collected before GC treatment, yielding a disease-only sample not confounded by steroid-induced gene expression changes (SSNS n = 8; SRNS n = 7). A novel "patient-specific" bioinformatic approach merged paired pretreatment and posttreatment proteomic and metabolomic data and identified candidate SRNS biomarkers and altered molecular pathways in SRNS versus SSNS. Results Joint pathway analyses revealed perturbations in nicotinate or nicotinamide and butanoate metabolic pathways in patients with SRNS. Patients with SSNS had perturbations of lysine degradation, mucin type O-glycan biosynthesis, and glycolysis or gluconeogenesis pathways. Molecular analyses revealed frequent alteration of molecules within these pathways that had not been observed by separate proteomic and metabolomic studies. We observed upregulation of NAMPT, NMNAT1, and SETMAR in patients with SRNS, in contrast to upregulation of ALDH1B1, ACAT1, AASS, ENPP1, and pyruvate in patients with SSNS. Pyruvate regulation was the change seen in our previous analysis; all other targets were novel. Immunoblotting confirmed increased NAMPT expression in SRNS and increased ALDH1B1 and ACAT1 expression in SSNS, following GC treatment. Conclusion These studies confirmed that a novel "patient-specific" bioinformatic approach can integrate disparate omics datasets and identify candidate SRNS biomarkers not observed by separate proteomic or metabolomic analysis.
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Affiliation(s)
- Sagar Bhayana
- Center for Clinical and Translational Research, Nationwide Children’s Hospital; Columbus, Ohio, USA
| | - Yue Zhao
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Michael Merchant
- Department of Medicine, Division of Nephrology and Hypertension, University of Louisville; Louisville, Kentucky, USA
| | - Timothy Cummins
- Department of Medicine, Division of Nephrology and Hypertension, University of Louisville; Louisville, Kentucky, USA
| | - Julie A. Dougherty
- Center for Clinical and Translational Research, Nationwide Children’s Hospital; Columbus, Ohio, USA
| | - Yu Kamigaki
- Center for Clinical and Translational Research, Nationwide Children’s Hospital; Columbus, Ohio, USA
| | - Wimal Pathmasiri
- Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill; Kannapolis, North Carolina, USA
| | - Susan McRitchie
- Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill; Kannapolis, North Carolina, USA
| | - Laura H. Mariani
- Division of Nephrology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Susan Sumner
- Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill; Kannapolis, North Carolina, USA
| | - Jon B. Klein
- Department of Medicine, Division of Nephrology and Hypertension, University of Louisville; Louisville, Kentucky, USA
- Robley Rex VA Medical Center, Louisville, Kentucky, USA
| | - Lang Li
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA
| | - William E. Smoyer
- Center for Clinical and Translational Research, Nationwide Children’s Hospital; Columbus, Ohio, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA
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22
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Chen ZA, Ma HH, Wang Y, Tian H, Mi JW, Yao DM, Yang CJ. Integrated multiple microarray studies by robust rank aggregation to identify immune-associated biomarkers in Crohn's disease based on three machine learning methods. Sci Rep 2023; 13:2694. [PMID: 36792688 PMCID: PMC9931764 DOI: 10.1038/s41598-022-26345-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/13/2022] [Indexed: 02/17/2023] Open
Abstract
Crohn's disease (CD) is a complex autoimmune disorder presumed to be driven by complex interactions of genetic, immune, microbial and even environmental factors. Intrinsic molecular mechanisms in CD, however, remain poorly understood. The identification of novel biomarkers in CD cases based on larger samples through machine learning approaches may inform the diagnosis and treatment of diseases. A comprehensive analysis was conducted on all CD datasets of Gene Expression Omnibus (GEO); our team then used the robust rank aggregation (RRA) method to identify differentially expressed genes (DEGs) between controls and CD patients. PPI (protein‒protein interaction) network and functional enrichment analyses were performed to investigate the potential functions of the DEGs, with molecular complex detection (MCODE) identifying some important functional modules from the PPI network. Three machine learning algorithms, support vector machine-recursive feature elimination (SVM-RFE), random forest (RF), and least absolute shrinkage and selection operator (LASSO), were applied to determine characteristic genes, which were verified by ROC curve analysis and immunohistochemistry (IHC) using clinical samples. Univariable and multivariable logistic regression were used to establish a machine learning score for diagnosis. Single-sample GSEA (ssGSEA) was performed to examine the correlation between immune infiltration and biomarkers. In total, 5 datasets met the inclusion criteria: GSE75214, GSE95095, GSE126124, GSE179285, and GSE186582. Based on RRA integrated analysis, 203 significant DEGs were identified (120 upregulated genes and 83 downregulated genes), and MCODE revealed some important functional modules in the PPI network. Machine learning identified LCN2, REG1A, AQP9, CCL2, GIP, PROK2, DEFA5, CXCL9, and NAMPT; AQP9, PROK2, LCN2, and NAMPT were further verified by ROC curves and IHC in the external cohort. The final machine learning score was defined as [Expression level of AQP9 × (2.644)] + [Expression level of LCN2 × (0.958)] + [Expression level of NAMPT × (1.115)]. ssGSEA showed markedly elevated levels of dendritic cells and innate immune cells, such as macrophages and NK cells, in CD, consistent with the gene enrichment results that the DEGs are mainly involved in the IL-17 signaling pathway and humoral immune response. The selected biomarkers analyzed by the RRA method and machine learning are highly reliable. These findings improve our understanding of the molecular mechanisms of CD pathogenesis.
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Affiliation(s)
- Zi-An Chen
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Hui-hui Ma
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Yan Wang
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Hui Tian
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Jian-wei Mi
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Dong-Mei Yao
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. .,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000, Hebei, China.
| | - Chuan-Jie Yang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. .,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000, Hebei, China.
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23
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Morshedzadeh N, Rahimlou M, Shahrokh S, Chaleshi V, Mirmiran P, Zali MR. The effects of flaxseed supplementation on concentration of circulating adipokines in patients with ulcerative colitis. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2023; 16:458-467. [PMID: 37070105 PMCID: PMC10105498 DOI: 10.22037/ghfbb.v16i1.2622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 10/09/2022] [Indexed: 04/19/2023]
Abstract
Aim This study aimed to evaluate the effect of supplementation with ground flaxseed (GF) on the concentrations of adiponectin, resistin, and visfatin in patients with ulcerative colitis (UC). Background Inflammatory bowel disease (IBD) is one of the most common gastrointestinal diseases affecting people of all ages. Adipokines secreted from adipose tissue have been shown to play an essential role in the pathogenesis of UC. Methods This trial is an open-labeled randomized controlled trial conducted on 70 patients with UC. The patients were randomly divided into two groups: flaxseed and control. The patients in the intervention received 30 g/day flaxseed powder for 12 weeks. Patients' anthropometric, nutritional, and biochemical factors were evaluated at the beginning and end of the intervention period. Results Totally, 64 patients (36 men and 28 women) with a mean age of 31.12±9.67 were included in the final analysis. There was no significant difference between the two groups regarding baseline weight and height (P>0.05). After the 12-week intervention, flaxseed supplementation led to a significant reduction in the resistin (-4.85±1.89 vs. -1.10±2.25, P<0.001) and visfatin concentration (-1.33±1.14 vs. -0.53±1.63, P=0.018). Further, we found a significant increase in the adiponectin levels after the GF supplementation (3.49±1.29 vs. -0.35±0.96, P<0.001). Conclusion Flaxseed supplementation could exert beneficial effects on adipokine levels in patients with UC.
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Affiliation(s)
- Nava Morshedzadeh
- Department of Nutrition, Faculty of Public Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Mehran Rahimlou
- Department of Nutrition, School of Medecine, Zanjan Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Chaleshi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parvin Mirmiran
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Sahu B, Bal NC. Adipokines from white adipose tissue in regulation of whole body energy homeostasis. Biochimie 2023; 204:92-107. [PMID: 36084909 DOI: 10.1016/j.biochi.2022.09.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 08/08/2022] [Accepted: 09/01/2022] [Indexed: 02/06/2023]
Abstract
Diseases originating from altered energy homeostasis including obesity, and type 2 diabetes are rapidly increasing worldwide. Research in the last few decades on animal models and humans demonstrates that the white adipose tissue (WAT) is critical for energy balance and more than just an energy storage site. WAT orchestrates the whole-body metabolism through inter-organ crosstalk primarily mediated by cytokines named "Adipokines". The adipokines influence metabolism and fuel selection of the skeletal muscle and liver thereby fine-tuning the load on WAT itself in physiological conditions like starvation, exercise and cold. In addition, adipokine secretion is influenced by various pathological conditions like obesity, inflammation and diabetes. In this review, we have surveyed the current state of knowledge on important adipokines and their significance in regulating energy balance and metabolic diseases. Furthermore, we have summarized the interplay of pro-inflammatory and anti-inflammatory adipokines in the modulation of pathological conditions.
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Affiliation(s)
- Bijayashree Sahu
- School of Biotechnology, KIIT University, Bhubaneswar, Odisha, 751024, India.
| | - Naresh C Bal
- School of Biotechnology, KIIT University, Bhubaneswar, Odisha, 751024, India.
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25
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Tumurkhuu G, Casanova NG, Kempf CL, Ercan Laguna D, Camp SM, Dagvadorj J, Song JH, Reyes Hernon V, Travelli C, Montano EN, Yu JM, Ishimori M, Wallace DJ, Sammani S, Jefferies C, Garcia JG. eNAMPT/TLR4 inflammatory cascade activation is a key contributor to SLE Lung vasculitis and alveolar hemorrhage. J Transl Autoimmun 2022; 6:100181. [PMID: 36619655 PMCID: PMC9816774 DOI: 10.1016/j.jtauto.2022.100181] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Rationale Effective therapies to reduce the severity and high mortality of pulmonary vasculitis and diffuse alveolar hemorrhage (DAH) in patients with systemic lupus erythematosus (SLE) is a serious unmet need. We explored whether biologic neutralization of eNAMPT (extracellular nicotinamide phosphoribosyl-transferase), a novel DAMP and Toll-like receptor 4 ligand, represents a viable therapeutic strategy in lupus vasculitis. Methods Serum was collected from SLE subjects (n = 37) for eNAMPT protein measurements. In the preclinical pristane-induced murine model of lung vasculitis/hemorrhage, C57BL/6 J mice (n = 5-10/group) were treated with PBS, IgG (1 mg/kg), or the eNAMPT-neutralizing ALT-100 mAb (1 mg/kg, IP or subcutaneously (SQ). Lung injury evaluation (Day 10) included histology/immuno-histochemistry, BAL protein/cellularity, tissue biochemistry, RNA sequencing, and plasma biomarker assessment. Results SLE subjects showed highly significant increases in blood NAMPT mRNA expression and eNAMPT protein levels compared to healthy controls. Preclinical pristane-exposed mice studies showed significantly increased NAMPT lung tissue expression and increased plasma eNAMPT levels accompanied by marked increases in alveolar hemorrhage and lung inflammation (BAL protein, PMNs, activated monocytes). In contrast, ALT-100 mAb-treated mice showed significant attenuation of inflammatory lung injury, alveolar hemorrhage, BAL protein, tissue leukocytes, and plasma inflammatory cytokines (eNAMPT, IL-6, IL-8). Lung RNA sequencing showed pristane-induced activation of inflammatory genes/pathways including NFkB, cytokine/chemokine, IL-1β, and MMP signaling pathways, each rectified in ALT-100 mAb-treated mice. Conclusions These findings highlight the role of eNAMPT/TLR4-mediated inflammatory signaling in the pathobiology of SLE pulmonary vasculitis and alveolar hemorrhage. Biologic neutralization of this novel DAMP appears to serve as a viable strategy to reduce the severity of SLE lung vasculitis.
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Affiliation(s)
- Gantsetseg Tumurkhuu
- Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Nancy G. Casanova
- Department of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Carrie L. Kempf
- Department of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Duygu Ercan Laguna
- Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Sara M. Camp
- Department of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | | | - Jin H. Song
- Department of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Vivian Reyes Hernon
- Department of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | | | - Erica N. Montano
- Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jeong Min Yu
- Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Mariko Ishimori
- Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | - Daniel J. Wallace
- Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | - Saad Sammani
- Department of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Caroline Jefferies
- Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Joe G.N. Garcia
- Department of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
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26
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Zhang Z, Xiao K, Wang S, Ansari AR, Niu X, Yang W, Lu M, Yang Z, Rehman ZU, Zou W, Bei W, Song H. Visfatin is a multifaceted molecule that exerts regulation effects on inflammation and apoptosis in RAW264.7 cells and mice immune organs. Front Immunol 2022; 13:1018973. [PMID: 36532047 PMCID: PMC9753570 DOI: 10.3389/fimmu.2022.1018973] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 11/15/2022] [Indexed: 12/03/2022] Open
Abstract
Visfatin, a multifunctional adipocytokine, is particularly important in the regulation of apoptosis and inflammation through an unidentified mechanism. Clarifying the control mechanisms of visfatin on inflammation and apoptosis in RAW264.7 cells and mice immunological organs was the goal of the current investigation. In order to create a pathophysiological model, the RAW264.7 cells were stimulated with 200 ng/mL visfatin and 20 μg/mL lipopolysaccharide (LPS), either separately or combined. The effects of exogenous visfatin on inflammation and apoptosis in RAW264.7 cells were investigated by flow cytometry assay, RNA-seq analysis and fluorescence quantitative PCR. According to the findings, exogenous visfatin exhibits dual effects on inflammation by modulating the expression of IL-1α, TNFRSF1B, and LIF as well as taking part in various signaling pathways, including the MAPK and Rap1 signaling pathways. By controlling the expression levels of Bcl2l1, Bcl2a1a, and Fas and primarily participating in the PI3K/AKT signaling pathway and Hippo signaling pathway, exogenous visfatin can inhibit apoptosis in RAW264.7 cells. The visfatin inhibitor FK866 was used to further confirm the effects of visfatin on inflammation and apoptosis in mice immune organs. Subsequently, mice spleen and thymus were collected. It is interesting to note that in LPS-treated mice, suppression of endogenous visfatin might worsen the immune system's inflammatory response and even result in rapid mortality. Additionally, endogenous visfatin promotes the apoptosis in mice immune organs by regulating the expression levels of Bcl2l1, Fas, Caspase 3, Bcl2a1a, and Bax. Together, these results imply that visfatin is a multifaceted molecule that regulates inflammation and apoptosis in RAW264.7 cells and mice immunological organs by taking part in a variety of biological processes and regulating the amounts of associated cytokines expression. Our findings offer additional understandings of how visfatin affects apoptosis and inflammation.
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Affiliation(s)
- Zhewei Zhang
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Ke Xiao
- The Brain Cognition and Brain Disease Institute of Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Sheng Wang
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Abdur Rahman Ansari
- Section of Anatomy and Histology, Department of Basic Sciences, College of Veterinary & Animal Sciences, Jhang University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Xiaoyu Niu
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Wenjie Yang
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Mengqi Lu
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Zhi Yang
- Animal Health Supervision Institute of Taihe County, Fuyang, China
| | - Zia ur Rehman
- College of Veterinary Sciences, Faculty of Animal Husbandry and Veterinary Sciences, University of Agriculture, Peshawar, Pakistan
| | - Weihua Zou
- Wuhan Keqian Biology Company Limited, Wuhan, China
| | - Weicheng Bei
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Hui Song
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China,*Correspondence: Hui Song,
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27
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Zanza C, Caputo G, Tornatore G, Romenskaya T, Piccioni A, Franceschi F, Artico M, Taurone S, Savioli G, Longhitano Y. Cellular Immuno-Profile in Septic Human Host: A Scoping Review. BIOLOGY 2022; 11:1626. [PMID: 36358327 PMCID: PMC9687154 DOI: 10.3390/biology11111626] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022]
Abstract
Innate and adaptive immune system cells play a critical role in the host response to sepsis. Sepsis is a life-threatening disease characterized by apoptosis-induced depletion of immune cells and immunodepression, which contribute to morbidity and mortality. Many alterations in the expression of surface markers of neutrophils and monocytes have been described in septic patients. The aim of this study was to inspect the recently published literature to inform the clinician about the most up-to-date techniques for the study of circulating leukocytes. The impact on cell phenotypes and on the function of leukocytes of extracorporeal and non-blood purification treatments proposed for sepsis were also analyzed. We conducted a systematic review using Pubmed/Medline, Ovid/Willey, the Cochrane Library, the Cochrane Controlled Trials Register, and EMBASE, combining key terms related to immunological function in sepsis and selected the most relevant clinical trials and review articles (excluding case reports) published in the last 50 years. The most important alteration in neutrophils during sepsis is that they activate an anti-apoptotic survival program. In septic monocytes, a reduced characteristic expression of HLA-DR is observed, but their role does not seem to be significantly altered in sepsis. As regards adaptive immunity, sepsis leads to lymphopenia and immunosuppression in patients with septic shock; this process involves all types of T cells (CD4, CD8 and Natural Killer), except for regulatory T cells, which retain their function. Several promising therapies that target the host immune response are currently under evaluation. During the worldwide pandemic caused by SARS-CoV-2, it was useful to study the "cytokine storm" to find additional treatments, such as the oXiris® filter. This therapy can decrease the concentration of inflammatory markers that affect the severity of the disease.
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Affiliation(s)
- Christian Zanza
- Foundation “Ospedale Alba e Bra”, Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, 12060 Verduno, Italy
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Giorgia Caputo
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Gilda Tornatore
- Department of Anesthesia and Intensive Care Medicine, University of Milan-Bicocca, 20126 Milan, Italy
| | - Tatsiana Romenskaya
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
| | - Andrea Piccioni
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Francesco Franceschi
- Department of Emergency Medicine, Policlinico Gemelli-RCCS-Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Marco Artico
- Department of Sensory Organs, Policlinico Umberto I, Sapienza University of Rome, 00185 Rome, Italy
| | - Samanta Taurone
- Department of Movement, Human and Health Sciences—Division of Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy
| | - Gabriele Savioli
- Department of Emergency Medicine, Polyclinic IRCCS S. Matteo, University of Pavia, 27100 Pavia, Italy
| | - Yaroslava Longhitano
- Foundation “Ospedale Alba e Bra”, Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, 12060 Verduno, Italy
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio Hospital, 15121 Alessandria, Italy
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28
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Feng A, Simpson E, Wu J, Robinson T, Ma W, Tieu K, Black SM, Wang T. NAMPT-associated gene signature in the prediction of severe sepsis. Am J Transl Res 2022; 14:7090-7097. [PMID: 36398242 PMCID: PMC9641493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 09/01/2022] [Indexed: 02/16/2023]
Abstract
OBJECTIVE Sepsis is a life-threatening condition of severe organ dysfunction induced by uncontrolled infection and dysregulated host response. However, standardized clinical biomarkers for sepsis are needed to improve patient care, especially in intensive care units (ICUs). Nicotinamide phosphoribosyltransferase (NAMPT) regulates the activity of nicotinamide adenine dinucleotide (NAD)-dependent enzymes and modulates multiple metabolic pathways. Elevated NAMPT gene expression is a risk factor in the pathogenesis and development of sepsis, which is strongly linked to patient morbidity and ICU mortality. At present, there is no identified NAMPT gene signature for prognosis of sepsis patients. METHODS By analyzing gene expression profiles in peripheral blood mononuclear cells, this study was designed to establish a NAMPT-associated biomarker that effectively predicts survival in sepsis patients. RESULTS We obtained 19 common genes by intersecting NAMPT-associated genes and sepsis survival-related genes, and this 19-gene signature is significantly enriched in metabolic pathways and NF-κB pathways related to sepsis development. Notably, this 19-gene NAMPT signature was able to discriminate high-risk sepsis from low-risk sepsis in both discovery and validation cohorts. Furthermore, we confirmed that this 19-gene NAMPT signature performed significantly better for sepsis prognosis than random gene sets with 19 genes. CONCLUSIONS We identified a novel NAMPT gene signature with effective prognostic power for sepsis. Further studies focusing on these biomarkers may also provide an early intervention system for sepsis treatment.
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Affiliation(s)
- Anlin Feng
- Center for Translational Science, Florida International UniversityPort St. Lucie, Miami, FL, USA
| | - Emma Simpson
- Department of Internal Medicine, University of Arizona College of Medicine Phoenix475 N. 5th Street Phoenix, Phoenix 85004, AZ, USA
| | - Jialin Wu
- Center for Translational Science, Florida International UniversityPort St. Lucie, Miami, FL, USA
| | - Tasleem Robinson
- Center for Translational Science, Florida International UniversityPort St. Lucie, Miami, FL, USA
| | - Wenli Ma
- Center for Translational Science, Florida International UniversityPort St. Lucie, Miami, FL, USA
| | - Kim Tieu
- Department of Environmental Health Sciences, Florida International UniversityMiami, FL, USA
| | - Stephen M Black
- Center for Translational Science, Florida International UniversityPort St. Lucie, Miami, FL, USA,Department of Environmental Health Sciences, Florida International UniversityMiami, FL, USA
| | - Ting Wang
- Center for Translational Science, Florida International UniversityPort St. Lucie, Miami, FL, USA,Department of Internal Medicine, University of Arizona College of Medicine Phoenix475 N. 5th Street Phoenix, Phoenix 85004, AZ, USA,Department of Environmental Health Sciences, Florida International UniversityMiami, FL, USA
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29
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Zhu CL, Wang Y, Liu Q, Li HR, Yu CM, Li P, Deng XM, Wang JF. Dysregulation of neutrophil death in sepsis. Front Immunol 2022; 13:963955. [PMID: 36059483 PMCID: PMC9434116 DOI: 10.3389/fimmu.2022.963955] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/02/2022] [Indexed: 11/13/2022] Open
Abstract
Sepsis is a prevalent disease that has alarmingly high mortality rates and, for several survivors, long-term morbidity. The modern definition of sepsis is an aberrant host response to infection followed by a life-threatening organ dysfunction. Sepsis has a complicated pathophysiology and involves multiple immune and non-immune mediators. It is now believed that in the initial stages of sepsis, excessive immune system activation and cascading inflammation are usually accompanied by immunosuppression. During the pathophysiology of severe sepsis, neutrophils are crucial. Recent researches have demonstrated a clear link between the process of neutrophil cell death and the emergence of organ dysfunction in sepsis. During sepsis, spontaneous apoptosis of neutrophils is inhibited and neutrophils may undergo some other types of cell death. In this review, we describe various types of neutrophil cell death, including necrosis, apoptosis, necroptosis, pyroptosis, NETosis, and autophagy, to reveal their known effects in the development and progression of sepsis. However, the exact role and mechanisms of neutrophil cell death in sepsis have not been fully elucidated, and this remains a major challenge for future neutrophil research. We hope that this review will provide hints for researches regarding neutrophil cell death in sepsis and provide insights for clinical practitioners.
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30
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Zhu CL, Xie J, Zhao ZZ, Li P, Liu Q, Guo Y, Meng Y, Wan XJ, Bian JJ, Deng XM, Wang JF. PD-L1 maintains neutrophil extracellular traps release by inhibiting neutrophil autophagy in endotoxin-induced lung injury. Front Immunol 2022; 13:949217. [PMID: 36016930 PMCID: PMC9396256 DOI: 10.3389/fimmu.2022.949217] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Programmed death ligand 1 (PD-L1) is not only an important molecule in mediating tumor immune escape, but also regulates inflammation development. Here we showed that PD-L1 was upregulated on neutrophils in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS). Neutrophil specific knockout of PD-L1 reduced lung injury in ARDS model induced by intratracheal LPS injection. The level of NET release was reduced and autophagy is elevated by PD-L1 knockout in ARDS neutrophils both in vivo and in vitro. Inhibition of autophagy could reverse the inhibitory effect of PD-L1 knockout on NET release. PD-L1 interacted with p85 subunit of PI3K at the endoplasmic reticulum (ER) in neutrophils from ARDS patients, activating the PI3K/Akt/mTOR pathway. An extrinsic neutralizing antibody against PD-L1 showed a protective effect against ARDS. Together, PD-L1 maintains the release of NETs by regulating autophagy through the PI3K/Akt/mTOR pathway in ARDS. Anti-PD-L1 therapy may be a promising measure in treating ARDS.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jin-jun Bian
- *Correspondence: Jin-jun Bian, ; Xiao-ming Deng, ; Jia-feng Wang,
| | - Xiao-ming Deng
- *Correspondence: Jin-jun Bian, ; Xiao-ming Deng, ; Jia-feng Wang,
| | - Jia-feng Wang
- *Correspondence: Jin-jun Bian, ; Xiao-ming Deng, ; Jia-feng Wang,
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31
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Salvianolic Acid A Protects against Lipopolysaccharide-Induced Acute Lung Injury by Inhibiting Neutrophil NETosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7411824. [PMID: 35910849 PMCID: PMC9334034 DOI: 10.1155/2022/7411824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/21/2022] [Accepted: 06/26/2022] [Indexed: 11/24/2022]
Abstract
Salvianolic acid A (SAA) is one of bioactive polyphenol extracted from a Salvia miltiorrhiza (Danshen), which was widely used to treat cardiovascular disease in traditional Chinese medicine. SAA has been reported to be protective in cardiovascular disease and ischemia injury, with anti-inflammatory and antioxidative effect, but its role in acute lung injury (ALI) is still unknown. In this study, we sought to investigate the therapeutic effects of SAA in a murine model of lipopolysaccharide- (LPS-) induced ALI. The optimal dose of SAA was determined by comparing the attenuation of lung injury score after administration of SAA at three different doses (low, 5 mg/kg; medium, 10 mg/kg; and, high 15 mg/kg). Dexamethasone (DEX) was used as a positive control for SAA. Here, we showed that the therapeutic effect of SAA (10 mg/kg) against LPS-induced pathologic injury in the lungs was comparable to DEX. SAA and DEX attenuated the increased W/D ratio and the protein level, counts of total cells and neutrophils, and cytokine levels in the BALF of ALI mice similarly. The oxidative stress was also relieved by SAA and DEX according to the superoxide dismutase and malondialdehyde. NET level in the lungs was elevated in the injured lung while SAA and DEX reduced it significantly. LPS induced phosphorylation of Src, Raf, MEK, and ERK in the lungs, which was inhibited by SAA and DEX. NET level and phosphorylation level of Src/Raf/MEK/ERK pathway in the neutrophils from acute respiratory distress syndrome (ARDS) patients were also inhibited by SAA and DEX in vitro, but the YEEI peptide reversed the protective effect of SAA completely. The inhibition of NET release by SAA was also reversed by YEEI peptide in LPS-challenged neutrophils from healthy volunteers. Our data demonstrated that SAA ameliorated ALI via attenuating inflammation, oxidative stress, and neutrophil NETosis. The mechanism of such protective effect might involve the inhibition of Src activation.
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32
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Filep JG. Targeting Neutrophils for Promoting the Resolution of Inflammation. Front Immunol 2022; 13:866747. [PMID: 35371088 PMCID: PMC8966391 DOI: 10.3389/fimmu.2022.866747] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 02/21/2022] [Indexed: 12/15/2022] Open
Abstract
Acute inflammation is a localized and self-limited innate host-defense mechanism against invading pathogens and tissue injury. Neutrophils, the most abundant immune cells in humans, play pivotal roles in host defense by eradicating invading pathogens and debris. Ideally, elimination of the offending insult prompts repair and return to homeostasis. However, the neutrophils` powerful weaponry to combat microbes can also cause tissue damage and neutrophil-driven inflammation is a unifying mechanism for many diseases. For timely resolution of inflammation, in addition to stopping neutrophil recruitment, emigrated neutrophils need to be disarmed and removed from the affected site. Accumulating evidence documents the phenotypic and functional versatility of neutrophils far beyond their antimicrobial functions. Hence, understanding the receptors that integrate opposing cues and checkpoints that determine the fate of neutrophils in inflamed tissues provides insight into the mechanisms that distinguish protective and dysregulated, excessive inflammation and govern resolution. This review aims to provide a brief overview and update with key points from recent advances on neutrophil heterogeneity, functional versatility and signaling, and discusses challenges and emerging therapeutic approaches that target neutrophils to enhance the resolution of inflammation.
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Affiliation(s)
- János G Filep
- Department of Pathology and Cell Biology, University of Montreal, Montreal, QC, Canada.,Research Center, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada
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33
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Hong SM, Lee AY, Hwang SM, Ha YJ, Kim MJ, Min S, Hwang W, Yoon G, Kwon SM, Woo HG, Kim HH, Jeong WI, Shen HM, Im SH, Lee D, Kim YS. NAMPT mitigates colitis severity by supporting redox-sensitive activation of phagocytosis in inflammatory macrophages. Redox Biol 2022; 50:102237. [PMID: 35063804 PMCID: PMC8784331 DOI: 10.1016/j.redox.2022.102237] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/05/2022] [Accepted: 01/12/2022] [Indexed: 12/02/2022] Open
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway and plays a crucial role in the maintenance of the NAD+ pool during inflammation. Considering that macrophages are essential for tissue homeostasis and inflammation, we sought to examine the functional impact of NAMPT in inflammatory macrophages, particularly in the context of inflammatory bowel disease (IBD). In this study, we show that mice with NAMPT deletion within the myeloid compartment (Namptf/fLysMCre+/-, Nampt mKO) have more pronounced colitis with lower survival rates, as well as numerous uncleared apoptotic corpses within the mucosal layer. Nampt-deficient macrophages exhibit reduced phagocytic activity due to insufficient NAD+ abundance, which is required to produce NADPH for the oxidative burst. Nicotinamide mononucleotide (NMN) treatment rescues NADPH levels in Nampt mKO macrophages and sustains superoxide generation via NADPH oxidase. Consequently, Nampt mKO mice fail to clear dead cells during tissue repair, leading to substantially prolonged chronic colitis. Moreover, systemic administration of NMN, to supply NAD+, effectively suppresses the disease severity of DSS-induced colitis. Collectively, our findings suggest that activation of the NAMPT-dependent NAD+ biosynthetic pathway, via NMN administration, is a potential therapeutic strategy for managing inflammatory diseases.
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Affiliation(s)
- Sun Mi Hong
- Department of Biochemistry, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea
| | - A-Yeon Lee
- Department of Biochemistry, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea; Department of Biomedical Sciences, Graduate School of Ajou University, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea
| | - Sung-Min Hwang
- Department of Biochemistry, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea
| | - Yu-Jin Ha
- Department of Biochemistry, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea; Department of Biomedical Sciences, Graduate School of Ajou University, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea
| | - Moo-Jin Kim
- Department of Biochemistry, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea; Department of Biomedical Sciences, Graduate School of Ajou University, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea
| | - Seongki Min
- Department of Biochemistry, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea; Department of Biomedical Sciences, Graduate School of Ajou University, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea
| | - Won Hwang
- MSBIOTECH. LTD, Chungbuk, 27672, Republic of Korea
| | - Gyesoon Yoon
- Department of Biochemistry, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea; Department of Biomedical Sciences, Graduate School of Ajou University, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea
| | - So Mee Kwon
- Department of Physiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea
| | - Hyun Goo Woo
- Department of Biomedical Sciences, Graduate School of Ajou University, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea; Department of Physiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea
| | - Hee-Hoon Kim
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Han-Ming Shen
- Faculty of Health Sciences, University of Macau, Macau, China
| | - Sin-Hyeog Im
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea; ImmunoBiome, Bio Open Innovation Center, Pohang, 37673, Republic of Korea
| | - Dakeun Lee
- Department of Pathology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea.
| | - You-Sun Kim
- Department of Biochemistry, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea; Department of Biomedical Sciences, Graduate School of Ajou University, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea.
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Tang Y, Liu X, Feng C, Zhou Z, Liu S. Nicotinamide phosphoribosyltransferase (Nampt) of hybrid crucian carp protects intestinal barrier and enhances host immune defense against bacterial infection. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2022; 128:104314. [PMID: 34785271 DOI: 10.1016/j.dci.2021.104314] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 11/11/2021] [Accepted: 11/11/2021] [Indexed: 06/13/2023]
Abstract
Nicotinamide phosphoribosyltransferase (Nampt) can act extracellularly as a mediator of inflammation or intracellularly as a rate-limiting enzyme, regulating nicotinamide adenine dinucleotide (NAD) biosynthesis in the NAD salvage pathway. Nampt exerts important immunological functions during infection in mammals. However, the in vivo function of fish Nampt in immune regulation and inflammation is essentially unknown. With an aim to elucidate the antimicrobial mechanism of Nampt in fish, we in this study examined the function of Nampt from hybrid crucian carp. Hybrid crucian carp Nampt (WR-Nampt) possesses the conserved nicotinamide phosphoribosyltransferase domain and shows high similarity to that of mammalian Nampt. WR-Nampt is expressed in multiple tissues and is upregulated by bacterial infection. Overexpression of WR-Nampt significantly increased the number of goblet cells of distal intestine. In addition, WR-Nampt induced significant inductions in the expression of the antimicrobial molecules (IL-22, Hepcidin-1, LEAP-2 and MUC2) and tight junctions (ZO-1 and Occludin). Consistent with this, fish administered with WR-Nampt significantly alleviated the intestinal permeability and apoptosis, thereby enhancing host's resistance against bacterial infection. Together these results revealed the potential effect of WR-Nampt in intestinal barrier and immune defense against bacterial infection.
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Affiliation(s)
- Yiyang Tang
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
| | - Xiaofeng Liu
- Department of Nutrition, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Chen Feng
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
| | - Zejun Zhou
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
| | - Shaojun Liu
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
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35
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Khanna D, Khanna S, Khanna P, Kahar P, Patel BM. Obesity: A Chronic Low-Grade Inflammation and Its Markers. Cureus 2022; 14:e22711. [PMID: 35386146 PMCID: PMC8967417 DOI: 10.7759/cureus.22711] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 02/28/2022] [Indexed: 12/15/2022] Open
Abstract
As the prevalence of obesity continues to rise, the world is facing a major public health concern. Obesity is a complex disease associated with an increase in several inflammatory markers, leading to chronic low-grade inflammation. Of multifactorial etiology, it is often used as a measurement of morbidity and mortality. There remains much unknown regarding the association between obesity and inflammation. This review seeks to compile scientific literature on obesity and its associated inflammatory markers in chronic disease and further discusses the role of adipose tissue, macrophages, B-cells, T-cells, fatty acids, amino acids, adipokines, and hormones in obesity. Data were obtained using PubMed and Google Scholar. Obesity, inflammation, immune cells, hormones, fatty acids, and others were search words used to acquire relevant articles. Studies suggest brown adipose tissue is negatively associated with body mass index (BMI) and body fat percentage. Researchers also found the adipose tissue of lean individuals predominantly secretes anti-inflammatory markers, while in obese individuals more pro-inflammatory markers are secreted. Many studies found that adipose tissue in obese individuals showed a shift in immune cells from anti-inflammatory M2 macrophages to pro-inflammatory M1 macrophages, which was also correlated with insulin resistance. Obese individuals generally present with higher levels of hormones such as leptin, visfatin, and resistin. With obesity on the rise globally, it is predicted that severe obesity will become most common amongst low-income adults, black individuals, and women by 2030, making the need for intervention urgent. Further investigation into the association between obesity and inflammation is required to understand the mechanism behind this disease.
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Affiliation(s)
- Deepesh Khanna
- Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA
| | - Siya Khanna
- Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA
| | - Pragya Khanna
- Pediatrics, Gujarat Medical Education and Research Society (GMERS) Medical College, Vadnagar, IND
| | - Payal Kahar
- Department of Health Sciences, Florida Gulf Coast University, Fort Myers, USA
| | - Bhavesh M Patel
- Pediatrics, Gujarat Medical Education and Research Society (GMERS) Medical College, Vadnagar, IND
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Álvarez-Vásquez JL, Bravo-Guapisaca MI, Gavidia-Pazmiño JF, Intriago-Morales RV. Adipokines in dental pulp: physiological, pathological, and potential therapeutic roles. J Oral Biosci 2021; 64:59-70. [PMID: 34808362 DOI: 10.1016/j.job.2021.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hundreds of adipokines have been identified, and their extensive range of endocrine functions-regulating distant organs such as oral tissues-and local autocrine/paracrine roles have been studied. In dentistry, however, adipokines are poorly known proteins in the dental pulp; few of them have been studied despite their large number. This study reviews recent advances in the investigation of dental-pulp adipokines, with an emphasis on their roles in inflammatory processes and their potential therapeutic applications. HIGHLIGHTS The most recently identified adipokines in dental pulp include leptin, adiponectin, resistin, ghrelin, oncostatin, chemerin, and visfatin. They have numerous physiological and pathological functions in the pulp tissue: they are closely related to pulp inflammatory mechanisms and actively participate in cell differentiation, mineralization, angiogenesis, and immune-system modulation. CONCLUSION Adipokines have potential clinical applications in regenerative endodontics and as biomarkers or targets for the pharmacological management of inflammatory and degenerative processes in dental pulp. A promising direction for the development of new therapies may be the use of agonists/antagonists to modulate the expression of the most studied adipokines.
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Nicotinamide phosphoribosyltransferase as a biomarker for the diagnosis of infectious pleural effusions. Sci Rep 2021; 11:21121. [PMID: 34702907 PMCID: PMC8548599 DOI: 10.1038/s41598-021-00653-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 10/15/2021] [Indexed: 11/08/2022] Open
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) has been reported to be involved in infectious diseases, but it is unknown whether it plays a role in infectious pleural effusions (IPEs). We observed the levels of NAMPT in pleural effusions of different etiologies and investigated the clinical value of NAMPT in the differential diagnosis of infectious pleural effusions. A total of 111 patients with pleural effusion were enrolled in the study, including 25 parapneumonic effusions (PPEs) (17 uncomplicated PPEs, 3 complicated PPEs, and 5 empyemas), 30 tuberculous pleural effusions (TPEs), 36 malignant pleural effusions (MPEs), and 20 transudative effusions. Pleural fluid NAMPT levels were highest in the patients with empyemas [575.4 (457.7, 649.3) ng/ml], followed by those with complicated PPEs [113.5 (103.5, 155.29) ng/ml], uncomplicated PPEs [24.9 (20.2, 46.7) ng/ml] and TPEs [88 (19.4, 182.6) ng/ml], and lower in patients with MPEs [11.5 (6.5, 18.4) ng/ml] and transudative effusions [4.3 (2.6, 5.1) ng/ml]. Pleural fluid NAMPT levels were significantly higher in PPEs (P < 0.001) or TPEs (P < 0.001) than in MPEs. Moreover, Pleural fluid NAMPT levels were positively correlated with the neutrophil percentage and lactate dehydrogenase (LDH) levels and inversely correlated with glucose levels in both PPEs and TPEs, indicating that NAMPT was implicated in the neutrophil-associated inflammatory response in infectious pleural effusion. Further, multivariate logistic regression analysis showed pleural fluid NAMPT was a significant predictor distinguishing PPEs from MPEs [odds ratio (OR) 1.180, 95% confidence interval (CI) 1.052-1.324, P = 0.005]. Receiver-operating characteristic (ROC) analysis demonstrated that NAMPT was a promising diagnostic factor for the diagnosis of infectious effusions, with the areas under the curve for pleural fluid NAMPT distinguishing PPEs from MPEs, TPEs from MPEs, and IPEs (PPEs and TPEs) from NIPEs were 0.92, 0.85, and 0.88, respectively. In conclusion, pleural fluid NAMPT could be used as a biomarker for the diagnosis of infectious pleural effusions.
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Live or die: PD-L1 delays neutrophil apoptosis. Blood 2021; 138:744-746. [PMID: 34473236 DOI: 10.1182/blood.2021012186] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 04/29/2021] [Indexed: 12/31/2022] Open
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Coutinho A, Reddy N, Chatterjee A, Khan MI. The Role of Visfatin (Adipocytokine) Biomarker in Oral Health and Diseases among Nonobese Indian Population: A Proteomic Assay. Glob Med Genet 2021; 8:104-108. [PMID: 34430962 PMCID: PMC8378923 DOI: 10.1055/s-0041-1728690] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Visfatin is an adipocytokine and a potential biomarker encoded by the nicotinamide phosphoribosyltransferase gene. It belongs to the nicotinic acid phosphoribosyltransferase family and involved in various metabolic processes and aging. The aim of this study was to evaluate the role of visfatin biomarker in oral diseases like periodontitis. A total of 60 patients (20–50 years) were included in this study, and they were divided into three groups. Group I consisted of 20 subjects with healthy periodontium, group II consisted of 20 subjects with generalized moderate gingivitis, and group III consisted of 20 subjects with generalized periodontitis. The clinical periodontal parameters, including plaque index, gingival index, probing pocket depth, and clinical attachment levels, were recorded, and saliva samples were collected. Salivary visfatin concentrations were assessed using standard enzyme-linked immunosorbent assay. The results of the study showed that the visfatin concentrations were higher in patients with gingivitis and periodontitis compared with those of healthy individuals. Visfatin was found highest in group III (38.22 ± 3.38 ng/mL) followed by group II (26.66 ± 2.24 ng/mL) and the group I (25.60 ± 2.19 ng/mL). Thus, salivary visfatin is a potential inflammatory biomarker and acts as a mediator in the pathogenesis of periodontal disease and, might serve as a diagnostic and therapeutic biomarker in oral diseases like periodontitis.
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Affiliation(s)
- Amita Coutinho
- Department of Periodontics, The Oxford Dental College, Bangalore, Karnataka, India
| | - Neethu Reddy
- Department of Periodontics, The Oxford Dental College, Bangalore, Karnataka, India
| | - Anirban Chatterjee
- Department of Periodontics, The Oxford Dental College, Bangalore, Karnataka, India
| | - Mahamad Irfanulla Khan
- Department of Orthodontics and Dentofacial Orthopedics, The Oxford Dental College, Bangalore, Karnataka, India
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Keane C, Coalter M, Martin-Loeches I. Immune System Disequilibrium-Neutrophils, Their Extracellular Traps, and COVID-19-Induced Sepsis. Front Med (Lausanne) 2021; 8:711397. [PMID: 34485339 PMCID: PMC8416266 DOI: 10.3389/fmed.2021.711397] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 07/27/2021] [Indexed: 12/15/2022] Open
Abstract
Equilibrium within the immune system can often determine the fate of its host. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic. Immune dysregulation remains one of the main pathophysiological components of SARS-CoV-2-associated organ injury, with over-activation of the innate immune system, and induced apoptosis of adaptive immune cells. Here, we provide an overview of the innate immune system, both in general and relating to COVID-19. We specifically discuss "NETosis," the process of neutrophil release of their extracellular traps, which may be a more recently described form of cell death that is different from apoptosis, and how this may propagate organ dysfunction in COVID-19. We complete this review by discussing Stem Cell Therapies in COVID-19 and emerging COVID-19 phenotypes, which may allow for more targeted therapy in the future. Finally, we consider the array of potential therapeutic targets in COVID-19, and associated therapeutics.
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Affiliation(s)
- Colm Keane
- Department of Anaesthesia and Intensive Care, St. James's Hospital, Dublin, Ireland
- Multidisciplinary Intensive Care Research Organization (MICRO), Trinity College Dublin, Dublin, Ireland
| | - Matthew Coalter
- Department of Anaesthesia and Intensive Care, St. James's Hospital, Dublin, Ireland
| | - Ignacio Martin-Loeches
- Department of Anaesthesia and Intensive Care, St. James's Hospital, Dublin, Ireland
- Multidisciplinary Intensive Care Research Organization (MICRO), Trinity College Dublin, Dublin, Ireland
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Roussin M, Salcedo SP. NAD+-targeting by bacteria: an emerging weapon in pathogenesis. FEMS Microbiol Rev 2021; 45:6315328. [PMID: 34223888 DOI: 10.1093/femsre/fuab037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 07/01/2021] [Indexed: 11/14/2022] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) is a major cofactor in redox reactions in all lifeforms. A stable level of NAD+ is vital to ensure cellular homeostasis. Some pathogens can modulate NAD+ metabolism to their advantage and even utilize or cleave NAD+ from the host using specialized effectors known as ADP-ribosyltransferase toxins and NADases, leading to energy store depletion, immune evasion, or even cell death. This review explores recent advances in the field of bacterial NAD+-targeting toxins, highlighting the relevance of NAD+ modulation as an emerging pathogenesis strategy. In addition, we discuss the role of specific NAD+-targeting toxins in niche colonization and bacterial lifestyle as components of Toxin/Antitoxin systems and key players in inter-bacterial competition. Understanding the mechanisms of toxicity, regulation, and secretion of these toxins will provide interesting leads in the search for new antimicrobial treatments in the fight against infectious diseases.
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Affiliation(s)
- Morgane Roussin
- Laboratory of Molecular Microbiology and Structural Biochemistry, Centre National de la Recherche Scientifique UMR5086, Université de Lyon, Lyon, France
| | - Suzana P Salcedo
- Laboratory of Molecular Microbiology and Structural Biochemistry, Centre National de la Recherche Scientifique UMR5086, Université de Lyon, Lyon, France
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Jablonska P, Kutryb‐Zajac B, Mierzejewska P, Jasztal A, Bocian B, Lango R, Rogowski J, Chlopicki S, Smolenski RT, Slominska EM. The new insight into extracellular NAD + degradation-the contribution of CD38 and CD73 in calcific aortic valve disease. J Cell Mol Med 2021; 25:5884-5898. [PMID: 34142751 PMCID: PMC8256368 DOI: 10.1111/jcmm.15912] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 08/03/2020] [Accepted: 08/21/2020] [Indexed: 12/26/2022] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+ ) is crucial for cell energy metabolism and many signalling processes. Recently, we proved the role of ecto-enzymes in controlling adenine nucleotide-dependent pathways during calcific aortic valve disease (CAVD). This study aimed to investigate extracellular hydrolysis of NAD+ and mononucleotide nicotinamide (NMN) in aortic valves and aorta fragments of CAVD patients and on the inner aortic surface of ecto-5'-nucleotidase knockout mice (CD73-/-). Human non-stenotic valves (n = 10) actively converted NAD+ and NMN via both CD73 and NAD+ -glycohydrolase (CD38) according to our analysis with RP-HPLC and immunofluorescence. In stenotic valves (n = 50), due to reduced CD73 activity, NAD+ was degraded predominantly by CD38 and additionally by ALP and eNPP1. CAVD patients had significantly higher hydrolytic rates of NAD+ (0.81 ± 0.07 vs 0.56 ± 0.10) and NMN (1.12 ± 0.10 vs 0.71 ± 0.08 nmol/min/cm2 ) compared with controls. CD38 was also primarily engaged in human vascular NAD+ metabolism. Studies using specific ecto-enzyme inhibitors and CD73-/- mice confirmed that CD73 is not the only enzyme involved in NAD+ and NMN hydrolysis and that CD38 had a significant contribution to these pathways. Modifications of extracellular NAD+ and NMN metabolism in aortic valve cells may be particularly important in valve pathology and could be a potential therapeutic target.
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Affiliation(s)
| | | | | | - Agnieszka Jasztal
- Jagiellonian Center for Experimental TherapeuticsJagiellonian UniversityKrakowPoland
| | - Barbara Bocian
- Department of Cardiac & Vascular SurgeryMedical University of GdanskGdanskPoland
| | - Romuald Lango
- Department of Cardiac AnaesthesiologyMedical University of GdanskGdanskPoland
| | - Jan Rogowski
- Department of Cardiac & Vascular SurgeryMedical University of GdanskGdanskPoland
| | - Stefan Chlopicki
- Jagiellonian Center for Experimental TherapeuticsJagiellonian UniversityKrakowPoland
| | | | - Ewa M. Slominska
- Department of BiochemistryMedical University of GdanskGdanskPoland
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eNAMPT Is Localised to Areas of Cartilage Damage in Patients with Hip Osteoarthritis and Promotes Cartilage Catabolism and Inflammation. Int J Mol Sci 2021; 22:ijms22136719. [PMID: 34201564 PMCID: PMC8269388 DOI: 10.3390/ijms22136719] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/16/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022] Open
Abstract
Obesity increases the risk of hip osteoarthritis (OA). Recent studies have shown that adipokine extracellular nicotinamide phosphoribosyltransferase (eNAMPT or visfatin) induces the production of IL-6 and matrix metalloproteases (MMPs) in chondrocytes, suggesting it may promote articular cartilage degradation. However, neither the functional effects of extracellular visfatin on human articular cartilage tissue, nor its expression in the joint of hip OA patients of varying BMI, have been reported. Hip OA joint tissues were collected from patients undergoing joint replacement surgery. Cartilage explants were stimulated with recombinant human visfatin. Pro-inflammatory cytokines and MMPs were measured by ELISA and Luminex. Localisation of visfatin expression in cartilage tissue was determined by immunohistochemistry. Cartilage matrix degradation was determined by quantifying proteoglycan release. Expression of visfatin was elevated in the synovial tissue of hip OA patients who were obese, and was co-localised with MMP-13 in areas of cartilage damage. Visfatin promoted the degradation of hip OA cartilage proteoglycan and induced the production of pro-inflammatory cytokines (IL-6, MCP-1, CCL20, and CCL4) and MMPs. The elevated expression of visfatin in the obese hip OA joint, and its functional effects on hip cartilage tissue, suggests it plays a central role in the loss of cartilage integrity in obese patients with hip OA.
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Shokrollahi B, Shang JH, Saadati N, Ahmad HI, Yang CY. Reproductive roles of novel adipokines apelin, visfatin, and irisin in farm animals. Theriogenology 2021; 172:178-186. [PMID: 34175524 DOI: 10.1016/j.theriogenology.2021.06.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/13/2021] [Accepted: 06/14/2021] [Indexed: 12/31/2022]
Abstract
The adipose tissue has a substantial impact on reproduction in mammals, specifically in females. As an energy depository organ, it is precisely associated with the reproductive success of mammals. Adipose tissue secretes many single molecules that are called 'adipokines' which mainly act as endocrine hormones. Adipokines homeostasis is fundamental to energy regulation, metabolic and cardiovascular diseases. The endocrine function of adipokines is influential for the long-term control of energy metabolism and performs an important function in metabolic state and fertility modulation. During the last years, new roles for adipokines have been appearing in the field of fertility. The adipokines have functions in reproduction at levels of the hypothalamus, the pituitary, and the gonads in humans, rodents, and other animals. Normal levels of adipokines are indispensable to protect the integrity of the hypothalamus-hypophysis-gonadal axis, regular ovulatory processes, and successful embryo implantation. Leptin and adiponectin are the most studied adipokines, but also the novel adipokines; apelin, visfatin, and irisin are important adipokines having several functions within the reproductive tract. Due to the known and unknown effects of these novel adipokines in the reproduction of farm animals, in this review, we will highlight the reproductive functions of apelin, visfatin, and irisin and summarize the known reproductive effects in farm animals to introduce the gaps for future studies in farm animals.
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Affiliation(s)
- Borhan Shokrollahi
- Department of Animal Science, Faculty of Agriculture, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran.
| | - Jiang-Hua Shang
- Key Laboratory of Buffalo Genetics, Breeding and Reproduction Technology, Guangxi Buffalo Research Institute, Chinese Academy of Agricultural Sciences, Nanning, 530001, China
| | - Nazila Saadati
- Department of Plant Biotechnology, Faculty of Agriculture, Kurdistan University, Sanandaj, Kurdistan province, Iran
| | - Hafiz Ishfaq Ahmad
- Department of Animal Breeding and Genetics, University of Veterinary and Animal Sciences, Ravi Campus, Pattoki, Pakistan
| | - Chun-Yan Yang
- Key Laboratory of Buffalo Genetics, Breeding and Reproduction Technology, Guangxi Buffalo Research Institute, Chinese Academy of Agricultural Sciences, Nanning, 530001, China
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Fantone K, Tucker SL, Miller A, Yadav R, Bernardy EE, Fricker R, Stecenko AA, Goldberg JB, Rada B. Cystic Fibrosis Sputum Impairs the Ability of Neutrophils to Kill Staphylococcus aureus. Pathogens 2021; 10:pathogens10060703. [PMID: 34200034 PMCID: PMC8229215 DOI: 10.3390/pathogens10060703] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/26/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Cystic fibrosis (CF) airway disease is characterized by chronic microbial infections and infiltration of inflammatory polymorphonuclear (PMN) granulocytes. Staphylococcus aureus (S. aureus) is a major lung pathogen in CF that persists despite the presence of PMNs and has been associated with CF lung function decline. While PMNs represent the main mechanism of the immune system to kill S. aureus, it remains largely unknown why PMNs fail to eliminate S. aureus in CF. The goal of this study was to observe how the CF airway environment affects S. aureus killing by PMNs. PMNs were isolated from the blood of healthy volunteers and CF patients. Clinical isolates of S. aureus were obtained from the airways of CF patients. The results show that PMNs from healthy volunteers were able to kill all CF isolates and laboratory strains of S. aureus tested in vitro. The extent of killing varied among strains. When PMNs were pretreated with supernatants of CF sputum, S. aureus killing was significantly inhibited suggesting that the CF airway environment compromises PMN antibacterial functions. CF blood PMNs were capable of killing S. aureus. Although bacterial killing was inhibited with CF sputum, PMN binding and phagocytosis of S. aureus was not diminished. The S. aureus-induced respiratory burst and neutrophil extracellular trap release from PMNs also remained uninhibited by CF sputum. In summary, our data demonstrate that the CF airway environment limits killing of S. aureus by PMNs and provides a new in vitro experimental model to study this phenomenon and its mechanism.
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Affiliation(s)
- Kayla Fantone
- Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; (K.F.); (S.L.T.); (A.M.); (R.Y.); (R.F.)
| | - Samantha L. Tucker
- Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; (K.F.); (S.L.T.); (A.M.); (R.Y.); (R.F.)
| | - Arthur Miller
- Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; (K.F.); (S.L.T.); (A.M.); (R.Y.); (R.F.)
| | - Ruchi Yadav
- Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; (K.F.); (S.L.T.); (A.M.); (R.Y.); (R.F.)
| | - Eryn E. Bernardy
- Division of Pulmonology, Allergy/Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; (E.E.B.); (A.A.S.); (J.B.G.)
| | - Rachel Fricker
- Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; (K.F.); (S.L.T.); (A.M.); (R.Y.); (R.F.)
| | - Arlene A. Stecenko
- Division of Pulmonology, Allergy/Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; (E.E.B.); (A.A.S.); (J.B.G.)
| | - Joanna B. Goldberg
- Division of Pulmonology, Allergy/Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; (E.E.B.); (A.A.S.); (J.B.G.)
| | - Balázs Rada
- Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; (K.F.); (S.L.T.); (A.M.); (R.Y.); (R.F.)
- Correspondence:
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Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental animal model of sepsis. Blood 2021; 138:806-810. [PMID: 34010409 DOI: 10.1182/blood.2020009417] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 04/17/2021] [Indexed: 11/20/2022] Open
Abstract
PD-L1 is a ligand for PD-1 and its expression has been shown to be upregulated in neutrophils harvested from septic patients. However, the effect of PD-L1 on neutrophil survival and sepsis-induced lung injury remains largely unknown. Here we show PD-L1 expression negatively correlates with rates of apoptosis in human neutrophils harvested from patients with sepsis. Using co-immunoprecipitation assays on control neutrophils challenged with IFN-γ and LPS, we show PD-L1 complexes with the p85 subunit of PI3-K to activate AKT-dependent survival signaling. Conditional CRE/LoxP deletion of neutrophil PD-L1 in vivo further protected against lung injury and reduced neutrophil lung infiltration in a cecal ligation and puncture (CLP) experimental sepsis animal model. Compared to wild-type animals, PD-L1-deficient animals presented lower plasma levels of plasma TNF-α and IL-6 and higher IL-10 following CLP, and reduced seven-day mortality in CLP PD-L1 knockout animals. Taken together, our data suggest that increased PD-L1 expression on human neutrophils delays cellular apoptosis by triggering PI-3K-dependent AKT phosphorylation to drive lung injury and increase mortality during clinical and experimental sepsis.
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Groth B, Venkatakrishnan P, Lin SJ. NAD + Metabolism, Metabolic Stress, and Infection. Front Mol Biosci 2021; 8:686412. [PMID: 34095234 PMCID: PMC8171187 DOI: 10.3389/fmolb.2021.686412] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 05/05/2021] [Indexed: 12/26/2022] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite with wide-ranging and significant roles in the cell. Defects in NAD+ metabolism have been associated with many human disorders; it is therefore an emerging therapeutic target. Moreover, NAD+ metabolism is perturbed during colonization by a variety of pathogens, either due to the molecular mechanisms employed by these infectious agents or by the host immune response they trigger. Three main biosynthetic pathways, including the de novo and salvage pathways, contribute to the production of NAD+ with a high degree of conservation from bacteria to humans. De novo biosynthesis, which begins with l-tryptophan in eukaryotes, is also known as the kynurenine pathway. Intermediates of this pathway have various beneficial and deleterious effects on cellular health in different contexts. For example, dysregulation of this pathway is linked to neurotoxicity and oxidative stress. Activation of the de novo pathway is also implicated in various infections and inflammatory signaling. Given the dynamic flexibility and multiple roles of NAD+ intermediates, it is important to understand the interconnections and cross-regulations of NAD+ precursors and associated signaling pathways to understand how cells regulate NAD+ homeostasis in response to various growth conditions. Although regulation of NAD+ homeostasis remains incompletely understood, studies in the genetically tractable budding yeast Saccharomyces cerevisiae may help provide some molecular basis for how NAD+ homeostasis factors contribute to the maintenance and regulation of cellular function and how they are regulated by various nutritional and stress signals. Here we present a brief overview of recent insights and discoveries made with respect to the relationship between NAD+ metabolism and selected human disorders and infections, with a particular focus on the de novo pathway. We also discuss how studies in budding yeast may help elucidate the regulation of NAD+ homeostasis.
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Affiliation(s)
- Benjamin Groth
- Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, Davis, CA, United States
| | - Padmaja Venkatakrishnan
- Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, Davis, CA, United States
| | - Su-Ju Lin
- Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, Davis, CA, United States
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Zou Q, Si J, Guo Y, Yu J, Shi H. Association between serum visfatin levels and psoriasis and their correlation with disease severity: a meta-analysis. J Int Med Res 2021; 49:3000605211002381. [PMID: 33771065 PMCID: PMC8168054 DOI: 10.1177/03000605211002381] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Objective To determine the association between serum visfatin levels and psoriasis and to evaluate the correlation between serum visfatin levels and the severity of psoriasis. Methods The electronic databases PubMed®, Embase® and the Cochrane Library were searched for articles published from inception to 1 May 2020. Data were extracted and then standard mean differences (SMDs) and 95% confidence intervals (CIs) were calculated for pooled estimates. Results A total of 11 studies met the inclusion criteria and were included (448 patients diagnosed with psoriasis and 377 controls). This meta-analysis demonstrated that patients with psoriasis had significantly higher levels of visfatin than the controls (SMD = 0.90, 95% CI 0.52, 1.28). Subgroup analyses showed that differences in serum visfatin levels between the patient group and the control group were associated with ethnicity, Psoriasis Area and Severity Index (PASI) and body mass index. Additionally, a meta-analysis of correlations showed that visfatin levels in patients with psoriasis were positively correlated with PASI (r = 0.51, 95% CI 0.14, 0.75). Conclusions This meta-analysis showed that serum visfatin levels in patients with psoriasis were significantly higher than those in the controls and a positive correlation between serum visfatin levels and psoriasis severity was observed.
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Affiliation(s)
- Qian Zou
- Department of Clinical Medicine, Ningxia Medical University, Ningxia, China
| | - Jiawei Si
- Department of Clinical Medicine, Ningxia Medical University, Ningxia, China
| | - Yatao Guo
- Department of Clinical Medicine, Ningxia Medical University, Ningxia, China
| | - Jiayu Yu
- Department of Clinical Medicine, Ningxia Medical University, Ningxia, China
| | - Huijuan Shi
- Department of Dermatovenereology, General Hospital of Ningxia Medical University, Ningxia, China
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Cici D, Corrado A, Rotondo C, Colia R, Cantatore FP. Adipokines and Chronic Rheumatic Diseases: from Inflammation to Bone Involvement. Clin Rev Bone Miner Metab 2021. [DOI: 10.1007/s12018-021-09275-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
AbstractBesides its well-known role as energy storage tissue, adipose tissue is a biologically active tissue that can also be considered as an endocrine organ, as it is able to secrete adipokines. These bioactive factors, similar in structure to cytokines, are involved in several physiological and pathological conditions, such as glucose homeostasis, angiogenesis, blood pressure regulation, control of food intake, and also inflammation and bone homeostasis via endocrine, paracrine, and autocrine mechanisms. Given their pleiotropic functions, the role of adipokines has been evaluated in chronic rheumatic osteoarticular inflammatory diseases, particularly focusing on their effects on inflammatory and immune response and on bone alterations. Indeed, these diseases are characterized by different bone complications, such as local and systemic bone loss and new bone formation. The aim of this review is to summarize the role of adipokines in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, osteoarthritis, and osteoporosis, especially considering their role in the pathogenesis of bone complications typical of these conditions.
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Pillai VB, Gupta MP. Is nuclear sirtuin SIRT6 a master regulator of immune function? Am J Physiol Endocrinol Metab 2021; 320:E399-E414. [PMID: 33308014 PMCID: PMC7988780 DOI: 10.1152/ajpendo.00483.2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/03/2020] [Accepted: 12/08/2020] [Indexed: 12/29/2022]
Abstract
The ability to ward off pathogens with minimal damage to the host determines the immune system's robustness. Multiple factors, including pathogen processing, identification, secretion of mediator and effector molecules, and immune cell proliferation and differentiation into various subsets, constitute the success of mounting an effective immune response. Cellular metabolism controls all of these intricate processes. Cells utilize diverse fuel sources and switch back and forth between different metabolic pathways depending on their energy needs. The three most critical metabolic pathways on which immune cells depend to meet their energy needs are oxidative metabolism, glycolysis, and glutaminolysis. Dynamic switching between these metabolic pathways is needed for optimal function of the immune cells. Moreover, switching between these metabolic pathways needs to be tightly regulated to achieve the best results. Immune cells depend on the Warburg effect for their growth, proliferation, secretory, and effector functions. Here, we hypothesize that the sirtuin, SIRT6, could be a negative regulator of the Warburg effect. We also postulate that SIRT6 could act as a master regulator of immune cell metabolism and function by regulating critical signaling pathways.
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Affiliation(s)
- Vinodkumar B Pillai
- Department of Surgery (Division of Cardiothoracic Surgery), Pritzker School of Medicine, Basic Science Division, University of Chicago, Chicago, Illinois
| | - Mahesh P Gupta
- Department of Surgery (Division of Cardiothoracic Surgery), Pritzker School of Medicine, Basic Science Division, University of Chicago, Chicago, Illinois
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