المؤلفون: Kageyama, Shoichi, Hirao, Hirofumi, Nakamura, Kojiro, Ke, Bibo, Zhang, Min, Ito, Takahiro, Aziz, Antony, Oncel, Damla, Kaldas, Fady M, Busuttil, Ronald W, Sosa, Rebecca A, Reed, Elaine F, Araujo, Jesus A, Kupiec‐Weglinski, Jerzy W

المصدر: American Journal of Transplantation. 19(2)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Immunology, Transplantation, Organ Transplantation, Digestive Diseases, Liver Disease, Animals, Apoptosis, Heme Oxygenase-1, Humans, Liver, Liver Transplantation, Macrophages, Mice, Mice, Inbred C57BL, Neutrophils, Reperfusion Injury, Signal Transduction, basic (laboratory) research, science, immunobiology, ischemia reperfusion injury, liver disease: immune, inflammatory, liver transplantation, hepatology, organ perfusion and preservation, protocol biopsy, tissue injury and repair, translational research, basic (laboratory) research/science, liver disease: immune/inflammatory, liver transplantation/hepatology, translational research/science, Medical and Health Sciences, Surgery, Clinical sciences

الوصف: By documenting potent antioxidative and anti-inflammatory functions, preclinical studies encourage heme oxygenase-1 (HO-1)-inducing regimens in clinical orthotopic liver transplantation (OLT). We aimed to determine the importance of recipient-derived HO-1 in murine and human OLTs. Hepatic biopsies from 51 OLT patients were screened for HO-1 expression (Western blots) prior to put-in (basal) and post reperfusion (stressed) and correlated with the hepatocellular function. In parallel, livers from HO-1 proficient mice (WT; C57/BL6), subjected to ex vivo cold storage (18 hour), were transplanted to syngeneic myeloid HO-1 deficient (mHO-1 KO) or FLOX (control) hosts, and sampled postreperfusion (6 hour). In human OLT, posttransplant but not pretransplant HO-1 expression correlated negatively with ALT levels (P = .0178). High posttransplant but not pretransplant HO-1 expression trended with improved OLT survival. Compared with controls, livers transplanted into mHO-1 KO recipient mice had decreased HO-1 levels, exacerbated hepatic damage/frequency of TUNEL+ cells, increased mRNA levels coding for TNFα/CXCL1/CXCL2/CXCL10, higher frequency of Ly6G+/4HN+ neutrophils; and enhanced MPO activity. Peritoneal neutrophils from mHO-1 KO mice exhibited higher CellRox+ ratio and increased TNFα/CXCL1/CXCL2/CXCL10 expression. By demonstrating the importance of posttransplant recipient HO-1 phenotype in hepatic macrophage/neutrophil regulation and function, this translational study identifies recipient HO-1 inducibility as a novel biomarker of ischemic stress resistance in OLT.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/80g8987vTest

المؤلفون: Marwan Habiba, Giuseppe Benagiano, Sun-Wei Guo

المصدر: Biomolecules; Volume 13; Issue 6; Pages: 975

مصطلحات موضوعية: adenomyosis, archimetra, archimetrosis, archimetrium, endometriosis, pathogenesis, tissue injury and repair

جغرافية الموضوع: agris

الوصف: As understanding their pathogenesis remains elusive, both endometriosis and adenomyosis are often referred to as “enigmatic diseases”. The uncertainty and heightened interest are reflected in the range of expressed views and opinions. There is a sense of urgency because of the entailed patient suffering. The plethora of opinions calls for a critical analysis of proposed theories, both old and new. A series of papers published since 2009 proposed that both endometriosis and adenomyosis originate from the same aberrations occurring within the uterus. This came to be recognized as the tissue injury and repair theory, and the newly coined term “archimetrosis” posits that the two diseases share the same origin. While the theory opens an interesting channel for exploration, its claim as a unifying theory necessitates a critical appraisal. We, thus, undertook this review of the theory and analyzed its underpinnings based on a comprehensive review of the literature. Our appraisal indicates that the theory is open to a range of criticisms. Chief among these is the need for confirmatory evidence of features of abnormal uterine contractility and the lack of data addressing the question of causality. In addition, the theory has, as yet, no supporting epidemiological evidence, which is a major weakness. The theory suffers as it is not open to the test of falsifiability, and it lacks the ability to make useful predictions. It has not addressed the questions, such as why only a small percentage of women develop adenomyosis or endometriosis, given the ubiquity of uterine peristalsis. On the other hand, the triggers and prevention of hyper- or dys-peristalsis become critical to a theory of causation. We conclude that additional supportive evidence is required for the theory to be accepted.

وصف الملف: application/pdf

العلاقة: Molecular Reproduction; https://dx.doi.org/10.3390/biom13060975Test

الإتاحة: https://doi.org/10.3390/biom13060975Test

المؤلفون: Sun-Wei Guo

المصدر: Journal of Clinical Medicine; Volume 12; Issue 3; Pages: 842

مصطلحات موضوعية: adenomyosis, coagulation, dysmenorrhea, fibrogenesis, heavy menstrual bleeding, repeated tissue injury and repair

الوصف: Widely viewed as an enigmatic disease, adenomyosis is a common gynecological disease with bewildering pathogenesis and pathophysiology. One defining hallmark of adenomyotic lesions is cyclic bleeding as in eutopic endometrium, yet bleeding is a quintessential trademark of tissue injury, which is invariably followed by tissue repair. Consequently, adenomyotic lesions resemble wounds. Following each bleeding episode, adenomyotic lesions undergo tissue repair, and, as such, platelets are the first responder that heralds the subsequent tissue repair. This repeated tissue injury and repair (ReTIAR) would elicit several key molecular events crucial for lesional progression, eventually leading to lesional fibrosis. Platelets interact with adenomyotic cells and actively participate in these events, promoting the lesional progression and fibrogenesis. Lesional fibrosis may also be propagated into their neighboring endometrial–myometrial interface and then to eutopic endometrium, impairing endometrial repair and causing heavy menstrual bleeding. Moreover, lesional progression may result in hyperinnervation and an enlarged uterus. In this review, the role of platelets in the pathogenesis, progression, and pathophysiology is reviewed, along with the therapeutic implication. In addition, I shall demonstrate how the notion of ReTIAR provides a much needed framework to tether to and piece together many seemingly unrelated findings and how it helps to make useful predictions.

وصف الملف: application/pdf

العلاقة: Pharmacology; https://dx.doi.org/10.3390/jcm12030842Test

الإتاحة: https://doi.org/10.3390/jcm12030842Test

المؤلفون: Kageyama, Shoichi, Nakamura, Kojiro, Ke, Bibo, Busuttil, Ronald W, Kupiec-Weglinski, Jerzy W

المصدر: American Journal of Transplantation. 18(7)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Transplantation, Liver Disease, Digestive Diseases, Biotechnology, Chronic Liver Disease and Cirrhosis, Organ Transplantation, 2.1 Biological and endogenous factors, Aetiology, Animals, Apoptosis, Humans, Liver, Liver Transplantation, Macrophages, Mice, Mice, Inbred C57BL, Prognosis, Receptor, Notch1, Recombinant Proteins, Relaxin, Reperfusion Injury, Signal Transduction, animal models: murine, basic (laboratory) research, science, immunobiology, Ischemia-reperfusion injury, liver disease: immune, inflammatory, liver transplantation, hepatology, macrophage, monocyte biology, tissue injury and repair, translational research, basic (laboratory) research/science, liver disease: immune/inflammatory, liver transplantation/hepatology, macrophage/monocyte biology, translational research/science, Medical and Health Sciences, Surgery, Clinical sciences, Immunology

الوصف: Liver ischemia-reperfusion injury (IRI) represents a risk factor for early graft dysfunction and an obstacle to expanding donor pool in orthotopic liver transplantation (OLT). We have reported on the crucial role of macrophage Notch1 signaling in mouse warm hepatic IRI model. However, its clinical relevance or therapeutic potential remain unknown. Here, we used Serelaxin (SER), to verify Notch1 induction and putative hepatoprotective function in ischemia-reperfusion-stressed OLT. C57BL/6 mouse livers subjected to extended (18-hour) cold storage were transplanted to syngeneic recipients. SER treatment at reperfusion ameliorated IRI, improved post-OLT survival, decreased neutrophil/macrophage infiltration, and suppressed proinflammatory cytokine programs, while simultaneously increasing Notch intracellular domain (NICD) and hairy and enhancer of split 1 (Hes1) target genes. In bone marrow-derived macrophage cultures, SER suppressed proinflammatory while enhancing antiinflammatory gene expression concomitantly with increased NICD and Hes1. Hepatic biopsies from 21 adult primary liver transplant patients (2 hours postreperfusion) were divided into low-NICD (n = 11) and high-NICD (n = 10) expression groups (western blots). Consistent with our murine findings, human livers characterized by high NICD were relatively IRI resistant, as shown by serum alanine aminotransferase (ALT) levels at day 1 post-OLT. Our study documents the efficacy of SER-Notch1 signaling in mouse OLT and highlights the protective function of Notch1 in liver transplant patients.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8kf8091zTest

المؤلفون: Nakamura, Kojiro, Kageyama, Shoichi, Yue, Shi, Huang, Jing, Fujii, Takehiro, Ke, Bibo, Sosa, Rebecca A, Reed, Elaine F, Datta, Nakul, Zarrinpar, Ali, Busuttil, Ronald W, Kupiec-Weglinski, Jerzy W

المصدر: American Journal of Transplantation. 18(5)

مصطلحات موضوعية: Chronic Liver Disease and Cirrhosis, Digestive Diseases, Liver Disease, Transplantation, Organ Transplantation, 2.1 Biological and endogenous factors, Aetiology, Animals, Apoptosis, Autophagy, Cells, Cultured, Cytoprotection, Gene Expression Regulation, Graft Survival, Heme Oxygenase-1, Humans, Liver Transplantation, Macrophages, Mice, Mice, Inbred C57BL, Reperfusion Injury, Signal Transduction, Sirtuin 1, basic (laboratory) research, science, biopsy, immunobiology, liver disease: immune, inflammatory, liver transplantation, hepatology, organ perfusion and preservation, tissue injury and repair, translational research, basic (laboratory) research/science, liver disease: immune/inflammatory, liver transplantation/hepatology, translational research/science, Medical and Health Sciences, Surgery

الوصف: Liver ischemia-reperfusion injury (IRI) represents a major risk factor of early graft dysfunction and a key obstacle to expanding the donor pool in orthotopic liver transplantation (OLT). Although graft autophagy is essential for resistance against hepatic IRI, its significance in clinical OLT remains unknown. Despite recent data identifying heme oxygenase-1 (HO-1) as a putative autophagy inducer, its role in OLT and interactions with sirtuin-1 (SIRT1), a key autophagy regulator, have not been studied. We aimed to examine HO-1-mediated autophagy induction in human OLT and in a murine OLT model with extended (20 hours) cold storage, as well as to analyze the requirement for SIRT1 in autophagy regulation by HO-1. Fifty-one hepatic biopsy specimens from OLT patients were collected under an institutional review board protocol 2 hours after portal reperfusion, followed by Western blot analyses. High HO-1 levels correlated with well-preserved hepatocellular function and enhanced SIRT1/LC3B expression. In mice, HO-1 overexpression by genetically modified HO-1 macrophage therapy was accompanied by decreased OLT damage and increased SIRT1/LC3B expression, whereas adjunctive inhibition of SIRT1 signaling diminished HO-1-mediated hepatoprotection and autophagy induction. Our translational study confirms the clinical relevance of HO-1 cytoprotection and identifies SIRT1-mediated autophagy pathway as a new essential regulator of HO-1 function in IR-stressed OLT.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/30m505znTest

المؤلفون: Gennai, S, Monsel, A, Hao, Q, Park, J, Matthay, MA, Lee, JW

المصدر: American Journal of Transplantation. 15(9)

مصطلحات موضوعية: Medical Biotechnology, Biomedical and Clinical Sciences, Cancer, Stem Cell Research, Regenerative Medicine, Transplantation, Lung, Stem Cell Research - Nonembryonic - Human, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, Respiratory, Adult, Cell-Derived Microparticles, Cells, Cultured, Donor Selection, Female, Follow-Up Studies, Humans, Lung Diseases, Lung Transplantation, Male, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells, Middle Aged, Organ Preservation, Perfusion, Prognosis, Pulmonary Alveoli, Pulmonary Edema, Tissue and Organ Procurement, lung failure, injury, stem cells, tissue injury and repair, lung failure/injury, Medical and Health Sciences, Surgery, Clinical sciences, Immunology

الوصف: The need to increase the donor pool for lung transplantation is a major public health issue. We previously found that administration of mesenchymal stem cells "rehabilitated" marginal donor lungs rejected for transplantation using ex vivo lung perfusion. However, the use of stem cells has some inherent limitation such as the potential for tumor formation. In the current study, we hypothesized that microvesicles, small anuclear membrane fragments constitutively released from mesenchymal stem cells, may be a good alternative to using stem cells. Using our well established ex vivo lung perfusion model, microvesicles derived from human mesenchymal stem cells increased alveolar fluid clearance (i.e. ability to absorb pulmonary edema fluid) in a dose-dependent manner, decreased lung weight gain following perfusion and ventilation, and improved airway and hemodynamic parameters compared to perfusion alone. Microvesicles derived from normal human lung fibroblasts as a control had no effect. Co-administration of microvesicles with anti-CD44 antibody attenuated these effects, suggesting a key role of the CD44 receptor in the internalization of the microvesicles into the injured host cell and its effect. In summary, microvesicles derived from human mesenchymal stem cells were as effective as the parent mesenchymal stem cells in rehabilitating marginal donor human lungs.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/30z6v3kkTest

المؤلفون: Sun‐Wei Guo

المصدر: Reproductive Medicine and Biology, Vol 17, Iss 4, Pp 369-397 (2018)

مصطلحات موضوعية: cancer driver mutation, endometriosis, fibrogenesis, natural history, repeated tissue injury and repair, Diseases of the endocrine glands. Clinical endocrinology, RC648-665, Reproduction, QH471-489

الوصف: Abstract Background One recent study reports cancer driver mutations in deep endometriosis, but its biological/clinical significance remains unclear. Since the natural history of endometriosis is essentially gradual progression toward fibrosis, it is thus hypothesized that the six driver genes reported to be mutated in endometriosis (the RP set) may play important roles in fibrogenesis but not necessarily malignant transformation. Methods Extensive PubMed search to see whether RP and another set of driver genes not yet reported (NR) to be mutated in endometriosis have any roles in fibrogenesis. All studies reporting on the role of fibrogenesis of the genes in both RP and NR sets were retrieved and evaluated in this review. Results All six RP genes were involved in various aspects of fibrogenesis as compared with only three NR genes. These nine genes can be anchored in networks linking with their upstream and downstream genes that are known to be aberrantly expressed in endometriosis, piecing together seemingly unrelated findings. Conclusions Given that somatic driver mutations can and do occur frequently in physiologically normal tissues, it is argued that these mutations in endometriosis are not necessarily synonymous with malignancy or premalignancy, but the result of enormous pressure for fibrogenesis.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1445-5781Test; https://doaj.org/toc/1447-0578Test

الوصول الحر: https://doaj.org/article/dafd3ae0720e4f869b7d09bafb2793fbTest

المؤلفون: Goh, YP Sharon, Henderson, Neil C, Heredia, Jose E, Eagle, Alex Red, Odegaard, Justin I, Lehwald, Nadja, Nguyen, Khoa D, Sheppard, Dean, Mukundan, Lata, Locksley, Richard M, Chawla, Ajay

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 110(24)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Liver Disease, Regenerative Medicine, Oral and gastrointestinal, Animals, Cell Cycle, Cell Proliferation, Eosinophils, Gene Expression Profiling, Hepatectomy, Hepatocytes, Immunoblotting, Interleukin-4, Interleukin-4 Receptor alpha Subunit, Liver, Liver Regeneration, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, type 2 immunity, tissue injury and repair, inflammation, parasites

الوصف: The liver is a central organ for the synthesis and storage of nutrients, production of serum proteins and hormones, and breakdown of toxins and metabolites. Because the liver is susceptible to toxin- or pathogen-mediated injury, it maintains a remarkable capacity to regenerate by compensatory growth. Specifically, in response to injury, quiescent hepatocytes enter the cell cycle and undergo DNA replication to promote liver regrowth. Despite the elucidation of a number of regenerative factors, the mechanisms by which liver injury triggers hepatocyte proliferation are incompletely understood. We demonstrate here that eosinophils stimulate liver regeneration after partial hepatectomy and toxin-mediated injury. Liver injury results in rapid recruitment of eosinophils, which secrete IL-4 to promote the proliferation of quiescent hepatocytes. Surprisingly, signaling via the IL-4Rα in macrophages, which have been implicated in tissue repair, is dispensable for hepatocyte proliferation and liver regrowth after injury. Instead, IL-4 exerts its proliferative actions via IL-4Rα in hepatocytes. Our findings thus provide a unique mechanism by which eosinophil-derived IL-4 stimulates hepatocyte proliferation in regenerating liver.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/69q0b6zmTest

المؤلفون: Guo

المصدر: Journal of Clinical Medicine; Volume 9; Issue 2; Pages: 485

مصطلحات موضوعية: adenomyosis, endometrial-myometrial interface disruption, endometriosis, pathogenesis, pathophysiology, repeated tissue injury and repair

الوصف: Adenomyosis is used to be called endometriosis interna, and deep endometriosis is now called adenomyosis externa. Thus, there is a question as to whether adenomyosis is simply endometriosis of the uterus, either from the perspective of pathogenesis or pathophysiology. In this manuscript, a comprehensive review was performed with a literature search using PubMed for all publications in English, related to adenomyosis and endometriosis, from inception to June 20, 2019. In addition, two prevailing theories, i.e., invagination—based on tissue injury and repair (TIAR) hypothesis—and metaplasia, on adenomyosis pathogenesis, are briefly overviewed and then critically scrutinized. Both theories have apparent limitations, i.e., difficulty in falsification, explaining existing data, and making useful predictions. Based on the current understanding of wound healing, a new hypothesis, called endometrial-myometrial interface disruption (EMID), is proposed to account for adenomyosis resulting from iatrogenic trauma to EMI. The EMID hypothesis not only highlights the more salient feature, i.e., hypoxia, at the wounding site, but also incorporates epithelial mesenchymal transition, recruitment of bone-marrow-derived stem cells, and enhanced survival and dissemination of endometrial cells dispersed and displaced due to iatrogenic procedures. More importantly, the EMID hypothesis predicts that the risk of adenomyosis can be reduced if certain perioperative interventions are performed. Consequently, from a pathogenic standpoint, adenomyosis is not simply endometriosis of the uterus, and, as such, may call for interventional procedures that are somewhat different from those for endometriosis to achieve the best results.

وصف الملف: application/pdf

العلاقة: Obstetrics & Gynecology; https://dx.doi.org/10.3390/jcm9020485Test

الإتاحة: https://doi.org/10.3390/jcm9020485Test

المؤلفون: Sun-Wei Guo

المصدر: Journal of Clinical Medicine, Vol 9, Iss 2, p 485 (2020)

مصطلحات موضوعية: adenomyosis, endometrial-myometrial interface disruption, endometriosis, pathogenesis, pathophysiology, repeated tissue injury and repair, Medicine

الوصف: Adenomyosis is used to be called endometriosis interna, and deep endometriosis is now called adenomyosis externa. Thus, there is a question as to whether adenomyosis is simply endometriosis of the uterus, either from the perspective of pathogenesis or pathophysiology. In this manuscript, a comprehensive review was performed with a literature search using PubMed for all publications in English, related to adenomyosis and endometriosis, from inception to June 20, 2019. In addition, two prevailing theories, i.e., invagination—based on tissue injury and repair (TIAR) hypothesis—and metaplasia, on adenomyosis pathogenesis, are briefly overviewed and then critically scrutinized. Both theories have apparent limitations, i.e., difficulty in falsification, explaining existing data, and making useful predictions. Based on the current understanding of wound healing, a new hypothesis, called endometrial-myometrial interface disruption (EMID), is proposed to account for adenomyosis resulting from iatrogenic trauma to EMI. The EMID hypothesis not only highlights the more salient feature, i.e., hypoxia, at the wounding site, but also incorporates epithelial mesenchymal transition, recruitment of bone-marrow-derived stem cells, and enhanced survival and dissemination of endometrial cells dispersed and displaced due to iatrogenic procedures. More importantly, the EMID hypothesis predicts that the risk of adenomyosis can be reduced if certain perioperative interventions are performed. Consequently, from a pathogenic standpoint, adenomyosis is not simply endometriosis of the uterus, and, as such, may call for interventional procedures that are somewhat different from those for endometriosis to achieve the best results.

العلاقة: https://www.mdpi.com/2077-0383/9/2/485Test; https://doaj.org/toc/2077-0383Test; https://doaj.org/article/9101ba7a7fe44bc4a932323cc00b234bTest

الإتاحة: https://doi.org/10.3390/jcm9020485Test
https://doaj.org/article/9101ba7a7fe44bc4a932323cc00b234bTest