scholarly journals Mucosal Epithelial Jak Kinases in Health and Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Narendra Kumar ◽  
Longxiang Kuang ◽  
Ryan Villa ◽  
Priyam Kumar ◽  
Jayshree Mishra
Keyword(s):  
Immune Cells ◽  
Wound Repair ◽  
Epithelial Mesenchymal Transition ◽  
Transplant Rejection ◽  
Severe Combined Immunodeficiency ◽  
Organ Transplant ◽  
Therapeutic Interventions ◽  
Cell Physiology ◽  
Mesenchymal Transition ◽  
Epithelial Cancers

Janus kinases (Jaks) are a family of nonreceptor tyrosine kinase that include four different members, viz., Jak1, Jak2, Jak3, and Tyk2. Jaks play critical roles in immune cells functions; however, recent studies suggest they also play essential roles in nonimmune cell physiology. This review highlights the significance of epithelial Jaks in understanding the molecular basis of some of the diseases through regulation of epithelial-mesenchymal transition, cell survival, cell growth, development, and differentiation. Growth factors and cytokines produced by the cells of hematopoietic origin use Jak kinases for signal transduction in both immune and nonimmune cells. Among Jaks, Jak3 is widely expressed in both immune cells and in intestinal epithelial cells (IECs) of both humans and mice. Mutations that abrogate Jak3 functions cause an autosomal severe combined immunodeficiency disease (SCID) while activating Jak3 mutations lead to the development of hematologic and epithelial cancers. A selective Jak3 inhibitor CP-690550 (Xeljanz) approved by the FDA for certain chronic inflammatory conditions demonstrates immunosuppressive activity in rheumatoid arthritis, psoriasis, and organ transplant rejection. Here, we also focus on the consequences of Jak3-directed drugs on adverse effects in light of recent discoveries in mucosal epithelial functions of Jak3 with some information on other Jaks. Lastly, we brief on structural implications of Jak3 domains beyond the immune cells. As information about the roles of Jak3 in gastrointestinal functions and associated diseases are only just emerging, in the review, we summarize its implications in gastrointestinal wound repair, inflammatory bowel disease, obesity-associated metabolic syndrome, and epithelial cancers. Lastly, we shed lights on identifying potential novel targets in developing therapeutic interventions of diseases associated with dysfunctional IEC.

scholarly journals Pathophysiology of Lung Disease and Wound Repair in Cystic Fibrosis

2021 ◽  
Vol 28 (1) ◽  
pp. 155-188
Author(s):  
Massimo Conese ◽  
Sante Di Gioia
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Wound Repair ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Interventions ◽  
In Vivo Studies ◽  
Mesenchymal Transition ◽  
Molecular Events

Cystic fibrosis (CF) is an autosomal recessive, life-threatening condition affecting many organs and tissues, the lung disease being the chief cause of morbidity and mortality. Mutations affecting the CF Transmembrane Conductance Regulator (CFTR) gene determine the expression of a dysfunctional protein that, in turn, triggers a pathophysiological cascade, leading to airway epithelium injury and remodeling. In vitro and in vivo studies point to a dysregulated regeneration and wound repair in CF airways, to be traced back to epithelial CFTR lack/dysfunction. Subsequent altered ion/fluid fluxes and/or signaling result in reduced cell migration and proliferation. Furthermore, the epithelial-mesenchymal transition appears to be partially triggered in CF, contributing to wound closure alteration. Finally, we pose our attention to diverse approaches to tackle this defect, discussing the therapeutic role of protease inhibitors, CFTR modulators and mesenchymal stem cells. Although the pathophysiology of wound repair in CF has been disclosed in some mechanisms, further studies are warranted to understand the cellular and molecular events in more details and to better address therapeutic interventions.

Analysis of DIP2C as a novel regulator for epithelial-mesenchymal transition of rheumatoid arthritis synovium and a potential therapeutic target

Impact ◽  
2021 ◽  
Vol 2021 (8) ◽  
pp. 28-30
Author(s):  
Masao Tanaka
Keyword(s):  
Rheumatoid Arthritis ◽  
Therapeutic Target ◽  
Epithelial Mesenchymal Transition ◽  
Poor Response ◽  
Associate Professor ◽  
Therapeutic Interventions ◽  
Response To Treatment ◽  
Potential Therapeutic Target ◽  
Mesenchymal Transition ◽  
Long Time

Rheumatoid arthritis (RA) is an autoimmune disease that can cause damage to the joints, cartilage and bone. There is no cure but early diagnosis can help mitigate damage. Sometimes RA is particularly difficult to treat, for example when the disease took a long time to be diagnosed. Associate Professor Masao Tanaka, Graduate School of Medicine, Kyoto University, Japan, leads a team of researchers working to improve understanding of the causes of poor response to treatment in RA with a long morbidity. The goal is to restore patients' therapeutic responsiveness, thereby improving outcomes. A previous focus for Tanaka was on a protein called FSTL1. He is now exploring DIP2 as a binding molecule for FSTL1. Other important mechanisms Tanaka is exploring are DNA methylation and the mechanisms of carnitine, which has been found to decrease a variety of activation signalling by inhibiting ceramide production in T cells. He and the team are exploring the involvement of these mechanisms in DIP2. In his most recent investigations, Tanaka is exploring DIP2C as a novel regulator for epithelial-mesenchymal transition of RA synovium and a potential therapeutic target. He is focusing on molecules that are expressed in the cells in joints, making the work directly applicable to RA. The team is carrying out a cohort study called KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) that involves around 2,000 outpatients with RA. Ultimately, Tanaka hopes to identify a reproducible combination of patient conditions and therapeutic interventions that achieve better treatment results for RA patients.

scholarly journals Recent Advances: The Imbalance of Immune Cells and Cytokines in the Pathogenesis of Hepatocellular Carcinoma

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 338
Author(s):  
Kumar Jayant ◽  
Nagy Habib ◽  
Kai W. Huang ◽  
Jane Warwick ◽  
Ramesh Arasaradnam
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Cells ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Liver Parenchyma ◽  
Tumour Microenvironment ◽  
Tumour Immunity ◽  
Mesenchymal Transition ◽  
Increased Risk ◽  
Inflammatory State

Recent advancement in the immunological understanding of genesis of hepatocellular carcinoma (HCC) has implicated a decline in anti-tumour immunity on the background of chronic inflammatory state of liver parenchyma. The development of HCC involves a network of immunological activity in the tumour microenvironment involving continuous interaction between tumour and stromal cells. The reduction in anti-tumour immunity is secondary to changes in various immune cells and cytokines, and the tumour microenvironment plays a critical role in modulating the process of liver fibrosis, hepatocarcinogenesis, epithelial-mesenchymal transition (EMT), tumor invasion and metastasis. Thus, it is considered as one of primary factor behind the despicable tumour behavior and observed poor survival; along with increased risk of recurrence following treatment in HCC. The primary intent of the present review is to facilitate the understanding of the complex network of immunological interactions of various immune cells, cytokines and tumour cells associated with the development and progression of HCC.

scholarly journals EMT-Inducing Molecular Factors in Gynecological Cancers

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Loredana Campo ◽  
Catherine Zhang ◽  
Eun-Kyoung Breuer
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Signs And Symptoms ◽  
Therapeutic Interventions ◽  
Gynecologic Cancers ◽  
Papilloma Virus ◽  
Mesenchymal Transition ◽  
Metastatic Relapse ◽  
Immunodeficiency Virus ◽  
Common Risk Factors ◽  
Molecular Aberrations

Gynecologic cancers are the unregulated growth of neoplastic cells that arise in the cervix, ovaries, fallopian tubes, uterus, vagina, and vulva. Although gynecologic cancers are characterized by different signs and symptoms, studies have shown that they share common risk factors, such as smoking, obesity, age, exposure to certain chemicals, infection with human immunodeficiency virus (HIV), and infection with human papilloma virus (HPV). Despite recent advancements in the preventative, diagnostic, and therapeutic interventions for gynecologic cancers, many patients still die as a result of metastasis and recurrence. Since mounting evidence indicates that the epithelial-mesenchymal transition (EMT) process plays an essential role in metastatic relapse of cancer, understanding the molecular aberrations responsible for the EMT and its underlying signaling should be given high priority in order to reduce cancer morbidity and mortality.

scholarly journals New Actors Driving the Epithelial–Mesenchymal Transition in Cancer: The Role of Leptin

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1676
Author(s):  
Monserrat Olea-Flores ◽  
Juan C. Juárez-Cruz ◽  
Miriam D. Zuñiga-Eulogio ◽  
Erika Acosta ◽  
Eduardo García-Rodríguez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Epithelial Cancers ◽  
Patients With Cancer

Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial–mesenchymal transition (EMT) markers in different study models, including in vitro, in vivo, and patient studies and in various types of cancer, including breast, prostate, lung, and ovarian cancer. The different studies report that leptin promotes the expression of mesenchymal markers and a decrease in epithelial markers, in addition to promoting EMT-related processes such as cell migration and invasion and poor prognosis in patients with cancer. Finally, we report that leptin has the greatest biological relevance in EMT and tumor progression in breast, lung, prostate, esophageal, and ovarian cancer. This relationship could be due to the key role played by the enriched tumor microenvironment in adipose tissue. Together, these findings demonstrate that leptin is a key biomolecule that drives EMT and metastasis in cancer.

scholarly journals Mechanophenotyping of 3D multicellular clusters using displacement arrays of rendered tractions

2020 ◽  
Vol 117 (11) ◽  
pp. 5655-5663 ◽  
Author(s):  
Susan E. Leggett ◽  
Mohak Patel ◽  
Thomas M. Valentin ◽  
Lena Gamboa ◽  
Amanda S. Khoo ◽  
...  
Keyword(s):  
Tumor Invasion ◽  
Wound Repair ◽  
Epithelial Mesenchymal Transition ◽  
Ex Vivo ◽  
Three Dimensional ◽  
Human Patient ◽  
Mesenchymal Transition ◽  
Successive Loss ◽  
Surrounding Extracellular Matrix

Epithelial tissues mechanically deform the surrounding extracellular matrix during embryonic development, wound repair, and tumor invasion. Ex vivo measurements of such multicellular tractions within three-dimensional (3D) biomaterials could elucidate collective dissemination during disease progression and enable preclinical testing of targeted antimigration therapies. However, past 3D traction measurements have been low throughput due to the challenges of imaging and analyzing information-rich 3D material deformations. Here, we demonstrate a method to profile multicellular clusters in a 96-well-plate format based on spatially heterogeneous contractile, protrusive, and circumferential tractions. As a case study, we profile multicellular clusters across varying states of the epithelial–mesenchymal transition, revealing a successive loss of protrusive and circumferential tractions, as well as the formation of localized contractile tractions with elongated cluster morphologies. These cluster phenotypes were biochemically perturbed by using drugs, biasing toward traction signatures of different epithelial or mesenchymal states. This higher-throughput analysis is promising to systematically interrogate and perturb aberrant mechanobiology, which could be utilized with human-patient samples to guide personalized therapies.

scholarly journals Airway Epithelial Repair by a Prebiotic Mannan Derived from Saccharomyces cerevisiae

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Christie F. Michael ◽  
Christopher M. Waters ◽  
Kim S. LeMessurier ◽  
Amali E. Samarasinghe ◽  
Chi Y. Song ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Wound Repair ◽  
Epithelial Mesenchymal Transition ◽  
Bronchial Epithelial Cells ◽  
Current Therapy ◽  
Airway Epithelial ◽  
Coated Pits ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition ◽  
Mannose Receptors

In asthmatic airways, repeated epithelial damage and repair occur. No current therapy directly targets this process. We aimed to determine the effects of mannan derived from S. cerevisiae (SC-MN) on airway epithelial wound repair, in vitro. The presence of functional mannose receptors in bronchial epithelial cells was shown by endocytosis of colloidal gold-Man BSA via clathrin-coated pits in 16HBE cells. In primary normal human bronchial epithelial cells (NHBEC), SC-MN significantly facilitated wound closure. Treatment with SC-MN stimulated cell spreading as indicated by a significant increase in the average lamellipodial width of wound edge 16HBE cells. In addition, NHBEC treated with SC-MN showed increased expression and activation of Krüppel-like factors (KLFs) 4 and 5, transcription factors important in epithelial cell survival and regulation of epithelial-mesenchymal transition. We conclude that SC-MN facilitates wound repair in human bronchial epithelium, involving mannose receptors.

scholarly journals The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

2021 ◽  
Vol 8 ◽  
Author(s):  
Feliciano Chanana Paquissi ◽  
Hugo Abensur
Keyword(s):  
Lupus Nephritis ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Tissue Damage ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Diseases ◽  
Special Focus ◽  
Renal Cells ◽  
Effector Cells ◽  
Mesenchymal Transition

Systemic lupus erythematosus (SLE) is a disease characterized by dysregulation and hyperreactivity of the immune response at various levels, including hyperactivation of effector cell subtypes, autoantibodies production, immune complex formation, and deposition in tissues. The consequences of hyperreactivity to the self are systemic and local inflammation and tissue damage in multiple organs. Lupus nephritis (LN) is one of the most worrying manifestations of SLE, and most patients have this involvement at some point in the course of the disease. Among the effector cells involved, the Th17, a subtype of T helper cells (CD4+), has shown significant hyperactivation and participates in kidney damage and many other organs. Th17 cells have IL-17A and IL-17F as main cytokines with receptors expressed in most renal cells, being involved in the activation of many proinflammatory and profibrotic pathways. The Th17/IL-17 axis promotes and maintains repetitive tissue damage and maladaptive repair; leading to fibrosis, loss of organ architecture and function. In the podocytes, the Th17/IL-17 axis effects include changes of the cytoskeleton with increased motility, decreased expression of health proteins, increased oxidative stress, and activation of the inflammasome and caspases resulting in podocytes apoptosis. In renal tubular epithelial cells, the Th17/IL-17 axis promotes the activation of profibrotic pathways such as increased TGF-β expression and epithelial-mesenchymal transition (EMT) with consequent increase of extracellular matrix proteins. In addition, the IL-17 promotes a proinflammatory environment by stimulating the synthesis of inflammatory cytokines by intrinsic renal cells and immune cells, and the synthesis of growth factors and chemokines, which together result in granulopoiesis/myelopoiesis, and further recruitment of immune cells to the kidney. The purpose of this work is to present the prognostic and immunopathologic role of the Th17/IL-17 axis in Kidney diseases, with a special focus on LN, including its exploration as a potential immunotherapeutic target in this complication.

scholarly journals Cancer Stem Cell Hypothesis: Implication for Cancer Prevention and Treatment

2016 ◽  
Vol 8 (1) ◽  
pp. 21
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
Cancer Prevention ◽  
Immune Cells ◽  
Epithelial Mesenchymal Transition ◽  
Cell Populations ◽  
Diverse Populations ◽  
Normal Organ ◽  
Mesenchymal Transition ◽  
Multiple Tumor ◽  
Microenvironmental Factors ◽  
Tumor Types

BACKGROUND: Cancer is a disease of genomic instability, evasion of immune cells, and adaptation of the tumor cells to the changing environment. Genetic heterogeneity caused by tumors and tumor microenvironmental factors forms the basis of aggressive behavior of some cancer cell populations.CONTENT: Cancers arise in self-renewing cell populations and that the resulting cancers, like their normal organ counterparts, are composed of hierarchically organized cell populations. Self – renewing “cancer stem cells” (CSC) maintain tumor growth and generate the diverse populations constituting the tumor bulk. CSCs in multiple tumor types have been demonstrated to be relatively resistant to radiation and chemotherapy. The clinical relevance of these studies has been supported by neoadjuvant breast cancer trials that demonstrated increases in the proportions of CSCs after therapy. The CSC hypothesis has tremendously important clinical implications.SUMMARY: In summary, a large and accumulating body of evidence supports the CSC hypothesis, which has important implications for cancer prevention and therapy. The ultimate test of this hypothesis will require clinical trials demonstrating that targeting of these pathways reduces cancer incidence and improves outcomes for patients with cancer.KEYWORDS: Somatic mutation, tumor heterogeneity, metastasis, epithelial-mesenchymal transition, CSC niche

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