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  1. Article ; Online: Epithelial to mesenchymal transition (EMT) of feto-maternal reproductive tissues generates inflammation: a detrimental factor for preterm birth.

    Menon, Ramkumar

    BMB reports

    2022  Volume 55, Issue 8, Page(s) 370–379

    Abstract: Human pregnancy is a delicate and complex process where multiorgan interactions between two independent systems, the mother, and her fetus, maintain pregnancy. Intercellular interactions that can define homeostasis at the various cellular level between ... ...

    Abstract Human pregnancy is a delicate and complex process where multiorgan interactions between two independent systems, the mother, and her fetus, maintain pregnancy. Intercellular interactions that can define homeostasis at the various cellular level between the two systems allow uninterrupted fetal growth and development until delivery. Interactions are needed for tissue remodeling during pregnancy at both fetal and maternal tissue layers. One of the mechanisms that help tissue remodeling is via cellular transitions where epithelial cells undergo a cyclic transition from epithelial to mesenchymal (EMT) and back from mesenchymal to epithelial (MET). Two major pregnancy-associated tissue systems that use EMT, and MET are the fetal membrane (amniochorion) amnion epithelial layer and cervical epithelial cells and will be reviewed here. EMT is often associated with localized inflammation, and it is a well-balanced process to facilitate tissue remodeling. Cyclic transition processes are important because a terminal state or the static state of EMT can cause accumulation of proinflammatory mesenchymal cells in the matrix regions of these tissues and increase localized inflammation that can cause tissue damage. Interactions that determine homeostasis are often controlled by both endocrine and paracrine mediators. Pregnancy maintenance hormone progesterone and its receptors are critical for maintaining the balance between EMT and MET. Increased intrauterine oxidative stress at term can force a static (terminal) EMT and increase inflammation that are physiologic processes that destabilize homeostasis that maintain pregnancy to promote labor and delivery of the fetus. However, conditions that can produce an untimely increase in EMT and inflammation can be pathologic. These tissue damages are often associated with adverse pregnancy complications such as preterm prelabor rupture of the membranes (pPROM) and spontaneous preterm birth (PTB). Therefore, an understanding of the biomolecular processes that maintain cyclic EMT-MET is critical to reducing the risk of pPROM and PTB. Extracellular vesicles (exosomes of 40-160 nm) that can carry various cargo are involved in cellular transitions as paracrine mediators. Exosomes can carry a variety of biomolecules as cargo. Studies specifically using exosomes from cells undergone EMT can carry a pro-inflammatory cargo and in a paracrine fashion can modify the neighboring tissue environment to cause enhancement of uterine inflammation. [BMB Reports 2022; 55(8): 370-379].
    MeSH term(s) Epithelial-Mesenchymal Transition ; Female ; Fetal Membranes, Premature Rupture ; Humans ; Infant, Newborn ; Inflammation ; Pregnancy ; Premature Birth
    Language English
    Publishing date 2022-07-25
    Publishing country Korea (South)
    Document type News
    ZDB-ID 2410389-5
    ISSN 1976-670X ; 1976-6696
    ISSN (online) 1976-670X
    ISSN 1976-6696
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Fetal inflammatory response at the fetomaternal interface: A requirement for labor at term and preterm.

    Menon, Ramkumar

    Immunological reviews

    2022  Volume 308, Issue 1, Page(s) 149–167

    Abstract: Human parturition at term and preterm is an inflammatory process synchronously executed by both fetomaternal tissues to transition them from a quiescent state t an active state of labor to ensure delivery. The initiators of the inflammatory signaling ... ...

    Abstract Human parturition at term and preterm is an inflammatory process synchronously executed by both fetomaternal tissues to transition them from a quiescent state t an active state of labor to ensure delivery. The initiators of the inflammatory signaling mechanism can be both maternal and fetal. The placental (fetal)-maternal immune and endocrine mediated homeostatic imbalances and inflammation are well reported. However, the fetal inflammatory response (FIR) theories initiated by the fetal membranes (amniochorion) at the choriodecidual interface are not well established. Although immune cell migration, activation, and production of proparturition cytokines to the fetal membranes are reported, cellular level events that can generate a unique set of inflammation are not well discussed. This review discusses derangements to fetal membrane cells (physiologically and pathologically at term and preterm, respectively) in response to both endogenous and exogenous factors to generate inflammatory signals. In addition, the mechanisms of inflammatory signal propagation (fetal signaling of parturition) and how these signals cause immune imbalances at the choriodecidual interface are discussed. In addition to maternal inflammation, this review projects FIR as an additional mediator of inflammatory overload required to promote parturition.
    MeSH term(s) Extraembryonic Membranes/metabolism ; Female ; Humans ; Infant, Newborn ; Inflammation/metabolism ; Labor, Obstetric/metabolism ; Parturition/metabolism ; Placenta/metabolism ; Pregnancy
    Language English
    Publishing date 2022-03-14
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 391796-4
    ISSN 1600-065X ; 0105-2896
    ISSN (online) 1600-065X
    ISSN 0105-2896
    DOI 10.1111/imr.13075
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Effects of Ureaplasma parvum infection in the exosome biogenesis-related proteins in ectocervical epithelial cells.

    Tantengco, Ourlad Alzeus G / Menon, Ramkumar

    American journal of reproductive immunology (New York, N.Y. : 1989)

    2023  Volume 91, Issue 1, Page(s) e13803

    Abstract: Ureaplasma parvum is a mycoplasma commonly associated with female reproductive pathologies, such as preterm birth and infertility. It can survive intracellularly and utilize exosomes to propagate infection and its virulence factors. This study explored ... ...

    Abstract Ureaplasma parvum is a mycoplasma commonly associated with female reproductive pathologies, such as preterm birth and infertility. It can survive intracellularly and utilize exosomes to propagate infection and its virulence factors. This study explored the differential protein composition of exosomes derived from normal and U. parvum-infected cells. We also investigated the impact of U. parvum on exosome biogenesis in ectocervical epithelial cells. Ectocervical epithelial (ECTO) cells were infected with U. parvum, and immunocytochemical staining was performed using U. parvum-specific marker multiple banded antigen (mba) and exosome marker CD9. NanoLC-MS/MS analysis was conducted to identify differentially expressed proteins in exosomes. Ingenuity Pathway Analysis (IPA) was performed to identify affected canonical pathways and biological functions associated with the protein cargo of exosomes. Western blot analysis of ECTO cells validated the proteomic findings in ECTO cells. U. parvum exhibited colonization of ECTO cells and colocalization with CD9-positive intraluminal vesicles. Proteomic analysis revealed decreased protein abundance and distinct protein profiles in exosomes derived from U. parvum-infected ECTO cells. Differentially expressed proteins were associated with clathrin-mediated endocytosis and various signaling pathways indicative of infection, inflammation, and cell death processes. Additionally, U. parvum infection altered proteins involved in exosome biogenesis. In ECTO cells, U. parvum infection significantly decreased clathrin, ALIX, CD9, and CD63 and significantly increased TSG101, Rab5, Rab35, and UGCG. These findings contribute to our understanding of the infection mechanism and shed light on the importance of exosome-mediated communication in the pathophysiology of diseases affecting the cervix, such as cervicitis and preterm birth.
    MeSH term(s) Humans ; Infant, Newborn ; Female ; Cervix Uteri ; Premature Birth ; Exosomes ; Proteomics ; Tandem Mass Spectrometry ; Ureaplasma/physiology ; Epithelial Cells ; Clathrin ; Ureaplasma Infections
    Chemical Substances Clathrin
    Language English
    Publishing date 2023-09-22
    Publishing country Denmark
    Document type Journal Article
    ZDB-ID 604542-x
    ISSN 1600-0897 ; 0271-7352 ; 8755-8920 ; 1046-7408
    ISSN (online) 1600-0897
    ISSN 0271-7352 ; 8755-8920 ; 1046-7408
    DOI 10.1111/aji.13803
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Surviving the Unforeseen: Successful Management of Transorbital Penetrating Intracranial Injury in a Pediatric Patient.

    Poonthottam, Nandakumar / Menon, Ramkumar

    Neurology India

    2023  Volume 71, Issue 5, Page(s) 1112–1113

    MeSH term(s) Humans ; Child ; Craniocerebral Trauma ; Wounds, Penetrating
    Language English
    Publishing date 2023-11-06
    Publishing country India
    Document type Journal Article
    ZDB-ID 415522-1
    ISSN 1998-4022 ; 0028-3886
    ISSN (online) 1998-4022
    ISSN 0028-3886
    DOI 10.4103/0028-3886.388085
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Delayed Tension Pneumocephalus Following Traumatic Brain Injury: A Rare Entity.

    Poonthottam, Nandakumar / Menon, Ramkumar

    Neurology India

    2023  Volume 71, Issue 5, Page(s) 1082–1083

    MeSH term(s) Humans ; Pneumocephalus/diagnostic imaging ; Pneumocephalus/etiology ; Brain Injuries, Traumatic/complications ; Brain Injuries, Traumatic/diagnostic imaging ; Tomography, X-Ray Computed
    Language English
    Publishing date 2023-11-06
    Publishing country India
    Document type Letter
    ZDB-ID 415522-1
    ISSN 1998-4022 ; 0028-3886
    ISSN (online) 1998-4022
    ISSN 0028-3886
    DOI 10.4103/0028-3886.388070
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: In utero priming of fetal immune activation: Myths and mechanisms.

    Vidal, Manuel S / Menon, Ramkumar

    Journal of reproductive immunology

    2023  Volume 157, Page(s) 103922

    Abstract: Mechanisms of fetal immune system development in utero remain incompletely elucidated. Protective immunity, the arm of reproductive immunology concerned with the progressive education of the fetal immune system as pregnancy advances, allows for ... ...

    Abstract Mechanisms of fetal immune system development in utero remain incompletely elucidated. Protective immunity, the arm of reproductive immunology concerned with the progressive education of the fetal immune system as pregnancy advances, allows for programming of the immune system and immune maturation in utero and provides a responsive system to respond to rapid microbial and other antigenic exposure ex utero. Challenges in studying fetal tissues, immune system development, and the contributions of various endogenous and exogenous factors to this process are difficult to study as a progressive sampling of fetal biological samples is impractical during pregnancy, and animal models are limited. This review provides a summary of mechanisms of protective immunity and how it has been shaped, from transplacental transfer of immunoglobulins, cytokines, metabolites, as well as antigenic microchimeric cells to perhaps more controversial notions of materno-fetal transfer of bacteria that subsequently organize into microbiomes within the fetal tissues. This review will also provide a quick overview of future direction in the area of research on fetal immune system development and discusses methods to visualize fetal immune populations and determine fetal immune functions, as well as a quick look into appropriate models for studying fetal immunity.
    MeSH term(s) Pregnancy ; Animals ; Female ; Fetus ; Cytokines/metabolism ; Models, Animal ; Immunoglobulins/metabolism
    Chemical Substances Cytokines ; Immunoglobulins
    Language English
    Publishing date 2023-03-02
    Publishing country Ireland
    Document type Review ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 424421-7
    ISSN 1872-7603 ; 0165-0378
    ISSN (online) 1872-7603
    ISSN 0165-0378
    DOI 10.1016/j.jri.2023.103922
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Initiation of human parturition: signaling from senescent fetal tissues via extracellular vesicle mediated paracrine mechanism.

    Menon, Ramkumar

    Obstetrics & gynecology science

    2019  Volume 62, Issue 4, Page(s) 199–211

    Abstract: A better understanding of the underlying mechanisms by which signals from the fetus initiate human parturition is required. Our recent findings support the core hypothesis that oxidative stress (OS) and cellular senescence of the fetal membranes (amnion ... ...

    Abstract A better understanding of the underlying mechanisms by which signals from the fetus initiate human parturition is required. Our recent findings support the core hypothesis that oxidative stress (OS) and cellular senescence of the fetal membranes (amnion and chorion) trigger human parturition. Fetal membrane cell senescence at term is a natural physiological response to OS that occurs as a result of increased metabolic demands by the maturing fetus. Fetal membrane senescence is affected by the activation of the p38 mitogen activated kinase-mediated pathway. Similarly, various risk factors of preterm labor and premature rupture of the membranes also cause OS-induced senescence. Data suggest that fetal cell senescence causes inflammatory senescence-associated secretory phenotype (SASP) release. Besides SASP, high mobility group box 1 and cell-free fetal telomere fragments translocate from the nucleus to the cytosol in senescent cells, where they represent damage-associated molecular pattern markers (DAMPs). In fetal membranes, both SASPs and DAMPs augment fetal cell senescence and an associated 'sterile' inflammatory reaction. In senescent cells, DAMPs are encapsulated in extracellular vesicles, specifically exosomes, which are 30-150 nm particles, and propagated to distant sites. Exosomes traffic from the fetus to the maternal side and cause labor-associated inflammatory changes in maternal uterine tissues. Thus, fetal membrane senescence and the inflammation generated from this process functions as a paracrine signaling system during parturition. A better understanding of the premature activation of these signals can provide insights into the mechanisms by which fetal signals initiate preterm parturition.
    Language English
    Publishing date 2019-06-28
    Publishing country Korea (South)
    Document type Journal Article ; Review
    ZDB-ID 2814367-X
    ISSN 2287-8580 ; 2287-8572
    ISSN (online) 2287-8580
    ISSN 2287-8572
    DOI 10.5468/ogs.2019.62.4.199
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Breaking Down the Barrier: The Role of Cervical Infection and Inflammation in Preterm Birth.

    Tantengco, Ourlad Alzeus G / Menon, Ramkumar

    Frontiers in global women's health

    2022  Volume 2, Page(s) 777643

    Abstract: Approximately 40% of cases of spontaneous preterm birth (sPTB) are associated with ascending intrauterine infections. The cervix serves as a physical and immunological gatekeeper, preventing the ascent of microorganisms from the vagina to the amniotic ... ...

    Abstract Approximately 40% of cases of spontaneous preterm birth (sPTB) are associated with ascending intrauterine infections. The cervix serves as a physical and immunological gatekeeper, preventing the ascent of microorganisms from the vagina to the amniotic cavity. The cervix undergoes remodeling during pregnancy. It remains firm and closed from the start until the late third trimester of pregnancy and then dilates and effaces to accommodate the passage of the fetus during delivery. Remodeling proceeds appropriately and timely to maintain the pregnancy until term delivery. However, risk factors, such as acute and chronic infection and local inflammation in the cervix, may compromise cervical integrity and result in premature remodeling, predisposing to sPTB. Previous clinical studies have established bacterial (i.e., chlamydia, gonorrhea, mycoplasma, etc.) and viral infections (i.e., herpesviruses and human papillomaviruses) as risk factors of PTB. However, the exact mechanism leading to PTB is still unknown. This review focuses on: (1) the epidemiology of cervical infections in pregnant patients; (2) cellular mechanisms that may explain the association of cervical infections to premature cervical ripening and PTB; (3) endogenous defense mechanisms of the cervix that protect the uterine cavity from infection and inflammation; and (4) potential inflammatory biomarkers associated with cervical infection that can serve as prognostic markers for premature cervical ripening and PTB. This review will provide mechanistic insights on cervical functions to assist in managing cervical infections during pregnancy.
    Language English
    Publishing date 2022-01-18
    Publishing country Switzerland
    Document type Journal Article ; Review
    ISSN 2673-5059
    ISSN (online) 2673-5059
    DOI 10.3389/fgwh.2021.777643
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Fetal membrane at the feto-maternal interface: An underappreciated and understudied intrauterine tissue.

    Richardson, Lauren / Menon, Ramkumar

    Placenta and reproductive medicine

    2022  Volume 1

    Language English
    Publishing date 2022-11-28
    Publishing country China
    Document type Journal Article
    ISSN 2790-0428
    ISSN (online) 2790-0428
    DOI 10.54844/prm.2022.0104
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Histologic Evidence of Epithelial-Mesenchymal Transition and Autophagy in Human Fetal Membranes.

    Severino, Mary E / Richardson, Lauren S / Kacerovsky, Marian / Menon, Ramkumar

    The American journal of pathology

    2024  Volume 194, Issue 5, Page(s) 684–692

    Abstract: Preterm, prelabor rupture of the human fetal membranes (pPROM) is involved in 40% of spontaneous preterm births worldwide. Cellular-level disturbances and inflammation are effectors of membrane degradation, weakening, and rupture. Maternal risk factors ... ...

    Abstract Preterm, prelabor rupture of the human fetal membranes (pPROM) is involved in 40% of spontaneous preterm births worldwide. Cellular-level disturbances and inflammation are effectors of membrane degradation, weakening, and rupture. Maternal risk factors induce oxidative stress (OS), senescence, and senescence-associated inflammation of the fetal membranes as reported mechanisms related to pPROM. Inflammation can also arise in fetal membrane cells (amnion/chorion) due to OS-induced autophagy and epithelial-mesenchymal transition (EMT). Autophagy, EMT, and their correlation in pPROM, along with OS-induced autophagy-related changes in amnion and chorion cells in vitro, were investigated. Immunocytochemistry staining of cytokeratin-18 (epithelial marker)/vimentin (mesenchymal marker) and proautophagy-inducing factor LC3B were performed in fetal membranes from pPROM, term not in labor, and term labor. Ultrastructural changes associated with autophagy were verified by transmission electron microscopy of the fetal membranes and in cells exposed to cigarette smoke extract (an OS inducer). EMT and LC3B staining was compared in the chorion from pPROM versus term not in labor. Transmission electron microscopy confirmed autophagosome formation in pPROM amnion and chorion. In cell culture, autophagosomes were formed in the amnion with OS treatment, while autophagosomes were accumulated in both cell types with autophagy inhibition. This study documents the association between pPROMs and amniochorion autophagy and EMT, and supports a role for OS in inducing dysfunctional cells that increase inflammation, predisposing membranes to rupture.
    MeSH term(s) Female ; Infant, Newborn ; Humans ; Extraembryonic Membranes/metabolism ; Fetal Membranes, Premature Rupture/metabolism ; Inflammation/pathology ; Epithelial-Mesenchymal Transition ; Autophagy
    Language English
    Publishing date 2024-02-04
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2943-9
    ISSN 1525-2191 ; 0002-9440
    ISSN (online) 1525-2191
    ISSN 0002-9440
    DOI 10.1016/j.ajpath.2023.12.011
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