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Endocrinology Apr 2023Premenopausal women have a lower incidence of cardiovascular disease (CVD) compared with their age-matched male counterparts; however, this discrepancy is abolished... (Review)
Review
Premenopausal women have a lower incidence of cardiovascular disease (CVD) compared with their age-matched male counterparts; however, this discrepancy is abolished following the transition to menopause or during low estrogen states. This, combined with a large amount of basic and preclinical data indicating that estrogen is vasculoprotective, supports the concept that hormone therapy could improve cardiovascular health. However, clinical outcomes in individuals undergoing estrogen treatment have been highly variable, challenging the current paradigm regarding the role of estrogen in the fight against heart disease. Increased risk for CVD correlates with long-term oral contraceptive use, hormone replacement therapy in older, postmenopausal cisgender females, and gender affirmation treatment for transgender females. Vascular endothelial dysfunction serves as a nidus for the development of many cardiovascular diseases and is highly predictive of future CVD risk. Despite preclinical studies indicating that estrogen promotes a quiescent, functional endothelium, it still remains unclear why these observations do not translate to improved CVD outcomes. The goal of this review is to explore our current understanding of the effect of estrogen on the vasculature, with a focus on endothelial health. Following a discussion regarding the influence of estrogen on large and small artery function, critical knowledge gaps are identified. Finally, novel mechanisms and hypotheses are presented that may explain the lack of cardiovascular benefit in unique patient populations.
Topics: Female; Male; Humans; Aged; Estrogen Replacement Therapy; Endothelium, Vascular; Estrogens; Menopause; Cardiovascular Diseases
PubMed: 37207450
DOI: 10.1210/endocr/bqad079 -
Nature Communications Apr 2020Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical...
Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.
Topics: Aged; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biopsy; Camptothecin; Carcinoma, Transitional Cell; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Variation; High-Throughput Nucleotide Sequencing; Humans; Immunoconjugates; Interleukin Receptor Common gamma Subunit; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Transplantation; Phenotype; Precision Medicine; Prospective Studies; Quinolines; Retrospective Studies; Sequence Analysis, RNA; Trastuzumab; Urinary Bladder Neoplasms; Urothelium
PubMed: 32332851
DOI: 10.1038/s41467-020-15885-7 -
Chemical Senses Dec 2020Olfactory sensory neurons (OSNs) are bipolar neurons, unusual because they turn over continuously and have a multiciliated dendrite. The extensive changes in gene... (Review)
Review
Olfactory sensory neurons (OSNs) are bipolar neurons, unusual because they turn over continuously and have a multiciliated dendrite. The extensive changes in gene expression accompanying OSN differentiation in mice are largely known, especially the transcriptional regulators responsible for altering gene expression, revealing much about how differentiation proceeds. Basal progenitor cells of the olfactory epithelium transition into nascent OSNs marked by Cxcr4 expression and the initial extension of basal and apical neurites. Nascent OSNs become immature OSNs within 24-48 h. Immature OSN differentiation requires about a week and at least 2 stages. Early-stage immature OSNs initiate expression of genes encoding key transcriptional regulators and structural proteins necessary for further neuritogenesis. Late-stage immature OSNs begin expressing genes encoding proteins important for energy production and neuronal homeostasis that carry over into mature OSNs. The transition to maturity depends on massive expression of one allele of one odorant receptor gene, and this results in expression of the last 8% of genes expressed by mature OSNs. Many of these genes encode proteins necessary for mature function of axons and synapses or for completing the elaboration of non-motile cilia, which began extending from the newly formed dendritic knobs of immature OSNs. The cilia from adjoining OSNs form a meshwork in the olfactory mucus and are the site of olfactory transduction. Immature OSNs also have a primary cilium, but its role is unknown, unlike the critical role in proliferation and differentiation played by the primary cilium of the olfactory epithelium's horizontal basal cell.
Topics: Animals; Axons; Cell Differentiation; Cell Line; Cilia; Gene Expression Regulation; Humans; Neurogenesis; Olfactory Mucosa; Olfactory Receptor Neurons; Receptors, CXCR4; Receptors, Odorant; Smell; Synapses
PubMed: 33075817
DOI: 10.1093/chemse/bjaa070 -
Annual Review of Physiology Feb 2024Glucose is the universal fuel of most mammalian cells, and it is largely replenished through dietary intake. Glucose availability to tissues is paramount for the... (Review)
Review
Glucose is the universal fuel of most mammalian cells, and it is largely replenished through dietary intake. Glucose availability to tissues is paramount for the maintenance of homeostatic energetics and, hence, supply should match demand by the consuming organs. In its journey through the body, glucose encounters cellular barriers for transit at the levels of the absorbing intestinal epithelial wall, the renal epithelium mediating glucose reabsorption, and the tight capillary endothelia (especially in the brain). Glucose transiting through these cellular barriers must escape degradation to ensure optimal glucose delivery to the bloodstream or tissues. The liver, which stores glycogen and generates glucose de novo, must similarly be able to release it intact to the circulation. We present the most up-to-date knowledge on glucose handling by the gut, liver, brain endothelium, and kidney, and discuss underlying molecular mechanisms and open questions. Diseases associated with defects in glucose delivery and homeostasis are also briefly addressed. We propose that the universal problem of sparing glucose from catabolism in favor of translocation across the barriers posed by epithelia and endothelia is resolved through common mechanisms involving glucose transfer to the endoplasmic reticulum, from where glucose exits the cells via unconventional cellular mechanisms.
Topics: Animals; Humans; Glucose; Epithelium; Brain; Biological Transport; Intestines; Mammals
PubMed: 38345907
DOI: 10.1146/annurev-physiol-042022-031657 -
JCI Insight May 2021Transitions between cell fates commonly occur in development and disease. However, reversing an unwanted cell transition in order to treat disease remains an unexplored...
Transitions between cell fates commonly occur in development and disease. However, reversing an unwanted cell transition in order to treat disease remains an unexplored area. Here, we report a successful process of guiding ill-fated transitions toward normalization in vascular calcification. Vascular calcification is a severe complication that increases the all-cause mortality of cardiovascular disease but lacks medical therapy. The vascular endothelium is a contributor of osteoprogenitor cells to vascular calcification through endothelial-mesenchymal transitions, in which endothelial cells (ECs) gain plasticity and the ability to differentiate into osteoblast-like cells. We created a high-throughput screening and identified SB216763, an inhibitor of glycogen synthase kinase 3 (GSK3), as an inducer of osteoblastic-endothelial transition. We demonstrated that SB216763 limited osteogenic differentiation in ECs at an early stage of vascular calcification. Lineage tracing showed that SB216763 redirected osteoblast-like cells to the endothelial lineage and reduced late-stage calcification. We also found that deletion of GSK3β in osteoblasts recapitulated osteoblastic-endothelial transition and reduced vascular calcification. Overall, inhibition of GSK3β promoted the transition of cells with osteoblastic characteristics to endothelial differentiation, thereby ameliorating vascular calcification.
Topics: Animals; Cell Differentiation; Cell Line; Endothelial Cells; Endothelium, Vascular; Glycogen Synthase Kinase 3; Indoles; Maleimides; Mice; Mice, Transgenic; Osteogenesis; Protein Kinase Inhibitors; Vascular Calcification
PubMed: 33848269
DOI: 10.1172/jci.insight.143023 -
American Journal of Physiology. Heart... Jan 2022Cardiovascular disease risk increases with age regardless of sex. Some of this risk is attributable to alterations in natural hormones throughout the life span. The... (Review)
Review
Cardiovascular disease risk increases with age regardless of sex. Some of this risk is attributable to alterations in natural hormones throughout the life span. The quintessential example of this being the dramatic increase in cardiovascular disease following the transition to menopause. Plasma levels of adiponectin, a "cardioprotective" adipokine released primarily by adipose tissue and regulated by hormones, also fluctuate throughout one's life. Plasma adiponectin levels increase with age in both men and women, with higher levels in both pre- and postmenopausal women compared with men. Younger cohorts seem to confer cardioprotective benefits from increased adiponectin levels yet elevated levels in the elderly and those with existing heart disease are associated with poor cardiovascular outcomes. Here, we review the most recent data regarding adiponectin signaling in the vasculature, highlight the differences observed between the sexes, and shed light on the apparent paradox regarding increased cardiovascular disease risk despite rising plasma adiponectin levels over time.
Topics: Adiponectin; Aging; Animals; Endothelium, Vascular; Humans; Signal Transduction
PubMed: 34797171
DOI: 10.1152/ajpheart.00533.2021 -
Archives of Pathology & Laboratory... May 2022Nephrogenic adenoma (NA) is a common urinary tract lesion typically associated with urothelial disruption, leading to implantation of shed renal tubular cells. NA may...
CONTEXT.—
Nephrogenic adenoma (NA) is a common urinary tract lesion typically associated with urothelial disruption, leading to implantation of shed renal tubular cells. NA may demonstrate a spectrum of architectural and cytologic features mimicking urothelial carcinoma (UC), adenocarcinoma (including clear cell adenocarcinoma and prostatic adenocarcinoma), and invasion. However, admixed UC and NA has not been described.
OBJECTIVE.—
To describe cases where the NA was intimately intermixed with UC, potentially mimicking variant differentiation or invasion.
DESIGN.—
In 3 health care systems we identified specimens of NA and UC intimately intermixed with each other to the extent that they could mimic a spectrum of one lesion. We assessed patterns of NA and clinical implications of misdiagnosing NA as glandular differentiation of UC.
RESULTS.—
There were 4 women and 29 men (median age, 72 years; range, 31-89 years). Twenty-four patients had transurethral resections, 3 had biopsies, and 6 had major resections. Fourteen had noninvasive high-grade papillary UC, 6 had carcinoma in situ, and 11 had invasive high-grade UC. In 2 patients, NA developed in a papillary urothelial neoplasm with extensive denudation. Three patients had fibromyxoid NA infiltrated by invasive UC. Classical NA (n = 30) had tubulopapillary (n = 18), pure tubular (n = 7), or pure papillary architecture (n = 5). In 1 lesion, NA was present in muscularis propria, and 2 lesions involved adventitia. NA could have been misdiagnosed as invasion in 17 of 22 (77%) noninvasive tumors or higher stage in 19 of 33 (58%).
CONCLUSIONS.—
NA can be intermingled with high-grade UC, expanding the spectrum of entities that must be considered in the differential diagnosis, as it may mimic glandular or tubular differentiation, invasion, and a higher stage of disease. Misinterpretation of NA in such a setting may incorrectly convey a more aggressive biological potential of cancer to clinicians.
Topics: Male; Humans; Female; Aged; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Carcinoma, Papillary; Carcinoma in Situ; Urothelium; Adenocarcinoma, Clear Cell; Adenoma
PubMed: 35976666
DOI: 10.5858/arpa.2021-0620-OA -
Nature Cell Biology Feb 2024Morphogenesis and cell state transitions must be coordinated in time and space to produce a functional tissue. An excellent paradigm to understand the coupling of these...
Morphogenesis and cell state transitions must be coordinated in time and space to produce a functional tissue. An excellent paradigm to understand the coupling of these processes is mammalian hair follicle development, which is initiated by the formation of an epithelial invagination-termed placode-that coincides with the emergence of a designated hair follicle stem cell population. The mechanisms directing the deformation of the epithelium, cell state transitions and physical compartmentalization of the placode are unknown. Here we identify a key role for coordinated mechanical forces stemming from contractile, proliferative and proteolytic activities across the epithelial and mesenchymal compartments in generating the placode structure. A ring of fibroblast cells gradually wraps around the placode cells to generate centripetal contractile forces, which, in collaboration with polarized epithelial myosin activity, promote elongation and local tissue thickening. These mechanical stresses further enhance compartmentalization of Sox9 expression to promote stem cell positioning. Subsequently, proteolytic remodelling locally softens the basement membrane to facilitate a release of pressure on the placode, enabling localized cell divisions, tissue fluidification and epithelial invagination into the underlying mesenchyme. Together, our experiments and modelling identify dynamic cell shape transformations and tissue-scale mechanical cooperation as key factors for orchestrating organ formation.
Topics: Animals; Cell Shape; Epithelium; Morphogenesis; Cell Division; Hair Follicle; Mammals
PubMed: 38302719
DOI: 10.1038/s41556-023-01332-4 -
Annals of Botany Jul 2021Stomata are adjustable pores on the surface of plant shoots for efficient gas exchange and water control. The presence of stomata is essential for plant growth and... (Review)
Review
BACKGROUND
Stomata are adjustable pores on the surface of plant shoots for efficient gas exchange and water control. The presence of stomata is essential for plant growth and survival, and the evolution of stomata is considered as a key developmental innovation of the land plants, allowing colonization on land from aquatic environments some 450 million years ago. In the past two decades, molecular genetic studies using the model plant Arabidopsis thaliana identified key genes and signalling modules that regulate stomatal development: master regulatory transcription factors that orchestrate cell state transitions and peptide-receptor signal transduction pathways, which, together, enforce proper patterning of stomata within the epidermis. Studies in diverse plant species, ranging from bryophytes to angiosperm grasses, have begun to unravel the conservation and uniqueness of the core modules in stomatal development.
SCOPE
Here, I review the mechanisms of stomatal development in the context of epidermal tissue patterning. First, I introduce the core regulatory mechanisms of stomatal patterning and differentiation in the model species A. thaliana. Subsequently, experimental evidence is presented supporting the idea that different cell types within the leaf epidermis, namely stomata, hydathodes pores, pavement cells and trichomes, either share developmental origins or mutually influence each other's gene regulatory circuits during development. Emphasis is placed on extrinsic and intrinsic signals regulating the balance between stomata and pavement cells, specifically by controlling the fate of stomatal-lineage ground cells (SLGCs) to remain within the stomatal cell lineage or differentiate into pavement cells. Finally, I discuss the influence of intertissue layer communication between the epidermis and underlying mesophyll/vascular tissues on stomatal differentiation. Understanding the dynamic behaviours of stomatal precursor cells and their differentiation in the broader context of tissue and organ development may help design plants tailored for optimal growth and productivity in specific agricultural applications and a changing environment.
Topics: Arabidopsis; Arabidopsis Proteins; Epidermis; Gene Expression Regulation, Plant; Plant Stomata
PubMed: 33877316
DOI: 10.1093/aob/mcab052 -
International Journal of Molecular... May 2023Intestinal fibrosis, the most common complication of inflammatory bowel disease (IBD), is characterized by an uncontrolled deposition of extracellular matrix proteins...
Intestinal fibrosis, the most common complication of inflammatory bowel disease (IBD), is characterized by an uncontrolled deposition of extracellular matrix proteins leading to complications resolvable only with surgery. Transforming growth factor is the key player in the epithelial-mesenchymal transition (EMT) and fibrogenesis process, and some molecules modulating its activity, including peroxisome proliferator-activated receptor (PPAR)-γ and its agonists, exert a promising antifibrotic action. The purpose of this study is to evaluate the contribution of signaling other than EMT, such as the AGE/RAGE (advanced glycation end products/receptor of AGEs) and the senescence pathways, in the etiopathogenesis of IBD. We used human biopsies from control and IBD patients, and we used a mouse model of colitis induced by dextran-sodium-sulfate (DSS), without/with treatments with GED (PPAR-gamma-agonist), or 5-aminosalicylic acid (5-ASA), a reference drug for IBD treatment. In patients, we found an increase in EMT markers, AGE/RAGE, and senescence signaling activation compared to controls. Consistently, we found the overexpression of the same pathways in DSS-treated mice. Surprisingly, the GED reduced all the pro-fibrotic pathways, in some circumstances more efficiently than 5-ASA. Results suggest that IBD patients could benefit from a combined pharmacological treatment targeting simultaneously different pathways involved in pro-fibrotic signals. In this scenario, PPAR-gamma activation could be a suitable strategy to alleviate the signs and symptoms of IBD and also its progression.
Topics: Humans; Mice; Animals; PPAR gamma; Epithelial-Mesenchymal Transition; Colon; Colitis; Inflammatory Bowel Diseases; Epithelium; Dextran Sulfate; Mice, Inbred C57BL
PubMed: 37240299
DOI: 10.3390/ijms24108952