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The FEBS Journal Apr 2022The adenosine monophosphate-activated protein kinase (AMPK) is an integrative metabolic sensor that maintains energy balance at the cellular level and plays an important... (Review)
Review
The adenosine monophosphate-activated protein kinase (AMPK) is an integrative metabolic sensor that maintains energy balance at the cellular level and plays an important role in orchestrating intertissue metabolic signaling. AMPK regulates cell survival, metabolism, and cellular homeostasis basally as well as in response to various metabolic stresses. Studies so far show that the AMPK pathway is associated with neurodegeneration and CNS pathology, but the mechanisms involved remain unclear. AMPK dysregulation has been reported in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and other neuropathies. AMPK activation appears to be both neuroprotective and pro-apoptotic, possibly dependent upon neural cell types, the nature of insults, and the intensity and duration of AMPK activation. While embryonic brain development in AMPK null mice appears to proceed normally without any overt structural abnormalities, our recent study confirmed the full impact of AMPK loss in the postnatal and aging brain. Our studies revealed that Ampk deletion in neurons increased basal neuronal excitability and reduced latency to seizure upon stimulation. Three major pathways, glycolysis, pentose phosphate shunt, and glycogen turnover, contribute to utilization of glucose in the brain. AMPK's regulation of aerobic glycolysis in astrocytic metabolism warrants further deliberation, particularly glycogen turnover and shuttling of glucose- and glycogen-derived lactate from astrocytes to neurons during activation. In this minireview, we focus on recent advances in AMPK and energy-sensing in the brain.
Topics: AMP-Activated Protein Kinases; Animals; Astrocytes; Brain; Energy Metabolism; Glucose; Glycogen; Mice
PubMed: 34355526
DOI: 10.1111/febs.16151 -
Cellular & Molecular Immunology Jun 2023Osteoarthritis (OA) is a degenerative multifactorial disease with concomitant structural, inflammatory, and metabolic changes that fluctuate in a temporal and... (Review)
Review
Osteoarthritis (OA) is a degenerative multifactorial disease with concomitant structural, inflammatory, and metabolic changes that fluctuate in a temporal and patient-specific manner. This complexity has contributed to refractory responses to various treatments. MSCs have shown promise as multimodal therapeutics in mitigating OA symptoms and disease progression. Here, we evaluated 15 randomized controlled clinical trials (RCTs) and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA, and we found net positive effects of MSCs on mitigating pain and symptoms (improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints) and on cartilage protection and/or repair (18/21 clinical studies). We examined MSC dose, tissue of origin, and autologous vs. allogeneic origins as well as patient clinical phenotype, endotype, age, sex and level of OA severity as key parameters in parsing MSC clinical effectiveness. The relatively small sample size of 610 patients limited the drawing of definitive conclusions. Nonetheless, we noted trends toward moderate to higher doses of MSCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage preservation. Evidence from preclinical studies is supportive of MSC anti-inflammatory and immunomodulatory effects, but additional investigations on immunomodulatory, chondroprotective and other clinical mechanisms of action are needed. We hypothesize that MSC basal immunomodulatory "fitness" correlates with OA treatment efficacy, but this hypothesis needs to be validated in future studies. We conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory "fit" or engineered-to-be-fit-for-OA MSCs in well-designed, data-intensive clinical trials to advance the field.
Topics: Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Osteoarthritis, Knee; Pain; Treatment Outcome; Randomized Controlled Trials as Topic; Non-Randomized Controlled Trials as Topic
PubMed: 37095295
DOI: 10.1038/s41423-023-01020-1 -
Cell Research Mar 2020Recent studies have shown that meningeal lymphatic vessels (MLVs), which are located both dorsally and basally beneath the skull, provide a route for draining...
Recent studies have shown that meningeal lymphatic vessels (MLVs), which are located both dorsally and basally beneath the skull, provide a route for draining macromolecules and trafficking immune cells from the central nervous system (CNS) into cervical lymph nodes (CLNs), and thus represent a potential therapeutic target for treating neurodegenerative and neuroinflammatory diseases. However, the roles of MLVs in brain tumor drainage and immunity remain unexplored. Here we show that dorsal MLVs undergo extensive remodeling in mice with intracranial gliomas or metastatic melanomas. RNA-seq analysis of MLV endothelial cells revealed changes in the gene sets involved in lymphatic remodeling, fluid drainage, as well as inflammatory and immunological responses. Disruption of dorsal MLVs alone impaired intratumor fluid drainage and the dissemination of brain tumor cells to deep CLNs (dCLNs). Notably, the dendritic cell (DC) trafficking from intracranial tumor tissues to dCLNs decreased in mice with defective dorsal MLVs, and increased in mice with enhanced dorsal meningeal lymphangiogenesis. Strikingly, disruption of dorsal MLVs alone, without affecting basal MLVs or nasal LVs, significantly reduced the efficacy of combined anti-PD-1/CTLA-4 checkpoint therapy in striatal tumor models. Furthermore, mice bearing tumors overexpressing VEGF-C displayed a better response to anti-PD-1/CTLA-4 combination therapy, and this was abolished by CCL21/CCR7 blockade, suggesting that VEGF-C potentiates checkpoint therapy via the CCL21/CCR7 pathway. Together, the results of our study not only demonstrate the functional aspects of MLVs as classic lymphatic vasculature, but also highlight that they are essential in generating an efficient immune response against brain tumors.
Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Glioma; HEK293 Cells; Humans; Lymphatic Vessels; Male; Melanoma; Melanoma, Experimental; Meninges; Mice; Mice, Inbred C57BL; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 32094452
DOI: 10.1038/s41422-020-0287-8 -
ELife Aug 2022Infections at the maternal-fetal interface can directly harm the fetus and induce complications that adversely impact pregnancy outcomes. Innate immune signaling by both...
Infections at the maternal-fetal interface can directly harm the fetus and induce complications that adversely impact pregnancy outcomes. Innate immune signaling by both fetal-derived placental trophoblasts and the maternal decidua must provide antimicrobial defenses at this critical interface without compromising its integrity. Here, we developed matched trophoblast (TO) and decidua organoids (DO) from human placentas to define the relative contributions of these cells to antiviral defenses at the maternal-fetal interface. We demonstrate that TO and DO basally secrete distinct immunomodulatory factors, including the constitutive release of the antiviral type III interferon IFN-λ2 from TOs, and differentially respond to viral infections through the induction of organoid-specific factors. Finally, we define the differential susceptibility and innate immune signaling of TO and DO to human cytomegalovirus (HCMV) and develop a co-culture model of TO and DO which showed that trophoblast-derived factors protect decidual cells from HCMV infection. Our findings establish matched TO and DO as ex vivo models to study vertically transmitted infections and highlight differences in innate immune signaling by fetal-derived trophoblasts and the maternal decidua.
Topics: Antiviral Agents; Decidua; Female; Humans; Immunity, Innate; Organoids; Placenta; Pregnancy; Trophoblasts
PubMed: 35975985
DOI: 10.7554/eLife.79794 -
Current Opinion in Cell Biology Feb 2020Most human cancers arise from epithelial tissues, which are apical-basally polarized and possess intercellular adhesive junctions. Epithelial cells grow to... (Review)
Review
Most human cancers arise from epithelial tissues, which are apical-basally polarized and possess intercellular adhesive junctions. Epithelial cells grow to characteristic densities, often from proliferative progenitors, which arrest as they mature. Homeostatic mechanisms can maintain this characteristic density if it is exceeded (crowding) or is too low (e.g. in response to wounding). During tumor initiation and progression this homeostatic mechanism is lost. Some aspects of cell polarity are also lost, although many carcinomas retain intercellular junctions and even apical domains. In other cases, and particularly in recurrent tumors, however, the cells become predominantly mesenchymal. A major question, still only incompletely answered, is whether the proteins that determine cell polarity function as tumor suppressors or tumor promoters. Here we discuss recent advances in understanding the role of polarity proteins and homeostasis in cancer.
Topics: Animals; Carcinogenesis; Cell Polarity; Cell Transformation, Neoplastic; Humans
PubMed: 31509786
DOI: 10.1016/j.ceb.2019.07.016 -
Frontiers in Cell and Developmental... 2021Apart from mutations in the gene, p53 functions can be alternatively compromised by a decrease in nuclear p53 protein levels or activities. In accordance, enhanced p53... (Review)
Review
Apart from mutations in the gene, p53 functions can be alternatively compromised by a decrease in nuclear p53 protein levels or activities. In accordance, enhanced p53 protein turnover due to elevated expression of the critical p53 E3 ligase MDM2 or MDM2/MDMX is found in many human cancers. Likewise, the HPV viral E6 protein-mediated p53 degradation critically contributes to the tumorigenesis of cervical cancer. In addition, growth-promoting signaling-induced cell proliferation is accompanied by p53 downregulation. Animal studies have also shown that loss of p53 is essential for oncogenes to drive malignant transformation. The close association between p53 downregulation and carcinogenesis implicates a critical role of basally expressed p53. In accordance, available evidence indicates that a reduced level of basal p53 is usually associated with disruption of homeostasis, suggesting a homeostatic function mediated by basal p53. However, basally expressed p53 under non-stress conditions is maintained at a relatively low abundance with little transcriptional activity, raising the question of how basal p53 could protect homeostasis. In this review, we summarize the findings pertinent to basal p53-mediated activities in the hope of developing a model in which basally expressed p53 functions as a barrier to anabolic metabolism to preserve homeostasis. Future investigation is necessary to characterize basal p53 functionally and to obtain an improved understanding of p53 homeostatic function, which would offer novel insight into the role of p53 in tumor suppression.
PubMed: 34888311
DOI: 10.3389/fcell.2021.775312 -
Psychiatria Danubina Dec 2015This paper presents first before the clinical picture of dementia and is further on dedicated to ways of dealing with people who suffer from dementia. They often show -... (Review)
Review
This paper presents first before the clinical picture of dementia and is further on dedicated to ways of dealing with people who suffer from dementia. They often show - from the perspective of this often loaded and challenged social environment - unexpected and/or unpredictable behavior. There is no panacea for the ends of successful dealing with people with dementia. But experience in terms of both - general and specialized nursing strategies - may facilitate the handling and may ease the situation of affected. After a number of general strategies the specialist care strategies Fördernde Prozesspflege, Validation, Basale Stimulation(©) and Psychobiographisches Pflegemodell are presented.
Topics: Dementia; Disease Management; Humans
PubMed: 26609661
DOI: No ID Found -
Current Opinion in Cell Biology Oct 2018Cell extrusion drives most epithelial cell death while maintaining a functional epithelial barrier. To extrude, a cell produces a lipid signal that triggers the... (Review)
Review
Cell extrusion drives most epithelial cell death while maintaining a functional epithelial barrier. To extrude, a cell produces a lipid signal that triggers the neighboring cells to reorganize actin and myosin basally to squeeze the extruding cell out apically from the barrier. More studies continue to reveal other signals and mechanisms controlling apical extrusion. New developmental studies are uncovering mechanisms controlling basal extrusion, or ingression, which occurs when apical extrusion is defective or during de-differentiation in development. Here, we review recent advances in epithelial extrusion, focusing particularly on forces exerted upon extruding cells and their various later fates ranging from cell death, normal development, and cancer.
Topics: Actins; Animals; Biomechanical Phenomena; Disease; Epithelial Cells; Humans; Myosins; Nervous System
PubMed: 29727745
DOI: 10.1016/j.ceb.2018.04.007