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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 Stem Cell Nov 2008Here, we demonstrate self-organized formation of apico-basally polarized cortical tissues from ESCs using an efficient three-dimensional aggregation culture (SFEBq...
Here, we demonstrate self-organized formation of apico-basally polarized cortical tissues from ESCs using an efficient three-dimensional aggregation culture (SFEBq culture). The generated cortical neurons are functional, transplantable, and capable of forming proper long-range connections in vivo and in vitro. The regional identity of the generated pallial tissues can be selectively controlled (into olfactory bulb, rostral and caudal cortices, hem, and choroid plexus) by secreted patterning factors such as Fgf, Wnt, and BMP. In addition, the in vivo-mimicking birth order of distinct cortical neurons permits the selective generation of particular layer-specific neurons by timed induction of cell-cycle exit. Importantly, cortical tissues generated from mouse and human ESCs form a self-organized structure that includes four distinct zones (ventricular, early and late cortical-plate, and Cajal-Retzius cell zones) along the apico-basal direction. Thus, spatial and temporal aspects of early corticogenesis are recapitulated and can be manipulated in this ESC culture.
Topics: Animals; Antigens, Differentiation; Body Patterning; Bone Morphogenetic Protein 4; Cell Cycle; Cell Differentiation; Cerebral Cortex; Embryonic Stem Cells; Fibroblast Growth Factor 8; Gene Expression Regulation, Developmental; Homeostasis; Humans; Immunohistochemistry; Mice; Neurons; Signal Transduction; Tissue Culture Techniques; Wnt Proteins; Wnt3 Protein
PubMed: 18983967
DOI: 10.1016/j.stem.2008.09.002 -
Proceedings of the National Academy of... Dec 2013Here, using further optimized 3D culture that allows highly selective induction and long-term growth of human ES cell (hESC)-derived cortical neuroepithelium, we...
Here, using further optimized 3D culture that allows highly selective induction and long-term growth of human ES cell (hESC)-derived cortical neuroepithelium, we demonstrate unique aspects of self-organization in human neocorticogenesis. Self-organized cortical tissue spontaneously forms a polarity along the dorsocaudal-ventrorostral axis and undergoes region-specific rolling morphogenesis that generates a semispherical structure. The neuroepithelium self-forms a multilayered structure including three neuronal zones (subplate, cortical plate, and Cajal-Retzius cell zones) and three progenitor zones (ventricular, subventricular, and intermediate zones) in the same apical-basal order as seen in the human fetal cortex in the early second trimester. In the cortical plate, late-born neurons tend to localize more basally to early-born neurons, consistent with the inside-out pattern seen in vivo. Furthermore, the outer subventricular zone contains basal progenitors that share characteristics with outer radial glia abundantly found in the human, but not mouse, fetal brain. Thus, human neocorticogenesis involves intrinsic programs that enable the emergence of complex neocortical features.
Topics: Amides; Cell Culture Techniques; Cell Polarity; Collagen; Drug Combinations; Embryonic Stem Cells; Humans; Laminin; Neocortex; Neuroglia; Organogenesis; Proteoglycans; Pyridines; Species Specificity
PubMed: 24277810
DOI: 10.1073/pnas.1315710110 -
Developmental Cell Dec 2023The extrahepatic branches of the biliary tree have glands that connect to the surface epithelium through narrow pits. The duct epithelia undergo homeostatic renewal, yet...
The extrahepatic branches of the biliary tree have glands that connect to the surface epithelium through narrow pits. The duct epithelia undergo homeostatic renewal, yet the identity and multiplicity of cells that maintain this tissue is unknown. Using marker-free and targeted clonal fate mapping in mice, we provide evidence that the extrahepatic bile duct is compartmentalized. Pit cholangiocytes of extramural glands renewed the surface epithelium, whereas basally oriented cholangiocytes maintained the gland itself. In contrast, basally positioned cholangiocytes replenished the surface epithelium in mural glands. Single-cell sequencing identified genes enriched in the base and surface epithelial populations, with trajectory analysis showing graded gene expression between these compartments. Epithelia were plastic, changing cellular identity upon fasting and refeeding. Gain of canonical Wnt signaling caused basal cell expansion, gastric chief cell marker expression, and a decrease in surface epithelial markers. Our results identify the cellular hierarchy governing extrahepatic biliary epithelial renewal.
Topics: Animals; Mice; Biliary Tract; Bile Ducts, Extrahepatic; Epithelium; Epithelial Cells; Cell Proliferation
PubMed: 37909044
DOI: 10.1016/j.devcel.2023.10.004 -
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 -
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 -
Canadian Journal of Diabetes Jun 2023Our aim in this study was to compare the efficacy and safety of commercially available fixed-ratio combinations (FRCs) of glucagon-like peptide-1 receptor agonists... (Meta-Analysis)
Meta-Analysis
Comparison of Efficacy and Safety of Commercially Available Fixed-Ratio Combinations of Insulin Degludec/Liraglutide and Insulin Glargine/Lixisenatide: A Network Meta-analysis.
OBJECTIVES
Our aim in this study was to compare the efficacy and safety of commercially available fixed-ratio combinations (FRCs) of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and basal insulins by a network meta-analysis of randomized controlled trials (RCTs) of people with type 2 diabetes.
METHODS
We present a systematic review and network meta-analyses of RCTs of individuals with type 2 diabetes randomized to FRCs or to their components for ≥24 weeks. All reports were obtained from PubMed or ClinicalTrials.gov up to February 28, 2022. The primary outcome was glycated hemoglobin (A1C) level attained. Secondary outcomes included fasting plasma glucose, change in body weight, and incident hypoglycemia. Treatment effects were estimated as mean difference (MD) and standard error (SE), or as odds ratio (OR) with 95% confidence interval (CI) using the fixed combination of insulin glargine 100 IU/mL and lixisenatide (iGlarLixi) as reference.
RESULTS
We included 29 RCTs from among the 1,404 articles identified. No direct comparisons between FRCs were found. After excluding some insulin-capped trials to reach model consistency, both FRCs were more efficacious regarding A1C than their components, but no difference between FRCs was found (MD, -0.10%; SE, 0.10%). The effect of the fixed combination of insulin degludec and liraglutide (IDegLira) (MD, -0.47 mmol/L; SE, 0.24 mmol/L) and basal insulins was similar to that of iGlarLixi (reference) on fasting glucose, whereas GLP-1RAs had lower efficacy than iGlarLixi. Weight gain was lower with GLP-1RAs and IDegLira (MD, -0.72 kg; SE, 0.32 kg) than with iGlarLixi (reference) and higher with basal insulins. Incident hypoglycemia (based on different definitions) was least frequent with GLP-1RAs, followed by IDegLira (OR, 0.78; 95% CI, 0.39 to 1.57), iGlarLixi (reference), and basal insulins.
CONCLUSIONS
For A1C, both FRCs were more efficacious over their individual components, with similar efficacies of the 2 FRCs.
Topics: Humans; Liraglutide; Insulin Glargine; Network Meta-Analysis; Glycated Hemoglobin; Blood Glucose; Drug Combinations; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Hypoglycemia; Randomized Controlled Trials as Topic
PubMed: 36963632
DOI: 10.1016/j.jcjd.2023.03.002