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The Journal of Biological Chemistry May 2023Energy balance and nutrient availability are key determinants of cellular decisions to remain quiescent, proliferate, or differentiate into a mature cell. After...
Energy balance and nutrient availability are key determinants of cellular decisions to remain quiescent, proliferate, or differentiate into a mature cell. After assessing its environmental state, the cell must rewire its metabolism to support distinct cellular outcomes. Mechanistically, how metabolites regulate cell fate decisions is poorly understood. We used adipogenesis as our model system to ascertain the role of metabolism in differentiation. We isolated adipose tissue stromal vascular fraction cells and profiled metabolites before and after adipogenic differentiation to identify metabolic signatures associated with these distinct cellular states. We found that differentiation alters nucleotide accumulation. Furthermore, inhibition of nucleotide biosynthesis prevented lipid storage within adipocytes and downregulated the expression of lipogenic factors. In contrast to proliferating cells, in which mechanistic target of rapamycin complex 1 is activated by purine accumulation, mechanistic target of rapamycin complex 1 signaling was unaffected by purine levels in differentiating adipocytes. Rather, our data indicated that purines regulate transcriptional activators of adipogenesis, peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α, to promote differentiation. Although de novo nucleotide biosynthesis has mainly been studied in proliferation, our study points to its requirement in adipocyte differentiation.
Topics: Animals; Mice; 3T3-L1 Cells; Adipocytes; Adipogenesis; Cell Differentiation; Lipid Metabolism; Mechanistic Target of Rapamycin Complex 1; PPAR gamma; Nucleotides; Purines; CCAAT-Enhancer-Binding Protein-alpha; Signal Transduction
PubMed: 36963490
DOI: 10.1016/j.jbc.2023.104635 -
Archives of Medical Science : AMS 2023To explore the function of interleukin 1α (IL-1α) in bladder cancer (BCa).
INTRODUCTION
To explore the function of interleukin 1α (IL-1α) in bladder cancer (BCa).
MATERIAL AND METHODS
Immunohistochemistry (IHC) was used to test the protein expression of IL-1α in BCa tissues. The relationship between IL-1α and clinical characteristics was analyzed by the Kaplan-Meier curve method. The gene and protein expression was tested by reverse transcription (RT-q-PCR) and western blot, respectively. Colony formation and MTT assays were used to detect the potential of proliferation , and scratch and transwell chamber assays were used to detect the potential of invasion . Markers of proliferation such as Ki-67 and proliferating cell nuclear antigen (PCNA) and markers of invasion such as MMP-2 and MMP-9 were detected by western blot. Xenograft study was used for the experiment.
RESULTS
We found that IL-1α was highly expressed in BCa patients while highly expressed IL-1α was significantly related to short overall survival and progression-free survival in BCa as well. Moreover, knockdown of IL-1α might inhibit the ability of cancer cells to proliferate and invade or migrate both and .
CONCLUSIONS
Our findings suggested that IL-1α might be a therapy target for BCa malignant progression.
PubMed: 36817666
DOI: 10.5114/aoms.2020.100677 -
Clinics and Practice Feb 2021A broad spectrum of lesions, including hyperplastic, metaplastic, inflammatory, infectious, and reactive, may mimic cancer all along the urinary tract. This narrative... (Review)
Review
A broad spectrum of lesions, including hyperplastic, metaplastic, inflammatory, infectious, and reactive, may mimic cancer all along the urinary tract. This narrative collects most of them from a clinical and pathologic perspective, offering urologists and general pathologists their most salient definitory features. Together with classical, well-known, entities such as urothelial papillomas (conventional (UP) and inverted (IUP)), nephrogenic adenoma (NA), polypoid cystitis (PC), fibroepithelial polyp (FP), prostatic-type polyp (PP), verumontanum cyst (VC), xanthogranulomatous inflammation (XI), reactive changes secondary to BCG instillations (BCGitis), schistosomiasis (SC), keratinizing desquamative squamous metaplasia (KSM), post-radiation changes (PRC), vaginal-type metaplasia (VM), endocervicosis (EC)/endometriosis (EM) (müllerianosis), malakoplakia (MK), florid von Brunn nest proliferation (VB), cystitis/ureteritis cystica (CC), and glandularis (CG), among others, still other cellular proliferations with concerning histological features and poorly understood etiopathogenesis like IgG4-related disease (IGG4), PEComa (PEC), and pseudosarcomatous myofibroblastic proliferations (post-operative spindle cell nodule (POS), inflammatory myofibroblastic tumor (IMT)), are reviewed. Some of these diagnoses are problematic for urologists, other for pathologists, and still others for both. Interestingly, the right identification of their definitory features will allow their correct diagnoses, thus, avoiding overtreatment. The literature selected for this review also focuses on the immunohistochemical and/or molecular data useful to delineate prognosis.
PubMed: 33668963
DOI: 10.3390/clinpract11010017 -
Journal of Developmental Biology May 2022Turner syndrome (TS) is a chromosomal disorder that is caused by a missing or structurally abnormal second sex chromosome. Subjects with TS are at an increased risk of... (Review)
Review
Turner syndrome (TS) is a chromosomal disorder that is caused by a missing or structurally abnormal second sex chromosome. Subjects with TS are at an increased risk of developing intrauterine growth retardation, low birth weight, short stature, congenital heart diseases, infertility, obesity, dyslipidemia, hypertension, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases (stroke and myocardial infarction). The underlying pathogenetic mechanism of TS is unknown. The assumption that X chromosome-linked gene haploinsufficiency is associated with the TS phenotype is questioned since such genes have not been identified. Thus, other pathogenic mechanisms have been suggested to explain this phenotype. Morphogenesis encompasses a series of events that includes cell division, the production of migratory precursors and their progeny, differentiation, programmed cell death, and integration into organs and systems. The precise control of the growth and differentiation of cells is essential for normal development. The cell cycle frequency and the number of proliferating cells are essential in cell growth. 45,X cells have a failure to proliferate at a normal rate, leading to a decreased cell number in a given tissue during organogenesis. A convergence of data indicates an association between a prolonged cell cycle and the phenotypical features in Turner syndrome. This review aims to examine old and new findings concerning the relationship between a prolonged cell cycle and TS phenotype. These studies reveal a diversity of phenotypic features in TS that could be explained by reduced cell proliferation. The implications of this hypothesis for our understanding of the TS phenotype and its pathogenesis are discussed. It is not surprising that 45,X monosomy leads to cellular growth pathway dysregulation with profound deleterious effects on both embryonic and later stages of development. The prolonged cell cycle could represent the beginning of the pathogenesis of TS, leading to a series of phenotypic consequences in embryonic/fetal, neonatal, pediatric, adolescence, and adulthood life.
PubMed: 35645292
DOI: 10.3390/jdb10020016 -
Neuro-oncology Advances 2022The actin-binding protein filamin A (FLNA) regulates oncogenic signal transduction important for tumor growth, but the role of FLNA in the progression of neuroblastoma...
BACKGROUND
The actin-binding protein filamin A (FLNA) regulates oncogenic signal transduction important for tumor growth, but the role of FLNA in the progression of neuroblastoma (NB) has not been explored.
METHODS
We analyzed mRNA expression in the R2 NB-database and FLNA protein expression in human NB tumors. We then silenced expression in human SKNBE2 and IMR32 NB cells by lentiviral vector encoding shRNA and assayed the cells for proliferation, migration, colony, spheroid formation, and apoptosis. SKNBE2 xenografts expressing or lacking FLNA in BALB/c nude mice were analyzed by both routine histopathology and immunohistochemistry.
RESULTS
We observed shorter patient survival with higher expression of mRNA than patients with lower mRNA expression, and high-risk NB tumors expressed higher FLNA levels. Overexpression of FLNA increased proliferation of SH-SY5 NB cells. NB cell lines transfected with siRNA proliferated and migrated less, expressed lower levels of phosphorylated AKT and ERK1/2, formed smaller colonies and spheroids, as well as increased apoptosis. After inoculation of SKNBE2 cells infected with lentivirus expressing shRNA , size of NB tumors and number of proliferating cells were decreased. Furthermore, we identified STAT3 as an interacting partner of FLNA. Silencing mRNA reduced levels of NF-κB, STAT3 and MYCN, and increased levels of p53 and cleaved caspase 3.
CONCLUSION
Inhibition of FLNA impaired NB cell signaling and function and reduced NB tumor size , suggesting that drugs targeting either FLNA or its interaction with STAT3 may be useful in the treatment of NB.
PubMed: 35441138
DOI: 10.1093/noajnl/vdac028 -
Oncology Research May 2020PRKAA1 (protein kinase AMP-activated catalytic subunit α 1) is a catalytic subunit of AMP-activated protein kinase (AMPK), which plays a key role in regulating cellular...
PRKAA1 (protein kinase AMP-activated catalytic subunit α 1) is a catalytic subunit of AMP-activated protein kinase (AMPK), which plays a key role in regulating cellular energy metabolism through phosphorylation, and genetic variations in the PRKAA1 have been found to be associated with gastric cancer risk. However, the effect and underlying molecular mechanism of PRKAA1 on gastric cancer tumorigenesis, especially the proliferation and apoptosis, are not fully understood. Our data showed that PRKAA1 is highly expressed in BGC-823 and MKN45 cells and is expressed low in SGC-7901 and MGC-803 cells in comparison with the other gastric cancer cells. PRKAA1 downregulation by shRNA or treatment of AMPK inhibitor compound C significantly inhibited proliferation as well as promoted cell cycle arrest and apoptosis of BGC-823 and MKN45 cells. Moreover, the expression of PCNA and Bcl-2 and the activity of JNK1 and Akt signaling were also reduced in BGC-823 and MKN45 cells after PRKAA1 downregulation. In vivo experiments demonstrated that tumor growth in nude mice was significantly inhibited after PRKAA1 silencing. Importantly, inactivation of JNK1 or Akt signaling pathway significantly inhibited PRKAA1 overexpression-induced increased cell proliferation and decreased cell apoptosis in MGC-803 cells. In conclusion, our findings suggest that PRKAA1 increases proliferation and restrains apoptosis of gastric cancer cells through activating JNK1 and Akt pathways.
Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Gene Expression; Humans; Male; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 8; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Stomach Neoplasms; Xenograft Model Antitumor Assays
PubMed: 31558185
DOI: 10.3727/096504019X15668125347026 -
BioMed Research International 2022Three hundred sixty ( = 360) broiler chickens were equally divided into control (C) and thiram (T) groups. Furthermore, the C and T groups were dividedinto 8-, 9-, 11-,...
MATERIALS AND METHODS
Three hundred sixty ( = 360) broiler chickens were equally divided into control (C) and thiram (T) groups. Furthermore, the C and T groups were dividedinto 8-, 9-, 11-, and 13-day-old chickens.
RESULTS
Clinically, it was observed that broiler chickens of group T had abnormal posture, gait, and lameness, and histopathological results revealed dead and abnormal chondrocytes of T group on day 6. Real-time qPCR results showed that HDAC1, MTA1, H4, and PCNA genes were significantly expressed ( < 0.05). HDAC1 was upregulated on days 1, 2, 4, and 6 ( < 0.01); MTA1 was upregulated on days 1 and 2 ( < 0.01); H4 was upregulated on days 2 and 4 ( < 0.01), and PCNA was downregulated on days 1, 2, and 4 ( < 0.01). Furthermore, IHC results of HDAC1 protein were significantly ( < 0.01) expressed in proliferative zone of day 1 and hypertrophic zone of day 6. MTA1 protein was significantly ( < 0.01) expressed on days 1, 2, and 6 in all zones, except prehypertrophic zone of day 2.
CONCLUSION
In conclusion, the mRNA expressions of HDAC1, MTA1, H4, and PCNA were differentially expressed in the chondrocytes of thiram-induced TD chickens. HDAC1 and MTA1 protein expression found involved and responsible in the abnormal chondrocytes' proliferation of broiler chicken.
Topics: Animals; Cell Proliferation; Chickens; Growth Plate; Osteochondrodysplasias; Poultry Diseases; Proliferating Cell Nuclear Antigen; Thiram; Tibia
PubMed: 35872845
DOI: 10.1155/2022/6209047 -
Frontiers in Neuroscience 2020Astrocytes exhibit a region-dependent molecular and functional heterogeneity in the CNS. Although cortical astrocytes proliferate robustly during the first postnatal...
Astrocytes exhibit a region-dependent molecular and functional heterogeneity in the CNS. Although cortical astrocytes proliferate robustly during the first postnatal week and become proliferation quiescent, the temporal proliferation dynamics of astrocytes in subcortical regions during postnatal development remain essentially unknown. Whether subcortical astrocytes mature similarly to cortical astrocytes is also unexplored. In this current study, we examined proliferation of subcortical, especially hypothalamic, astrocytes during postnatal development using genetic labeling of astrocytes and pulse-chase EdU labeling of proliferating cells. While a lower number of proliferating astrocytes was found in the hypothalamus compared to cortex during the first postnatal week, astrocyte proliferation is much more active in hypothalamus than in cortex from P15 to P30 in both proliferating astrocyte density and percentage, indicating a persistent and distinct proliferation pattern of astrocytes in hypothalamus. This observation is further confirmed by Ki67 immunostaining with genetically or immunolabeled astrocytes in hypothalamus and cortex during P15-30. In addition, astrocytes in representative subcortical regions have a modest growth of their domain size and exhibit a significantly smaller domain size compared to cortical astrocytes at P30 when astrocytes have generally completed postnatal maturation. However, the expression of astrocyte-derived Sparc, an important synaptogenic inhibitor, is consistently higher in hypothalamic astrocytes than in cortical astrocytes throughout postnatal development. In summary, our study unveiled a distinct proliferation and maturation pattern of subcortical, especially hypothalamic, astrocytes during postnatal development.
PubMed: 32457572
DOI: 10.3389/fnins.2020.00435 -
British Journal of Cancer Feb 2023In this perspective, the authors summarise some properties of the solid tumour micro-environment that have been explored during the last 55 years. It is well established... (Review)
Review
In this perspective, the authors summarise some properties of the solid tumour micro-environment that have been explored during the last 55 years. It is well established that the concentrations of nutrients, including oxygen, decrease with increasing distance from tumour blood vessels, and that low extracellular pH is found in nutrient-poor regions. Cell proliferation is dependent on nutrient metabolites and decreases in regions distal from patent blood vessels. Proliferating cells cause migration of neighbouring cells further from blood vessels where they may die, and their breakdown products pass into regions of necrosis. Anticancer drugs reach solid tumours via the vascular system and establish concentration gradients such that drug concentration within tumours may be quite variable. Treatment with chemotherapy such as doxorubicin or docetaxel can kill well-nourished proliferating cells close to blood vessels, thereby interrupting migration toward necrotic regions and lead to re-oxygenation and renewed proliferation of distal cells, as can occur with radiotherapy. This effect leads to the paradox that cancer treatment can rescue cells that were destined to die in the untreated tumour. Renewed and sometimes accelerated repopulation of surviving tumour cells can counter the effects of cell killing from repeated treatments, leading to tumour shrinkage and regrowth without changes in the intrinsic sensitivity of cells to the administered treatment. Strategies to prevent these effects include the combined use of chemotherapy with agents that selectively kill hypoxic tumour cells, including inhibitors of autophagy, since this is a process that may allow recycling of cellular macromolecules from dying cells and improve their survival.
Topics: Humans; Neoplasms; Antineoplastic Agents; Cell Proliferation; Doxorubicin; Docetaxel; Tumor Microenvironment
PubMed: 36564562
DOI: 10.1038/s41416-022-02109-6 -
Physiological Reports Feb 2022Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. PAH is characterized by pulmonary artery remodeling, elevated right...
Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. PAH is characterized by pulmonary artery remodeling, elevated right ventricular pressure (RVP) and, ultimately, cardiac failure. Pulmonary endothelial cells can sense danger or damage caused by mechanical injury or pathogens through alarmin cytokines. These cytokines can signal proliferation to restore barrier integrity or aberrant hyperproliferation and remodeling. We hypothesized that IL-33 signals pulmonary artery endothelial cells to proliferate under hypertensive conditions during the remodeling response and rise in RVP. To test this hypothesis, pulmonary hypertension (PH) was induced in C57Bl/6J, IL-33 receptor gene deleted (ST2 ) and MYD88 gene deleted (MYD88 ) mice by exposure to 10% O and SU5416 injections (SUHX). RVP, arterial wall thickness, endothelial cell proliferation and IL-33 levels and signaling were evaluated. In response to SUHX. RVP increased in C57Bl/6J mice in response to SUHX (49% male and 70% female; p < 0.0001) and this SUHX response was attenuated in ST2 mice (29% male p = 0.003; 30% female p = 0.001) and absent in MYD88 mice. Wall thickness was increased in SUHX C57Bl/6J mice (p = 0.005), but not in ST2 or MYD88 mice. Proliferating cells were detected in C57Bl/6J mice by flow cytometry (CD31 /BrDU ; p = 0.02) and immunofluorescence methods (Ki-67+). IL-33 was increased by SUHX (p = 0.03) but a genotype effect was not observed (p = 0.76). We observed that in hPAECs, IL-33 expression is regulated by both IL-33 and DLL4. These data suggest IL-33/ST2 signaling is essential for the endothelial cell proliferative response in PH.
Topics: Animals; Cells, Cultured; Female; Gene Deletion; Hypertension, Pulmonary; Indoles; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Male; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; Pyrroles; Signal Transduction
PubMed: 35150208
DOI: 10.14814/phy2.15185