scholarly journals Natural Products and Obesity: A Focus on the Regulation of Mitotic Clonal Expansion during Adipogenesis

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1157 ◽  
Author(s):  
Eugene Chang ◽  
Choon Kim
Keyword(s):  
Cell Cycle ◽  
Natural Products ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Inhibitory Effects ◽  
Health Crisis ◽  
Health Complications ◽  
Key Steps

Obesity is recognized as a worldwide health crisis. Obesity and its associated health complications such as diabetes, dyslipidemia, hypertension, and cardiovascular diseases impose a big social and economic burden. In an effort to identify safe, efficient, and long-term effective methods to treat obesity, various natural products with potential for inhibiting adipogenesis were revealed. This review aimed to discuss the molecular mechanisms underlying adipogenesis and the inhibitory effects of various phytochemicals, including those from natural sources, on the early stage of adipogenesis. We discuss key steps (proliferation and cell cycle) and their regulators (cell-cycle regulator, transcription factors, and intracellular signaling pathways) at the early stage of adipocyte differentiation as the mechanisms responsible for obesity.

scholarly journals The distinct effects of P18 overexpression on different stages of hematopoiesis involve TGF-β and NF-κB signaling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Danying Yi ◽  
Lijiao Zhu ◽  
Yuanling Liu ◽  
Jiahui Zeng ◽  
Jing Chang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitors ◽  
Early Stage ◽  
Cyclin Dependent Kinase ◽  
Hematopoietic Differentiation ◽  
Inhibitory Effects ◽  
Hematopoietic Stem ◽  
Hesc Lines ◽  
Cell Cycle Status

AbstractDeficiency of P18 can significantly improve the self-renewal potential of hematopoietic stem cells (HSC) and the success of long-term engraftment. However, the effects of P18 overexpression, which is involved in the inhibitory effects of RUNX1b at the early stage of hematopoiesis, have not been examined in detail. In this study, we established inducible P18/hESC lines and monitored the effects of P18 overexpression on hematopoietic differentiation. Induction of P18 from day 0 (D0) dramatically decreased production of CD34highCD43− cells and derivative populations, but not that of CD34lowCD43− cells, changed the cell cycle status and apoptosis of KDR+ cells and downregulated the key hematopoietic genes at D4, which might cause the severe blockage of hematopoietic differentiation at the early stage. By contrast, induction of P18 from D10 dramatically increased production of classic hematopoietic populations and changed the cell cycle status and apoptosis of CD45+ cells at D14. These effects can be counteracted by inhibition of TGF-β or NF-κB signaling respectively. This is the first evidence that P18 promotes hematopoiesis, a rare property among cyclin-dependent kinase inhibitors (CKIs).

Cellular and Molecular Mechanisms for the Bone Response to Mechanical Loading

2001 ◽  
Vol 11 (s1) ◽  
pp. S128-S136 ◽  
Author(s):  
Susan A. Bloomfield
Keyword(s):  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Interstitial Fluid Flow ◽  
Effector Cells ◽  
Bone Response ◽  
Osteogenic Response ◽  
Mechanical Signal ◽  
Endocrine Factors ◽  
Key Steps

To define the cellular and molecular mechanisms for the osteogenic response of bone to increased loading, several key steps must be defined: sensing of the mechanical signal by cells in bone, transduction of the mechanical signal to a biochemical one, and transmission of that biochemical signal to effector cells. Osteocytes are likely to serve as sensors of loading, probably via interstitial fluid flow produced during loading. Evidence is presented for the role of integrins, the cell’s actin cytoskeleton, G proteins, and various intracellular signaling pathways in transducing that mechanical signal to a biochemical one. Nitric oxide, prostaglandins, and insulin-like growth factors all play important roles in these pathways. There is growing evidence for modulation of these mechanotransduction steps by endocrine factors, particularly parathyroid hormone and estrogen. The efficiency of this process is also impaired in the aged animal, yet what remains undefined is at what step mechanotransduction is affected.

scholarly journals Sulforaphane Reduces Prostate Cancer Cell Growth and Proliferation In Vitro by Modulating the Cdk-Cyclin Axis and Expression of the CD44 Variants 4, 5, and 7

2020 ◽  
Vol 21 (22) ◽  
pp. 8724
Author(s):  
Jochen Rutz ◽  
Sarah Thaler ◽  
Sebastian Maxeiner ◽  
Felix K.-H. Chun ◽  
Roman A. Blaheta
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Growth ◽  
Cell Lines ◽  
Cancer Cell ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Prostate Cancer Cell ◽  
Cancer Cell Lines ◽  
Prostate Cancer Cell Lines

Prostate cancer patients whose tumors develop resistance to conventional treatment often turn to natural, plant-derived products, one of which is sulforaphane (SFN). This study was designed to determine whether anti-tumor properties of SFN, identified in other tumor entities, are also evident in cultivated DU145 and PC3 prostate cancer cells. The cells were incubated with SFN (1–20 µM) and tumor cell growth and proliferative activity were evaluated. Having found a considerable anti-growth, anti-proliferative, and anti-clonogenic influence of SFN on both prostate cancer cell lines, further investigation into possible mechanisms of action were performed by evaluating the cell cycle phases and cell-cycle-regulating proteins. SFN induced a cell cycle arrest at the S- and G2/M-phase in both DU145 and PC3 cells. Elevation of histone H3 and H4 acetylation was also evident in both cell lines following SFN exposure. However, alterations occurring in the Cdk-cyclin axis, modification of the p19 and p27 proteins and changes in CD44v4, v5, and v7 expression because of SFN exposure differed in the two cell lines. SFN, therefore, does exert anti-tumor properties on these two prostate cancer cell lines by histone acetylation and altering the intracellular signaling cascade, but not through the same molecular mechanisms.

Ineffective erythropoiesis and its treatment

Blood ◽  
2021 ◽  
Author(s):  
Mario Cazzola
Keyword(s):  
Molecular Mechanisms ◽  
Early Stage ◽  
Iron Loading ◽  
Murine Models ◽  
Ineffective Erythropoiesis ◽  
Inherited Disorders ◽  
Iron Restriction ◽  
Novel Treatments ◽  
Ring Sideroblasts

The erythroid marrow and circulating red blood cells (RBCs) are the key components of the human erythron. Abnormalities of the erythron that are responsible for anemia can be distinguished into 3 major categories, that is, erythroid hypoproliferation, ineffective erythropoiesis, and peripheral hemolysis. Ineffective erythropoiesis is characterized by erythropoietin-driven expansion of early-stage erythroid precursors, associated with apoptosis of late-stage precursors. This mechanism is primarily responsible for anemia in inherited disorders like β-thalassemia, inherited sideroblastic anemias, and congenital dyserythropoietic anemias, as well as in acquired conditions like some subtypes of myelodysplastic syndromes (MDS). The inherited anemias due to ineffective erythropoiesis are also defined as iron loading anemias because of the associated parenchymal iron loading caused by the release of erythroid factors that suppress hepcidin production. Novel treatments specifically targeting ineffective erythropoiesis are being developed. Iron restriction through enhancement of hepcidin activity or inhibition of ferroportin function has been shown to reduce ineffective erythropoiesis in murine models of β-thalassemia. Luspatercept is a TGF-β ligand trap that inhibits SMAD2/3 signaling. Based on pre-clinical and clinical studies, this compound is now approved for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. Luspatercept is also approved for the treatment of transfusion-dependent anemia in patients with MDS with ring sideroblasts, most of whom carry a somatic SF3B1mutation. While long-term efficacy and safety of luspatercept need to be evaluated both in β-thalassemia and MDS, defining the molecular mechanisms of ineffective erythropoiesis in different disorders might allow the discovery of new effective compounds.

HMGB1gene expression changes in the striatum and amigdal of the rat's brain under alcoholization and ethanol withdrawal

2021 ◽  
Vol 67 (1) ◽  
pp. 95-99
Author(s):  
M.I. Airapetov ◽  
S.O. Eresko ◽  
E.R. Bychkov ◽  
A.A. Lebedev ◽  
P.D. Shabanov
Keyword(s):  
Rat Brain ◽  
Alcohol Withdrawal ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Brain Structures ◽  
Ethanol Withdrawal ◽  
Hmgb1 Protein ◽  
Neuroimmune System ◽  
The Brain

Intracellular signaling mediated by the HMGB1 protein, an agonist of TLRs, is considered as a possible target for the correction of pathologies of the neuroimmune system, however, the expression level of the Hmgb1 gene has not been previously studied in various brain structures of rats exposed to prolonged alcoholization followed by ethanol withdrawal. The study showed that long-term use of ethanol caused to an increase in the level of Hmgb1 mRNA in the striatum of rat brain. Alcohol withdrawal changed the level Hmgb1 mRNA in the striatum and amygdala on the 1st and 14th day. The data obtained may indicate that in different structures of the brain there are multidirectional changes in the molecular mechanisms of the neuroimmune response with prolonged use of ethanol and its withdrawal.

Differential Localization Of RAC1 and RAC2 Reflects Their Specific Functions In Normal and Leukemic Human Hematopoietic Stem/Progenitor Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2892-2892
Author(s):  
Marta Ewa Capala ◽  
Francesco Bonardi ◽  
Henny Maat ◽  
Edo Vellenga ◽  
Jan Jacob Schuringa
Keyword(s):  
Cell Cycle ◽  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Specific Interaction ◽  
Hematopoietic Cells ◽  
Confocal Imaging ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Interaction Partners

Abstract Hematopoietic stem cells (HSCs) depend on the bone marrow niche to provide signals for their survival, quiescence and differentiation. Many of these microenvironmental signals converge on RAC GTPases. In the hematopoietic system, two members of the RAC family are expressed, RAC1 and RAC2. Although RAC1 and RAC2 share a very high sequence homology, specific functions of these proteins have been suggested. However, little has been revealed about the downstream effectors and molecular mechanisms. In this study, we used multiple approaches to gain insight into the molecular biology of RAC1 and RAC2 in normal and leukemic human HSCs. Firstly, GFP-tagged constructs of RAC1 and RAC2 were used to study localization of these proteins in CD34+/CD38-/Lin- HSCs. Time-lapse confocal imaging of living cells plated on stroma revealed that RAC1 was strongly enriched in the plasma membrane. In contrast, RAC2 localized predominantly in the cytoplasm of both resting and dividing HSCs, whereby localization changed dramatically when cells progressed from S to the G2 phase of the cell cycle. This very distinct localization pattern implied different functions of RAC1 and RAC2. Therefore, we specifically downregulated RAC1 and/or RAC2 to study the effects of their depletion in normal and BCR-ABL-transduced leukemic HSCs. In normal HSCs, simultaneous downregulation of RAC1 and RAC2 resulted in a modest but significant decrease in proliferation and progenitor frequencies in the long term stromal co-cultures. However, in BCR-ABL-transduced HSCs depletion of RAC2 alone, but not RAC1, was sufficient to induce a marked proliferative disadvantage, decreased progenitor frequency, reduced leukemic cobblestone formation and diminished replating capacity, indicative for reduced self-renewal. Consistently, the frequency of long-term culture initiating leukemic cells was markedly reduced upon RAC2 downregulation. To elucidate the mechanisms involved in the observed phenotypes, we employed an in vivo biotin labeling strategy of Avi-tagged RAC1 and RAC2 followed by pull down and mass-spectrometry to identify specific interaction partners of RAC1 and RAC2 in BCR-ABL-expressing hematopoietic cells. Several of the RAC1-specific interaction partners were annotated as plasma membrane proteins, involved in cell adhesion, cytoskeleton assembly and regulation of endocytosis. In contrast, RAC2-interacting proteins were cytoplasmic or mitochondria-associated, and involved in processes such as cell cycle progression and regulation of apoptosis. Consistently, the proportion of dividing cells was decreased in RAC2-depleted BCR-ABL leukemic cobblestones coinciding with an increased apoptosis. Finally, a marked decrease in mitochondrial membrane potential was observed upon RAC2 but not RAC1 downregulation pointing to mitochondrial dysfunction as the initiating event of the apoptotic response. Moreover, preliminary electron microscopy data suggest that this functional change may be paralleled by structural aberrations of mitochondria. Further functional characterization of RAC1 and RAC2-specific interactions is currently ongoing and will be discussed, but our data clearly indicate that distinct subcellular localization of RAC1 and RAC2 dictates their interaction with specific sets of proteins and consequently their specific functions in hematopoietic cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Identification of cell cycle as the critical pathway modulated by exosome-derived microRNAs in gallbladder carcinoma

2021 ◽  
Vol 38 (12) ◽  
Author(s):  
Li Su ◽  
Jicheng Zhang ◽  
Xinglong Zhang ◽  
Lei Zheng ◽  
Zhifa Zhu
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Expression Profiles ◽  
Enrichment Analysis ◽  
Cell Cycle Checkpoints ◽  
Gene Set Enrichment Analysis ◽  
Clinical Samples ◽  
Critical Pathway ◽  
Cerna Network

AbstractGallbladder cancer (GBC), the most common malignancy in the biliary tract, is highly lethal malignant due to seldomly specific symptoms in the early stage of GBC. This study aimed to identify exosome-derived miRNAs mediated competing endogenous RNAs (ceRNA) participant in GBC tumorigenesis. A total of 159 differentially expressed miRNAs (DEMs) was identified as exosome-derived miRNAs, contains 34 upregulated exo-DEMs and 125 downregulated exo-DEMs based on the expression profiles in GBC clinical samples downloaded from the Gene Expression Omnibus database with the R package. Among them, 2 up-regulated exo-DEMs, hsa-miR-125a-3p and hsa-miR-4647, and 5 down-regulated exo-DEMs, including hsa-miR-29c-5p, hsa-miR-145a-5p, hsa-miR-192-5p, hsa-miR-194-5p, and hsa-miR-338-3p, were associated with the survival of GBC patients. Results of the gene set enrichment analysis showed that the cell cycle-related pathways were activated in GBC tumor tissues, mainly including cell cycle, M phase, and cell cycle checkpoints. Furthermore, the dysregulated ceRNA network was constructed based on the lncRNA-miRNA-mRNA interactions using miRDB, TargetScan, miRTarBase, miRcode, and starBase v2.0., consisting of 27 lncRNAs, 6 prognostic exo-DEMs, and 176 mRNAs. Together with prognostic exo-DEMs, the STEAP3-AS1/hsa-miR-192-5p/MAD2L1 axis was identified, suggesting lncRNA STEAP3-AS1, might as a sponge of exosome-derived hsa-miR-192-5p, modulates cell cycle progression via affecting MAD2L1 expression in GBC tumorigenesis. In addition, the biological functions of genes in the ceRNA network were also annotated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Our study promotes exploration of the molecular mechanisms associated with tumorigenesis and provide potential targets for GBC diagnosis and treatment.

scholarly journals A Comprehensive Review of Natural Products against Liver Fibrosis: Flavonoids, Quinones, Lignans, Phenols, and Acids

2020 ◽  
Vol 2020 ◽  
pp. 1-19
Author(s):  
Xiaoqi Pan ◽  
Xiao Ma ◽  
Yinxiao Jiang ◽  
Jianxia Wen ◽  
Lian Yang ◽  
...  
Keyword(s):  
Natural Products ◽  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Stellate Cell ◽  
Combined Application ◽  
Heavy Burden ◽  
Ecm Degradation

Liver fibrosis resulting from continuous long-term hepatic damage represents a heavy burden worldwide. Liver fibrosis is recognized as a complicated pathogenic mechanism with extracellular matrix (ECM) accumulation and hepatic stellate cell (HSC) activation. A series of drugs demonstrate significant antifibrotic activity in vitro and in vivo. No specific agents with ideally clinical efficacy for liver fibrosis treatment have been developed. In this review, we summarized the antifibrotic effects and molecular mechanisms of 29 kinds of common natural products. The mechanism of these compounds is correlated with anti-inflammatory, antiapoptotic, and antifibrotic activities. Moreover, parenchymal hepatic cell survival, HSC deactivation, and ECM degradation by interfering with multiple targets and signaling pathways are also involved in the antifibrotic effects of these compounds. However, there remain two bottlenecks for clinical breakthroughs. The low bioavailability of natural products should be improved, and the combined application of two or more compounds should be investigated for more prominent pharmacological effects. In summary, exploration on natural products against liver fibrosis is becoming increasingly extensive. Therefore, natural products are potential resources for the development of agents to treat liver fibrosis.

scholarly journals Estivation-responsive microRNAs in a hypometabolic terrestrial snail

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6515 ◽  
Author(s):  
Myriam P. Hoyeck ◽  
Hanane Hadj-Moussa ◽  
Kenneth B. Storey
Keyword(s):  
Cell Cycle ◽  
Metabolic Rate ◽  
Molecular Mechanisms ◽  
Metabolic Rate Depression ◽  
Strong Reduction ◽  
Term Survival ◽  
Cell Functions ◽  
Cycle Arrest ◽  
Hypometabolic State

When faced with extreme environmental conditions, the milk snail (Otala lactea) enters a state of dormancy known as estivation. This is characterized by a strong reduction in metabolic rate to <30% of normal resting rate that is facilitated by various behavioural, physiological, and molecular mechanisms. Herein, we investigated the regulation of microRNA in the induction of estivation. Changes in the expression levels of 75 highly conserved microRNAs were analysed in snail foot muscle, of which 26 were significantly upregulated during estivation compared with controls. These estivation-responsive microRNAs were linked to cell functions that are crucial for long-term survival in a hypometabolic state including anti-apoptosis, cell-cycle arrest, and maintenance of muscle functionality. Several of the microRNA responses by snail foot muscle also characterize hypometabolism in other species and support the existence of a conserved suite of miRNA responses that regulate environmental stress responsive metabolic rate depression across phylogeny.

scholarly journals The disease of theories: unravelling the mechanisms of pre-eclampsia

2017 ◽  
Vol 39 (1) ◽  
pp. 22-25 ◽  
Author(s):  
Eric M. George
Keyword(s):  
United States ◽  
Cardiovascular Disease ◽  
Premature Birth ◽  
Molecular Mechanisms ◽  
The United States ◽  
Life Meaning ◽  
Increased Risk ◽  
Health Complications ◽  
Developed World

Perhaps no disease of pregnancy has been more thoroughly studied than pre-eclampsia (PE), and yet despite all of our efforts we are only beginning to understand the molecular mechanisms which underpin the disease. Many people are surprised by the frequency of PE in the population, as it is believed to occur in approximately one pregnancy out of 20 in the United States, with similar rates throughout the developed world. In severe cases the disorder can progress to eclampsia, which is characterized by maternal seizures and can lead to death. PE can only be treated by ending the pregnancy, often by inducing labour prior to term, making PE a leading cause of premature birth and all of the associated health complications which accompany it. All in all, PE is one of the leading causes of maternal and fetal morbidity and mortality. It is now also becoming apparent that PE disposes both the mother and the baby to increased risk of cardiovascular disease throughout life, meaning that we still don't fully understand the long-term implications of the disease.

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