scholarly journals A Potential Nutraceutical Candidate Lactucin Inhibits Adipogenesis through Downregulation of JAK2/STAT3 Signaling Pathway-Mediated Mitotic Clonal Expansion

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 331 ◽  
Author(s):  
Xin Wang ◽  
Min Liu ◽  
Guo He Cai ◽  
Yan Chen ◽  
Xiao Chen Shi ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Early Stage ◽  
Lipid Synthesis ◽  
Clonal Expansion ◽  
Inhibitory Effect ◽  
Limiting Factor ◽  
Stat3 Signaling Pathway ◽  
Mitotic Clonal Expansion

The prevalence of obesity has increased dramatically worldwide in the past ~50 years. Searching for safe and effective anti-obesity strategies are urgently needed. Lactucin, a plant-derived natural small molecule, is known for anti-malaria and anti-hyperalgesia. The study is to investigate whether lactucin plays a key role in adipogenesis. To this end, in vivo male C57BL/6 mice fed a high-fat diet (HFD) were treated with 20 mg/kg/day of lactucin or vehicle by gavage for seven weeks. Compared with vehicle-treated controls, Lactucin-treated mice showed lower body mass and mass of adipose tissue. Consistently, in vitro 3T3-L1 cells were treated with 20 μM of lactucin. Compared to controls, lactucin-treated cells showed significantly less lipid accumulation during adipocyte differentiation and lower levels of lipid synthesis markers. Mechanistically, we showed the anti-adipogenic property of lactucin was largely limited to the early stage of adipogenesis. Lactucin-treated cells fail to undergo mitotic clonal expansion (MCE). Further studies demonstrate that lactucin-induced MCE arrests might result from reduced phosphorylation of JAK2 and STAT3. We then asked whether activation of JAK2/STAT3 would restore the inhibitory effect of lactucin on adipogenesis with pharmacological STAT3 activator colivelin. Our results revealed similar levels of lipid accumulation between lactucin-treated cells and controls in the presence of colivelin, indicating that inactivation of STAT3 is the limiting factor for the anti-adipogenesis of lactucin in these cells. Together, our results provide the indication that lactucin exerts an anti-adipogenesis effect, which may open new therapeutic options for obesity.

scholarly journals 905 FASN prevents immunogenicity of irradiated glioblastoma by inhibiting ER stress

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A950-A950
Author(s):  
Mara De Martino ◽  
Camille Daviaud ◽  
Claire Vanpouille-Box
Keyword(s):  
Er Stress ◽  
Lipid Accumulation ◽  
Fatty Acid Synthase ◽  
Immune Escape ◽  
De Novo ◽  
Lipid Synthesis ◽  
Adult Brain ◽  
Immune Recognition

BackgroundGlioblastoma (GBM) is the most aggressive and incurable adult brain tumor. Radiation therapy (RT) is an essential modality for GBM treatment and is recognized to stimulate anti-tumor immunity by inducing immunogenic cell death (ICD) subsequent to endoplasmic reticulum (ER) stress. However, RT also exacerbates potent immunosuppressive mechanisms that facilitate immune evasion. Notably, increased de novo lipid synthesis by the fatty acid synthase (FASN) is emerging as a mechanism of therapy resistance and immune escape. Here, we hypothesize that RT induces FASN to promote GBM survival and evade immune recognition by inhibiting ER stress and ICD.MethodsTo determine if lipid synthesis is altered in response to RT, we first assessed FASN expression by western blot (WB) and lipid accumulation by BODIPY staining in murine (CT2A and GL261) and human (U118) GBM cell lines. Next, FASN expression was blocked in CT2A cells using CRISPR-Cas9 or an inducible shRNA directed against Fasn to evaluate ICD and ER stress markers by ELISA, WB, and electron microscopy. Finally, CT2AshFASN cells or its non-silencing control (CT2AshNS) were orthotopically implanted and FASN knockdown was induced by feeding the mice with doxycycline. The immune contexture was determined by in situ immunofluorescence (n=3/group). Remaining mice were followed for survival (n=7/group).ResultsWe found that in vitro irradiation of GBM cells induces lipid accumulation in a dose-dependent fashion; an effect that is magnified over time lasting at least 6/7 days. Consistent with these findings, FASN expression was upregulated in irradiated GBM cells. Confirming the role of FASN, RT-induced accumulation of lipids was reverted when GBM cells were incubated with a FASN inhibitor. Next, we found that FASN ablation in CT2A cells induces mitochondria disruption and was sufficient to increase the expression of the ER stress makers BIP and CHOP. Along similar lines, shFASN enhances the secretion of the ICD markers HMGB1, IFN-beta and CXCL10 in irradiated CT2A cells. In vivo, CT2AshFASN tumors presented increased infiltration of CD11c+ cells and CD8+ T cells, consistent with prolonged mice survival (56 days vs. 28 days for CT2AshNS). Importantly, 43% of CT2AshFASN-bearing mice remained tumor-free for more than 70 days, while none of the CT2AshNS-bearing mice survived.ConclusionsAltogether, our data suggest that FASN-mediated lipid synthesis is an important mechanism to prevent ER stress, ICD, and anti-tumor immune responses in GBM. While much work remains to be done, our data propose FASN as a novel therapeutic target to overcome immunosuppression and sensitize GBM to immunotherapies.

scholarly journals Inhibitory Effect of Dihydroartemisinin on the Proliferation and Migration of Melanoma Cells and Experimental Lung Metastasis From Melanoma in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Qi Zhang ◽  
Linbo Jin ◽  
Quanxin Jin ◽  
Qiang Wei ◽  
Mingyuan Sun ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Early Stage ◽  
Metastatic Tumor ◽  
Treg Cells ◽  
Inhibitory Effect ◽  
B16f10 Cells ◽  
And Migration ◽  
Migration Capacity

Melanoma is aggressive and can metastasize in the early stage of tumor. It has been proved that dihydroartemisinin (DHA) positively affects the treatment of tumors and has no apparent toxic and side effects. Our previous research has shown that DHA can suppress the formation of melanoma. However, it remains poorly established how DHA impacts the invasion and metastasis of melanoma. In this study, B16F10 and A375 cell lines and metastatic tumor models will be used to investigate the effects of DHA. The present results demonstrated that DHA inhibited the proliferative capacity in A375 and B16F10 cells. As expected, the migration capacity of A375 and B16F10 cells was also reduced after DHA administration. DHA alleviated the severity and histopathological changes of melanoma in mice. DHA induced expansion of CD8+CTL in the tumor microenvironment. By contrast, DHA inhibited Treg cells infiltration into the tumor microenvironment. DHA enhanced apoptosis of melanoma by regulating FasL expression and Granzyme B secretion in CD8+CTLs. Moreover, DHA impacts STAT3-induced EMT and MMPS in tumor tissue. Furthermore, Metabolomics analysis indicated that PGD2 and EPA significantly increased after DHA administration. In conclusion, DHA inhibited the proliferation, migration and metastasis of melanoma in vitro and in vivo. These results have important implications for the potential use of DHA in the treatment of melanoma in humans.

scholarly journals Lignan from Alnus japonica Inhibits Adipocyte Differentiation via Cell Cycle and FOXO1 Regulation

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3346
Author(s):  
Hyejin Lee ◽  
Ji Hye Jeong ◽  
Jae-Ha Ryu
Keyword(s):  
Cell Cycle ◽  
Adipocyte Differentiation ◽  
Early Stage ◽  
Inhibitory Effect ◽  
Alnus Japonica ◽  
Akt Phosphorylation ◽  
Cycle Arrest ◽  
Forkhead Box ◽  
Mitotic Clonal Expansion

In the present study, we isolated a lignan ((−)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol, DFS) from Alnus japonica and evaluated its antiobesity potential in vitro. We also determined its mechanism of action in a mouse pre-adipocyte 3T3-L1 cell line. DFS dose- and day-dependently inhibited adipogenesis by downregulation of adipogenic factors and lipid metabolism-regulating factors during adipocyte differentiation. In particular, DFS suppressed cell cycle-regulating factors and induced G0/G1 cell cycle arrest, implying that it had an inhibitory effect on mitotic clonal expansion which occurred at an early stage of adipogenesis. DFS also suppressed adipogenesis through decreasing Akt phosphorylation and increasing the level of Forkhead box protein-O1 (FOXO1). These results suggest that DFS may be a pharmacological candidate for the development of antiobesity, therapeutic, and nutraceutical products.

scholarly journals Rohitukine inhibits in vitro adipogenesis arresting mitotic clonal expansion and improves dyslipidemia in vivo

2014 ◽  
Vol 55 (6) ◽  
pp. 1019-1032 ◽  
Author(s):  
Salil Varshney ◽  
Kripa Shankar ◽  
Muheeb Beg ◽  
Vishal M. Balaramnavar ◽  
Sunil Kumar Mishra ◽  
...  
Keyword(s):  
Clonal Expansion ◽  
Mitotic Clonal Expansion

scholarly journals The Effect of Growth Hormone on Lipid Accumulation or Maturation in Adipocytes

2016 ◽  
Vol 39 (6) ◽  
pp. 2135-2148 ◽  
Author(s):  
Yuchao Zhang ◽  
Hongsheng Yu ◽  
Peng Gao ◽  
Jicui Chen ◽  
Cong Yu ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cdna Microarray ◽  
Lipid Accumulation ◽  
Lipid Synthesis ◽  
Epididymal Adipose Tissue ◽  
Gh Treatment ◽  
Gh Secretion ◽  
Expression Of Genes

Background: Adipogenesis of adipocytes includes two stages: initiation and maturation. Growth hormone (GH) secretion is decreased in obese subjects and GH levels are inversely correlated with abdominal fat mass. The effects of growth hormone (GH) on lipids accumulation or maturation of adipocytes remains elusive. Methods: In the present study, effect of GH on lipid accumulation in vitro and in vivo was examined. cDNA microarray, quantitative real time-PCR (qPCR) and western blotting was used to analyze the expression of genes related to adipocyte lipid accumulation or degradation in pre- or mature 3T3-F442A adipocytes treated with GH and in epididymal adipose tissue of C57BL/6 mice administrated with GH. Level of adiponectin in supernatants of cultured F442A adipocytes was determined by enzyme-linked immune-sorbent assay. Results: We found that in 3T3-F442A especially 6 days post initiation of adipogenesis, GH intervention resulted in decreased expression of adipocyte maturation regulators (C/EBPα, PPARγ) and prominent genes related to lipid synthesis such as FAS and FABP, while the expression of UCP1 was markedly enhanced. cDNA microarray analysis and qPCR showed that the expression of SOCS2 and Adipor2 was increased under GH-treatment in mature 3T3-F442A adipocytes. GH treatment increased the mRNA expression of adiponectin and UCP1 in mature adipocytes. The above results were confirmed by in vivo study. Conclusions: GH potentially negatively modulates the maturation and accumulation of lipid in adipocytes.

scholarly journals In Vitro Effects of Five Different Classes of Fungicides on Growth and Development of Botrytis cinerea Isolated from Tree Peony in China

HortScience ◽  
2019 ◽  
Vol 54 (11) ◽  
pp. 1984-1988 ◽  
Author(s):  
Yuee Tian ◽  
Zhiping Che ◽  
Di Sun ◽  
Jiaxuan He ◽  
Shengming Liu ◽  
...  
Keyword(s):  
Botrytis Cinerea ◽  
Germ Tube ◽  
Early Stage ◽  
Petri Dish ◽  
Inhibitory Effect ◽  
Limiting Factor ◽  
Tree Peony ◽  
Disease Occurrence ◽  
Germ Tube Elongation

Gray mold caused by Botrytis cinerea has become an important limiting factor for tree peony production. Currently, chemical control is still the main means of managing the disease in China. The objective of this study was to test fungicides with different mechanisms of action in controlling B. cinerea on tree peony. The inhibitory efficacy of five fungicides on four asexual stages was measured in the petri dish containing culture medium amended with a tested fungicide at various concentrations. The results showed that carbendazim had the strongest inhibition effect against all four stages of B. cinerea, with the EC50 values of 0.1037, 0.0563, 0.5578, and 0.0797 mg·L–1, respectively. The inhibitory effect of diethofencarb was only slightly less than that of carbendazim on conidia production, germination, and germ tube elongation. The inhibitory effect of procymidone was second only to that of carbendazim on colony expansion. The results indicated that carbendazim and diethofencarb could be used as protective fungicides to spray in the early stage of disease occurrence to inhibit conidia germination and germ tube elongation, so as to reduce the infection rate of B. cinerea and prevent disease occurrence. Carbendazim, procymidone, and diethofencarb mainly inhibit the reinfection of B. cinerea by inhibiting the growth of mycelium and the production of conidia, so they could be used as control fungicides during the occurrence phase of the disease.

118 ARE LIPID CONTENTS AND APOPTOSIS DETERMINANTS OF IN VITRO-PRODUCED BOVINE EMBRYO SUSCEPTIBILITY TO VITRIFICATION?

2010 ◽  
Vol 22 (1) ◽  
pp. 217 ◽  
Author(s):  
M. J. Sudano ◽  
D. M. Paschoal ◽  
L. C. O. Magalhães ◽  
L. F. Crocomo ◽  
F. D. Landim-Alvarenga
Keyword(s):  
Lipid Accumulation ◽  
Lipid Droplets ◽  
Calf Serum ◽  
Limiting Factor ◽  
Bovine Embryo ◽  
Apoptotic Cells ◽  
Blastocyst Formation ◽  
Fresh Embryos

Supplementation of fetal calf serum (FCS) during culture of bovine in vitro-produced embryos (IVPE) has been correlated with lipid accumulation, representing a limiting factor on embryo cryotolerance. In the present experiment we studied lipid content and apoptosis in Nelore IVPE cultured in different concentrations of FCS. The experimental design was a 4 × 2 × 2 factorial, in which embryos, exposed or not to the metabolic regulator, phenazine ethosulfate (PES), were cultured in 4 concentrations of FCS. In 16 replicates, 560 IVPE were vitrified after cultured in SOFaa supplemented with 0, 2.5, 5 or 10% FCS. On Day 2.5 of culture, one-half of the embryos in each group were treated with 0.3 μM of PES and then returned to standard culture conditions (5% O2, 5% CO2 and 90% N2 atmosphere at 38.5°C). All embryos were vitrified on Day 7 (Campos-Chillòn LF et al. 2006 Theriogenology 65, 1200-1214). After warming, embryos were placed into culture for 12 h under standard conditions. A sample of fresh embryos was stained with Sudan Black B for quantification of small (<2 μm), medium (2-6 μm), and large (>6 μm) cytoplasmic lipid droplets. Apoptosis was analyzed, before and after vitrification, using TUNEL. As a positive control (CV), in vivo-produced embryos were collected from a superovulated Nelore cow. Data were analyzed using ANOVA followed by Tukey’s test; and Pearson’s linear correlation (P < 0.05). The results indicate that FCS concentration and PES treatment had no influence (P > 0.05) on cleavage and blastocyst formation rates (mean of 85.7 ± 2 and 36.6 ± 5, respectively). The total number of cells in fresh embryos was also similar (P > 0.05) among groups (mean of 134.1 ± 28). Additional results are shown in Table 1. Elevated concentrations of FCS increased lipid accumulation (r = 0.9) and the percentage of apoptotic cells in fresh and vitrified embryos, reducing the re-expansion rate after warming. Moreover, the number of apoptotic cells observed in fresh embryos was strongly correlated with the apoptosis observed after vitrification (r = 0.95). Although PES was able to reduce lipid accumulation, it was not efficient at preventing apoptosis in vitrified embryos. In summary, the results of this experiment indicate that the concentration of FCS during culture did not influence cleavage and blastocyst formation in bovine IVPE. We conclude that the apoptosis rate in fresh embryos is a key factor affecting survival after vitrification. Table 1.Lipid droplets, re-expansion, apoptosis of in vivo and IVPE Acknowledgements: FAPESP (07/57766-4).

scholarly journals Tamoxifen Protects from Vesicular Stomatitis Virus Infection

2019 ◽  
Vol 12 (4) ◽  
pp. 142 ◽  
Author(s):  
Lamin B. Cham ◽  
Sarah-Kim Friedrich ◽  
Tom Adomati ◽  
Hilal Bhat ◽  
Maximilian Schiller ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Vesicular Stomatitis Virus ◽  
Early Stage ◽  
Vero Cells ◽  
Inhibitory Effect ◽  
Virus Infections ◽  
Biological Targets ◽  
Vesicular Stomatitis

Background: Tamoxifen (TAM) is an estrogen-receptor antagonist, widely used in the adjuvant treatment of early stage estrogen-sensitive breast cancer. Several studies have revealed new biological targets of TAM that mediate the estrogen receptor independent activities of the drug. Recently, the antiviral activity of TAM on replication of human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Herpes simplex virus (HSV-1) in vitro was described. In the current study, we aimed to investigate the effect of TAM on infection with vesicular stomatitis virus (VSV). Methods: Vero cells were treated with different concentrations of TAM for 24 h and then infected with VSV. Additionally, C57BL/6 mice were pretreated with 4 mg TAM, one day and three days before infection with VSV. Results: Treatment of Vero cells with TAM suppressed the viral replication of VSV in vitro and in vivo. The inhibitory effect of TAM on VSV replication correlated with an enhanced interferon-I response and stimulation of macrophages. Conclusions: TAM was identified as being capable to protect from VSV infection in vitro and in vivo. Consequently, this antiviral function (as an advantageous side-effect of TAM) might give rise to new clinical applications, such as treatment of resistant virus infections, or serve as an add-on to standard antiviral therapy.

scholarly journals Aromatisation of steroids in the bivalve Mytilus trossulus

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6953 ◽  
Author(s):  
Anna Hallmann ◽  
Lucyna Konieczna ◽  
Justyna Swiezak ◽  
Ryszard Milczarek ◽  
Katarzyna Smolarz
Keyword(s):  
Mitochondrial Fraction ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Limiting Factor ◽  
Mytilus Trossulus ◽  
Mitochondrial Fractions ◽  
Estrogen Synthesis ◽  
Enzymatic Complex

In this study, we demonstrated the presence of the enzymatic complex able to perform aromatization (estrogen synthesis) in both, the microsomal and mitochondrial fractions of gills and gonads from Mytilus trossulus. Based on in vitro experiments, we highlighted the importance of temperature as the limiting factor of aromatisation efficiency (AE) in mussels. After testing range of temperatures (4–23 °C), the highest AE was found during incubation at 8 °C and pH 7.6 (41.66 pmol/h/mg protein in gills and 58.37 pmol/h/mg protein in gonads). The results were confirmed during field studies where the most efficient aromatisation occurred in bivalves collected in spring while the least effective in those collected in winter. During in vitro studies, AE turned out to be more intensive in female gonads than in male gonads. The process was also more intensive in mitochondrial fraction than in microsomal one (62.97 pmol/h/mg protein in male gills and 73.94 pmol/h/mg protein in female gonads). Enzymatic complex (aromatase-like enzyme) catalysing aromatisation in mussels was found to be insensitive to inhibitory effect of selective inhibitors of mammalian aromatase such as letrozole and anastrazole, suggesting its different structure from vertebrate aromatase. Further in vivo studies using 13C-labeled steroids at 8 °C temperature window confirmed that bivalves are able to uptake testosterone and androstenedione from the ambient environment and metabolise them to estrone and 17β-estradiol thus confirming endogenous estrogen’ synthesis.

Cytological changes induced by platinum-thymine in sarcoma-180 cells: Electron microscopy study

1990 ◽  
Vol 48 (3) ◽  
pp. 290-291
Author(s):  
Gustav Ofosu
Keyword(s):  
Mammalian Cells ◽  
Antitumor Agent ◽  
Microscopy Study ◽  
Electron Microscopy Study ◽  
Limiting Factor ◽  
Sarcoma 180 ◽  
Electron Microscopic ◽  
Cytological Changes

Platinum-thymine has been found to be a potent antitumor agent, which is quite soluble in water, and lack nephrotoxicity as the dose-limiting factor. The drug has been shown to interact with DNA and inhibits DNA, RNA and protein synthesis in mammalian cells in vitro. This investigation was undertaken to elucidate the cytotoxic effects of piatinum-thymine on sarcoma-180 cells in vitro ultrastructurally, Sarcoma-180 tumor bearing mice were treated with intraperitoneal injection of platinum-thymine 40mg/kg. A concentration of 60μg/ml dose of platinum-thymine was used in in vitro experiments. Treatments were at varying time intervals of 3, 7 and 21 days for in vivo experiments, and 30, 60 and 120 min., 6, 12, and 24th in vitro. Controls were not treated with platinum-thymine.Electron microscopic analyses of the treated cells in vivo and in vitro showed drastic cytotoxic effect.

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