scholarly journals Impact of Deoxycholic Acid on Oesophageal Adenocarcinoma Invasion: Effect on Matrix Metalloproteinases

2020 ◽  
Vol 21 (21) ◽  
pp. 8042
Author(s):  
Fran Quilty ◽  
Anne-Marie Byrne ◽  
John Aird ◽  
Sheeren El Mashad ◽  
Adolfo Parra-Blanco ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Deoxycholic Acid ◽  
Therapeutic Strategies ◽  
Oesophageal Adenocarcinoma ◽  
Low Concentrations ◽  
Cancer Invasiveness ◽  
Mrna And Protein Expression

Bile acids (BAs) have been implicated in the development of oesophagitis, Barrett’s oesophagus and oesophageal adenocarcinoma (OAC). However, whether BAs promote cancer invasiveness has not been elucidated. We evaluated the role of BAs, in particular deoxycholic acid (DCA), in OAC invasion. Migration and invasiveness in untreated and BA-treated oesophageal SKGT-4 cancer cells were evaluated. Activity and expression of different matrix metalloproteinases (MMPs) were determined by zymography, ELISA, PCR and Western blot. Finally, human OAC tissues were stained for MMP-10 by immunohistochemistry. It was found that SKGT-4 cells incubated with low concentrations of DCA had a significant increase in invasion. In addition, MMP-10 mRNA and protein expression were also increased in the presence of DCA. MMP-10 was found to be highly expressed both in-vitro and in-vivo in neoplastic OAC cells relative to non-neoplastic squamous epithelial cells. Our results show that DCA promotes OAC invasion and MMP-10 overexpression. This study will advance our understanding of the pathophysiological mechanisms involved in human OAC and shows promise for the development of new therapeutic strategies.

scholarly journals The role of divalent cations in the regulation of microtubule assembly. In vivo studies on microtubules of the heliozoan axopodium using the ionophore A23187.

1976 ◽  
Vol 70 (3) ◽  
pp. 527-540 ◽  
Author(s):  
M Schliwa
Keyword(s):  
Divalent Cations ◽  
Light And Electron Microscopy ◽  
Microtubule Assembly ◽  
In Vivo Studies ◽  
Ionophore A23187 ◽  
Low Concentrations ◽  
Microtubule Formation

Low concentrations of calcium and magnesium ions have been shown to influence microtubule assembly in vitro. To test whether these cations also have an effect on microtubules in vivo, specimens of Actinosphaerium eichhorni were exposed to different concentrations of Ca++ and Mg++ and the divalent cation ionophore A23187. Experimental degradation and reformation of axopodia were studied by light and electron microscopy. In the presence of Ca++ and the ionophore axopodia gradually shorten, the rate of shortening depending on the concentrations of Ca++ and the ionophore used. Retraction of axopodia was observed with a concentration of Ca++ as low as 0.01 mM. After transfer to a Ca++-free solution containing EGTA, axopodia re-extend; the initial length is reached after about 2 h. Likewise, reformation of axopodia of cold-treated organisms is observed only in solutions of EGTA or Mg++, whereas it is completely inhibited in a Ca++ solution. Electron microscope studies demonstrate degradation of the axonemal microtubular array in organisms treated with Ca++ and A23187. No alteration was observed in organisms treated with Mg++ or EGTA plus ionophore. The results suggest that, in the presence of the ionophore, formation of axonemal microtubules can be regulated by varying the Ca++ concentration in the medium. Since A23187 tends to equilibrate the concentrations of divalent cations between external medium and cell interior, it is likely that microtubule formation invivo is influenced by micromolar concentrations of Ca++. These concentrations are low enough to be of physiological significance for a role in the regulation of microtubule assembly in vivo.

scholarly journals CDK12 Promotes Cervical Cancer Progression through Enhancing Macrophage Infiltration

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Bikang Yang ◽  
Jing Chen ◽  
Yincheng Teng
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Therapeutic Target ◽  
Macrophage Infiltration ◽  
Patient Death ◽  
Mrna And Protein Expression ◽  
Underlying Mechanisms

Cervical cancer (CC) is a commonly diagnosed and primary consideration of cancer patient death in female reproductive system malignancy. Cyclin-dependent kinase 12 (CDK12), as a transcription-associated CDK, plays important roles in tumor-promoting behaviors, whereas the underlying mechanisms of CDK12 in CC progression are still obscure. In this report, we investigated the role of CDK12 in cervical cancer. The current study identified CDK12 mRNA and protein expression remarkably upregulated in CC patients. Upregulated CDK12 was closely associated with CC progression and poor prognosis. In vitro and in vivo functional experiments showed that knockdown of CDK12 inhibited cancer cell proliferation and colony formation and promoted apoptosis. Further investigations demonstrated that CDK12 regulated the immune microenvironment to facilitate the progression of CC cells by promoting macrophage infiltration. Meanwhile, we first demonstrated that nuclear import of CDK12 is mediated by TNPO1 and might be a new therapeutic target in oncology. Collectively, this study pointed out the potential of CDK12 to serve as a novel therapeutic target in restricting CC proliferation and cell cycle process through promoting macrophage infiltration.

scholarly journals ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies

2021 ◽  
Vol 8 ◽  
Author(s):  
Lejian Jiang ◽  
Jiachen Lin ◽  
Sen Zhao ◽  
Jiaqian Wu ◽  
Yongming Jin ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Biological Process ◽  
Therapeutic Strategies ◽  
Molecular Signaling ◽  
Biological Functions ◽  
Fundamental Understanding

ADAMTS5 is involved in the pathogenesis of OA. As the major aggrecanase-degrading articular cartilage matrix, ADAMTS5, has been regarded as a potential target for OA treatment. We here provide an updated insight on the regulation of ADAMTS5 and newly discovered therapeutic strategies for OA. Pathophysiological and molecular mechanisms underlying articular inflammation and mechanotransduction, as well as chondrocyte hypertrophy were discussed, and the role of ADAMTS5 in each biological process was reviewed, respectively. Senescence, inheritance, inflammation, and mechanical stress are involved in the overactivation of ADAMTS5, contributing to the pathogenesis of OA. Multiple molecular signaling pathways were observed to modulate ADAMTS5 expression, namely, Runx2, Fgf2, Notch, Wnt, NF-κB, YAP/TAZ, and the other inflammatory signaling pathways. Based on the fundamental understanding of ADAMTS5 in OA pathogenesis, monoclonal antibodies and small molecule inhibitors against ADAMTS5 were developed and proved to be beneficial pre-clinically both in vitro and in vivo. Recent novel RNA therapies demonstrated potentials in OA animal models. To sum up, ADAMTS5 inhibition and its signaling pathway–based modulations showed great potential in future therapeutic strategies for OA.

scholarly journals Dolichol is not a necessary moiety for lipid-linked oligosaccharide substrates of the mannosyltransferases involved in in vitro N-linked-oligosaccharide assembly

1995 ◽  
Vol 310 (3) ◽  
pp. 909-916 ◽  
Author(s):  
I B H Wilson ◽  
M C Webberley ◽  
L Revers ◽  
S L Flitsch
Keyword(s):  
Biosynthetic Pathway ◽  
Substrate Recognition ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
Enzyme Substrate ◽  
Low Concentrations ◽  
Enzyme Substrate Recognition

Dolichol is utilized in vivo as an unusually large anchor on which the precursor for N-linked oligosaccharides is assembled by a series of glycosyltransferases. The role of dolichol in enzyme substrate recognition is investigated. Thus the biosynthetic intermediate NN′-diacetylchitobiose was chemically linked to either dolichol or the much shorter fully saturated tetraisoprenoid phytanol. Both lipids were used as substrates by a recombinant, soluble beta-1,4-mannosyltransferase. beta-[3H]Mannosylated lipids from this reaction were then used as substrates for the subsequent mannosyltransferases from yeast or rat liver microsomes. It was found that both the dolichyl- and phytanyl-linked substrates were easily mannosylated to form Man5GlcNAc2, with some further mannosylation to Man7GlcNAc2 and Man9GlcNAc2 at low concentrations of lipid-linked substrate. It is concluded that dolichol is not necessary in vitro as part of the substrate for the mannosyltransferases in the biosynthetic pathway for N-glycosylation.

scholarly journals Impaired Signaling of NF-κB and NRF2 in CX3CR1-Deficient Microglia: Implications in Tauopathies

2018 ◽  
Author(s):  
Sara Castro-Sánchez ◽  
Ángel J. García-Yagüe ◽  
Sebastian Kügler ◽  
Isabel Lastres-Becker
Keyword(s):  
Transcription Factor ◽  
Tau Protein ◽  
Microglial Activation ◽  
Potential Role ◽  
Early Response ◽  
Therapeutic Strategies ◽  
Low Grade

ABSTRACTTAU protein aggregation is the main characteristic of neurodegenerative diseases known as tauopathies. Low-grade chronic inflammation is also another hallmark that indicates crosstalk between damaged neurons and glial cells. We have demonstrated that neurons overexpressing TAUP301L release CX3CL1, which activates anti-inflammatory NRF2 signalling in microglial cells in vitro and in vivo. However, the potential role of CX3CR1 in the context of tauopathies and its implication in neuroinflammation are poorly described. In this work we show that CX3CL1 activates the pro-inflammatory pathway as an early response mediated by the transcription factor NF-κB through the activation of mitogen-and stress-activated protein kinase-1 (MSK-1). At a functional level, CX3CR1-deficient microglia show decreased expression of NRF2, impaired cell migration and deficiency of phagocytosis. The relevance of these findings is evident in a tauopathy model, where the treatment with an inducer of NRF2, sulforaphane, is able to modulate astrogliosis but not microgliosis. These findings suggest that CX3CR1/NRF2 axis is essential in microglial activation associated with tauopathies and that polymorphisms have to be taken into account to development of therapeutic strategies

scholarly journals In Vivo and In Vitro Hepatoprotective Effects of Geranium koreanum Methanolic Extract via Downregulation of MAPK/Caspase-3 Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Md Rashedunnabi Akanda ◽  
In-Shik Kim ◽  
Dongchoon Ahn ◽  
Hyun-Jin Tae ◽  
Weishun Tian ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Hepg2 Cells ◽  
Caspase 3 ◽  
Hepatoprotective Activity ◽  
Intracellular Ros ◽  
Mrna And Protein Expression ◽  
Serum Biochemical

Geranium koreanum (GK) is an indigenous Chinese herbal medicine widely used for the treatment of various inflammation and liver disorders. However, the exact mechanism of action of GK remains unknown. This study aimed to investigate the protective effect and related molecular mechanism of GK on NaAsO2-induced cytotoxicity in HepG2 cells and liver damage in mice. The cytoprotective role of GK was assessed on HepG2 cells using MTT assay. Oxidative stress and lactate dehydrogenase levels were measured with ROS and LDH assay. Histopathology and serum enzymes levels were estimated. The molecular mechanism was evaluated by qPCR and immunoblotting to ensure the hepatoprotective role of GK against NaAsO2 intoxication in mice. We found cotreatment with GK significantly attenuated NaAsO2-induced cell viability loss, intracellular ROS, and LDH release. Hepatic histopathology and serum biochemical parameters, ALT, and AST were notably improved by cotreatment with GK. Beside, GK markedly altered both mRNA and protein expression level of MAPK. The proapoptotic and antiapoptotic protein Bax/Bcl-2 ratio was significantly regulated by GK. Moreover, GK remarkably suppressed the postapoptotic transcription protein cleaved caspase-3 expression. The present study reveals that GK possesses hepatoprotective activity which is probably involved in the modulation of the MAPK/caspase-3 pathway.

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