scholarly journals Differential MMP-14 Targeting by Lumican-Derived Peptides Unraveled by In Silico Approach

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4930
Author(s):  
Jonathan Dauvé ◽  
Nicolas Belloy ◽  
Romain Rivet ◽  
Nicolas Etique ◽  
Pierre Nizet ◽  
...  
Keyword(s):  
Amino Acids ◽  
In Silico ◽  
Primary Melanoma ◽  
Direct Interaction ◽  
Inhibitory Effect ◽  
Melanoma Tumor ◽  
And Migration ◽  
Key Residues

Lumican, a small leucine-rich proteoglycan (SLRP) of the extracellular matrix (ECM), displays anti-tumor properties through its direct interaction with MMP-14. Lumican-derived peptides, such as lumcorin (17 amino acids) or L9M (10 amino acids), are able to inhibit the proteolytic activity of MMP-14 and melanoma progression. This work aimed to visualize the interactions of lumican-derived peptides and MMP-14. Molecular modeling was used to characterize the interactions between lumican-derived peptides, such as lumcorin, L9M, and cyclic L9M (L9Mc, 12 amino acids), and MMP-14. The interaction of L9Mc with MMP-14 was preferential with the MT-Loop domain while lumcorin interacted more with the catalytic site. Key residues in the MMP-14 amino acid sequence were highlighted for the interaction between the inhibitory SLRP-derived peptides and MMP-14. In order to validate the in silico data, MMP-14 activity and migration assays were performed using murine B16F1 and human HT-144 melanoma cells. In contrast to the HT-144 melanoma cell line, L9Mc significantly inhibited the migration of B16F1 cells and the activity of MMP-14 but with less efficacy than lumican and lumcorin. L9Mc significantly inhibited the proliferation of B16F1 but not of HT-144 cells in vitro and primary melanoma tumor growth in vivo. Thus, the site of interaction between the domains of MMP-14 and lumcorin or L9Mc were different, which might explain the differences in the inhibitory effect of MMP-14 activity. Altogether, the biological assays validated the prediction of the in silico study. Possible and feasible improvements include molecular dynamics results.

scholarly journals Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation

2021 ◽  
Vol 22 (11) ◽  
pp. 5602
Author(s):  
Hyeon Young Park ◽  
Mi-Jin Kim ◽  
Seunghyeong Lee ◽  
Jonghwa Jin ◽  
Sungwoo Lee ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Metabolic Reprogramming ◽  
Neointima Formation ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
And Migration ◽  
Proliferation And Migration

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.

scholarly journals Studies on Analogues of L-Cysteine and L-Cystine

Blood ◽  
1956 ◽  
Vol 11 (1) ◽  
pp. 1-10 ◽  
Author(s):  
AUSTIN S. WEISBERGER ◽  
LEIF G. SUHRLAND ◽  
JOSEPH SEIFTER
Keyword(s):  
Amino Acids ◽  
Spatial Configuration ◽  
Spatial Relationship ◽  
Inhibitory Effect ◽  
Selenium Compounds ◽  
Low Concentrations ◽  
Relationship Of ◽  
Normal Cellular Function

Abstract The amino acids L-cysteine and L-cystine appear to have an important role in the metabolism of leukocytes. Decreased availability of these amino acids may therefore have important effects on leukocytes. The possibility of decreasing the influx of radioactive L-cystine into leukemic leukocytes was investigated by exposing the leukocytes to various analogues of cysteine (cystine) prior to incubation with S35 L-cystine. It was found that a highly specific structural and spatial configuration is required to decrease the influx of S35 L-cystine. Thus unlabeled L-cysteine is effective in decreasing the incorporation of radioactive L-cystine. However, analogues of cystine in which there is modification or substitution of the sulfhydryl, amino or carboxyl group do not decrease the influx of S35 L-cystine. Furthermore, any alteration in the spatial relationship of the sulfhydryl and amino groups of L-cysteine also results in a loss of the ability of an analogue to decrease the incorporation of S35 L-cystine. Of the compounds studied and in the concentrations employed, only unlabeled L-cysteine, selenium cystine and phenyl selenium cysteine were effective. Selenium cystine is identical with cystine except that selenium replaces the sulfur in the molecule. Phenyl selenium cysteine is also closely related structurally to cysteine. The mechanism of action of selenium cystine and phenyl selenium cysteine in decreasing the influx of S35 L-cystine is not known. Other selenium compounds tested were ineffective. These compounds may exert their inhibitory effect by (a) competitive combination with specific intracellular receptors for L-cysteine (L-cystine), (b) inactivation of enzymes or compounds essential for normal cellular function, (c) alteration in membrane permeability or (d) a toxic effect of selenium. Since selenium cystine and phenyl selenium cystine are inhibitory in low concentrations in vitro, these compounds may have important effects on leukemic leukocytes in vivo.

scholarly journals MTA1-Dependent Anticancer Activity of Gnetin C in Prostate Cancer

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2096 ◽  
Author(s):  
Avinash Kumar ◽  
Kshiti Dholakia ◽  
Gabriela Sikorska ◽  
Luis A. Martinez ◽  
Anait S. Levenson
Keyword(s):  
Prostate Cancer ◽  
Intraepithelial Neoplasia ◽  
Inhibitory Effect ◽  
Tumor Aggressiveness ◽  
Therapeutic Approaches ◽  
Anticancer Efficacy ◽  
Anticancer Effects ◽  
And Migration

The overexpression of metastasis-associated protein 1 (MTA1) in prostate cancer (PCa) contributes to tumor aggressiveness and metastasis. We have reported the inhibition of MTA1 by resveratrol and its potent analog pterostilbene in vitro and in vivo. We have demonstrated that pterostilbene treatment blocks the progression of prostatic intraepithelial neoplasia and adenocarcinoma in mouse models by inhibiting MTA1 expression and signaling. In the current study, we investigated the MTA1 targeted anticancer effects of Gnetin C, a resveratrol dimer, in comparison with resveratrol and pterostilbene. Using DU145 and PC3M PCa cells, we found that Gnetin C downregulates MTA1 more potently than resveratrol and pterostilbene. Further, Gnetin C demonstrated significant MTA1-mediated inhibitory effect on cell viability, colony formation, and migration, while showing a more potent induction of cell death than resveratrol or pterostilbene. In addition, we identified Gnetin C-induced substantial ETS2 (erythroblastosis E26 transformation-specific 2) downregulation, which is not only MTA1-dependent, but is also independent of MTA1 as a possible mechanism for the superior anticancer efficacy of Gnetin C in PCa. Together, these findings underscore the importance of novel potent resveratrol dimer, Gnetin C, as a clinically promising agent for the future development of chemopreventive and possibly combinatorial therapeutic approaches in PCa.

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 Cocoa (Theobroma cacao L.) Seed Proteins’ Anti-Obesity Potential through Lipase Inhibition Using In Silico, In Vitro and In Vivo Models

Foods ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 1359
Author(s):  
Luis Jorge Coronado-Cáceres ◽  
Griselda Rabadán-Chávez ◽  
Luis Mojica ◽  
Blanca Hernández-Ledesma ◽  
Lucía Quevedo-Corona ◽  
...  
Keyword(s):  
In Silico ◽  
Seed Proteins ◽  
Inhibitory Effect ◽  
Mean Value ◽  
Intragastric Administration ◽  
Degree Of Hydrolysis ◽  
In Vivo Models ◽  
Hydrolysis Of

The aim of this study was to determine the pancreatic lipase (PL) inhibitory effect of cocoa protein (CP) hydrolysates (CPH) using in silico and in vitro approaches, and an in vivo high-fat diet (HF) obese rat model. The results showed better theoretical affinity on PL for cocoa peptides EEQR, GGER, QTGVQ, and VSTDVNIE released from vicilin and albumins (−6.5, −6.3, −6.2, and −6.1 kcal/mol, respectively). Absorption, distribution, metabolism, and excretion (ADMET) prediction showed the human intestinal absorption (HIA) capacity of orlistat and eight cocoa peptides, demonstrating that they presented a low probability of toxicity with values lower than 0.6, while the orlistat has a high probability of hepatotoxicity with a mean value of 0.9. CPH (degree of hydrolysis of 55%) inhibited PL with an IC50 (concentration needed to inhibit 50% of enzyme activity) value of 1.38 mg/mL. The intragastric administration of 150 mg CP/kg/day to rats increased total lipids and triglycerides excretion in feces, ranging from 11% to 15% compared to the HF-diet. The HF + CP-diet also significantly decreased (p < 0.05) the apparent rate of fat absorption compared with the HF group. These results suggest that CP has anti-obesity potential by inhibiting PL, thus helping to prevent the development of non-communicable diseases.

scholarly journals LCZ696 Attenuated Doxorubicin-Induced Chronic Cardiomyopathy Through the TLR2-MyD88 Complex Formation

2021 ◽  
Vol 9 ◽  
Author(s):  
Shiju Ye ◽  
Lan Su ◽  
Peiren Shan ◽  
Bozhi Ye ◽  
Shengjie Wu ◽  
...  
Keyword(s):  
Heart Function ◽  
Cardiac Injury ◽  
Direct Interaction ◽  
Protective Role ◽  
Ligand Interaction ◽  
Computational Docking ◽  
Heart Damage ◽  
Key Residues

Background and PurposeThe profibrotic and proinflammatory effects induced by doxorubicin (DOX) are key processes in the development of serious heart damage. Lack of effective drugs and the unclear mechanisms of its side effects limit the clinical treatment of DOX-induced cardiac injury. This study aimed to explore the protective role of LCZ696 and the potential mechanism of Toll-like receptor 2 (TLR2) in doxorubicin-induced cardiac failure.Experimental ApproachDOX (5 mg/kg/week, three times) was used to establish a chronic cardiomyopathy mouse model. Heart function tests, pathology examinations and molecular biology analyses were used to explore the effects of LCZ696 and TLR2 deficiency in vivo and in vitro. Computational docking was applied to predict the key residues for protein-ligand interaction.Key ResultsThe EF% declined, and the LVIDd, pro-fibrosis marker levels and NF-κB related inflammatory response increased in the chronic cardiomyopathy group induced by DOX. LCZ696 treatment and TLR2 deficiency reversed these heart damage in vivo. In H9C2 cells, pre-treatment with LCZ696 and TLR2 knockdown suppressed the DOX-induced high expression of profibrotic and proinflammatory markers. Moreover, DOX notably increased the TLR2-MyD88 interaction in vivo and in vitro, which was inhibited by LCZ696. Finally, we demonstrated the direct interaction between DOX and TLR2 via hydrogen bonds on Pro-681 and Glu-727 and Pro-681 and Ser-704 may be the key residues by which LCZ696 affects the interaction between DOX and TLR2.Conclusion and ImplicationsLCZ696 prevents DOX-induced cardiac dilation failure, fibrosis and inflammation by reducing the formation of TLR2-MyD88 complexes. LZC696 may be a potential effective drug to treat DOX-induced heart failure.

scholarly journals WISP2 promotes cell proliferation via targeting ERK and YAP in ovarian cancer cells

2020 ◽  
Author(s):  
Zi-Qing Shi ◽  
Zi-Yan Chen ◽  
Yao Han ◽  
Heng-Yan Zhu ◽  
Meng-Dan Lyu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Ovarian Cancer Cells ◽  
Extracellular Signal ◽  
And Migration

Abstract Background: Wnt-inducible signaling pathway protein 2 (WISP2) is a wnt1-induced signaling pathway protein 2. Although studies indicate that WISP2 may promote the development of various tumors, its role in ovarian cancer remains unclear. The objective of the current study was to analyze the effects of WISP2 on the proliferation and migration of ovarian cancer cells in vitro and in vivo.Results: Immunohistochemistry and western blotting indicated that WISP2 was highly expressed in various ovarian cancer tissues and cell lines，but weakly expressed in normal ovary tissue. WISP2 deletion inhibited cell growth, clone formation, and migration of ovarian cancer cells while promoting cell apoptosis and affecting the cell cycle. This growth inhibitory effect caused by WISP2 loss is due to the inhibition of phosphorylated extracellular signal-related kinase (p-ERK)1/2, as well as CCAAT/enhancer-binding protein α (CEBPα) and CEPBβ. In addition, WISP2 deletion also activated the Yes-associated protein (YAP).Conclusion: WISP2 deletion inhibits ovarian cancer cell proliferation by affecting ERK signaling pathways.

scholarly journals WISP2 promotes cell proliferation via targeting ERK and YAP in ovarian cancer cells

2020 ◽  
Author(s):  
Zi-Qing Shi ◽  
Zi-Yan Chen ◽  
Yao Han ◽  
Heng-Yan Zhu ◽  
Meng-Dan Lyu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Inhibitory Effect ◽  
Ovarian Cancer Cells ◽  
Growth Inhibitory ◽  
Extracellular Signal ◽  
And Migration

Abstract Background Wnt inducible signaling protein 2 (WISP2) is a wnt1-induced signaling pathway protein 2. Although studies indicate that WISP2 may promote the development of various tumors, its role in ovarian cancer remains unclear. The objective of the current study was to analyze the effects of WISP2 on proliferation and migration of ovarian cancer cells in vitro and in vivo . Results Immunohistochemistry and western blot results indicated that WISP2 was highly expressed in various ovarian tissues and cell lines. WISP2 deletion inhibited cell growth, clone formation, and migration of ovarian cancer cells. WISP2 deletion promoted cell apoptosis and affected the cell cycle. This growth inhibitory effect caused by WISP2 loss is due to the inhibition of extracellular signal-related kinase (p-ERK)1/2, as well as CEBPα and CEBPβ. In addition, WISP2 deletion also activated the Yes-associated protein (YAP). Conclusion WISP2 deletion inhibits ovarian cancer cell proliferation by affecting ERK signaling pathways.

Endophytic Fungi Penicillium species BCt Phytochemicals Inhibit Replication of Enzymes of Human Immuno-deficiency Virus 1 in in vitro and in silico Studies

2021 ◽  
Vol 14 (5) ◽  
pp. 5624-5633
Author(s):  
Govindappa M ◽  
Channabasava ◽  
Ritu Pawar ◽  
Chandrasekhar Srinivasa ◽  
Chandan Shivamallu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Endophytic Fungi ◽  
In Silico ◽  
Methanol Extract ◽  
Penicillium Species ◽  
Ms Analysis ◽  
In Silico Studies ◽  
Hiv 1

The present investigation was aimed to know the coumarins in the methanol extract of endophytic fungi, Penicillium species BCt isolated from Calophyllum tomentosum bark tissues using qualitative and GC-MS analysis. The endophytic extract was evaluated for anti-HIV activity on three replicating enzymes in vitro and in silico. The methanol extract of Penicillium species confirmed the presence of coumarins in four qualitative methods and yielded four different types of coumarins in GC-MS. In GC-MS analysis, totally seven different phytochemicals were identified based on retention time and compared with available library data. The four coumarins are coumarin (2H-1-benzopyran-2-one), coumaric acid (3-benzofuran-carboxylic acid), hynecromone (coumarin 4), 4-hydroxy-9-(3-methyl-2-butyl) furo (3,2-g) chloronen-7-one) and other three are common phytochemicals. The HIV-1 RT (98) was strongly inhibited by the endophytic fungal extract compared to integrase (118) and protease (158) in vitro analysis. Highest inhibition of integrase was observed with coumarilic acid (-17.62) when attached to Glu-35, Asn-38, Ser-39 amino acids. The protease was inhibited strongly by hymecromone (-16.39) when attached to amino acids of Val-77, Glu-34, Pro-79, Gly-78. The inhibition of RT was observed with coumarilic acid by attaching to Ala-445, Arg-567, Asp-456, Glu-478, Ser-499, Asn-474 (-23.54) significantly. Based on above results, the endophytic fungal coumarins have the ability to inhibit the three replicating enzymes of HIV-1 significantly. The in-silico results are evidence for how coumarins inhibiting the HIV replicating proteins by binding at specific amino acids. The results will help to understand how and where phytochemicals bind to target proteins to inhibit their action and it may help to identification of drugs to treat HIV. To validate our results, the in vivo research is needed.   

scholarly journals An immunoinformatics study: designing multivalent T-cell epitope vaccine against canine circovirus

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Pankaj Jain ◽  
Amit Joshi ◽  
Nahid Akhtar ◽  
Sunil Krishnan ◽  
Vikas Kaushik
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Molecular Docking ◽  
In Silico ◽  
Cell Epitope ◽  
Cost Effective ◽  
Dynamics Simulation ◽  
Cloning And Expression

Abstract Background Canine circovirus is a deadly pathogen of dogs and causes vasculitis and hemorrhagic enteritis. It causes lethal gastroenteritis in pigs, fox, and dogs. Canine circovirus genome contains two main (and opposite) transcription units which encode two open reading frames (ORFs), a replicase-associated protein (Rep) and the capsid (Cap) protein. The replicase protein and capsid protein consist of 303 amino acids and 270 amino acids respectively. Several immuno-informatics methods such as epitope screening, molecular docking, and molecular-dynamics simulations were used to craft peptide-based vaccine construct against canine circovirus. Results The vaccine construct was designed by joining the selected epitopes with adjuvants by suitable linker. The cloning and expression of the vaccine construct was also performed using in silico methods. Screening of epitopes was conducted by NetMHC server that uses ANN (Artificial neural networking) algorithm. These methods are fast and cost-effective for screening epitopes that can interact with dog leukocyte antigens (DLA) and initiate an immune response. Overall, 5 epitopes, YQHLPPFRF, YIRAKWINW, ALYRRLTLI, HLQGFVNLK, and GTMNFVARR, were selected and used to design a vaccine construct. The molecular docking and molecular dynamics simulation studies show that these epitopes can bind with DLA molecules with stability. The codon adaptation and in silico cloning studies show that the vaccine can be expressed by Escherichia coli K12 strain. Conclusion The results suggest that the vaccine construct can be useful in preventing the dogs from canine circovirus infections. However, the results need further validation by performing other in vitro and in vivo experiments.

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