Tomatidine Suppresses the Destructive Behaviors of Fibroblast-Like Synoviocytes and Ameliorates Type II Collagen-Induced Arthritis in Rats

Fibroblast-like synoviocytes (FLSs) are the prominent non-immune cells in synovium and play a pivotal role in rheumatoid arthritis (RA) pathogenesis. Searching for natural compounds that may suppress the pathological phenotypes of FLSs is important for the development of RA treatment. Tomatidine (Td), a steroidal alkaloid derived from the solanaceae family, has been reported to have anti-inflammatory, anti-tumor and immunomodulatory effects. However, its effect on RA remains unknown. Here, we examined the inhibitory effect of Td on TNFα-induced arthritic FLSs, and subsequently investigated its therapeutic effect on collagen-induced arthritis (CIA) rats. Our results revealed that Td significantly inhibited TNFα-induced proliferation and migration of arthritic FLSs. In addition, we found that Td treatment could efficaciously ameliorate synovial inflammation and joint destruction of rats with CIA. Both in vitro and in vivo studies showed that Td significantly suppressed the production of pro-inflammatory cytokines including IL-1β, IL-6 and TNFα, and downregulated the expression of MMP-9 and RANKL. Further molecular mechanism studies revealed that the inhibitory effect of Td on RA might attribute to the decreased activations of MAPKs (ERK and JNK) and NF-κB. These findings provide evidence that Td has the potential to be developed into a complementary or alternative agent for RA therapy.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22115602 ◽

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.

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MTA1-Dependent Anticancer Activity of Gnetin C in Prostate Cancer

Nutrients ◽

10.3390/nu11092096 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2096 ◽

Cited By ~ 3

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.

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The natural compound Notopterol targets JAK2/3 to ameliorate macrophage-induced inflammation and arthritis

10.1101/832782 ◽

2019 ◽

Author(s):

Qiong Wang ◽

Xin Zhou ◽

Long Yang ◽

Yongjian Zhao ◽

Jun Xiao ◽

...

Keyword(s):

Natural Compound ◽

Intraperitoneal Administration ◽

Inhibitory Effect ◽

Therapeutic Effects ◽

Treatment Combination ◽

Collagen Induced Arthritis ◽

Chinese Medicinal Herb ◽

Cytokines And Chemokines

Abstract:Notopterol (NOT) is one of the main constituents of the traditional Chinese medicinal herb Notopterygium incisum Ting ex H.T. Chang has anti-rheumatism activity, but the target of NOT remains unknown. Here we have demonstrated that orally or intraperitoneal administration of NOT exhibits significant therapeutic effects on the collagen-induced arthritis (CIA) model in both DBA/1J and C57/BL6 mice. NOT treatment in vivo and in vitro reduces production of inflammatory cytokines and chemokines in TNFα- or LPS/IFNγ-stimulated macrophages via blocking the JAK2/3-STAT3/5 activation. Mechanistically, NOT directly binds JAK2 to inhibit its activity via Arg980, Asn981, and Leu932 in the JH1 domain. Importantly, expression of the L938A/R980A/N981A mutant in zebrafish significantly inhibited the in vivo inflammatory response after LPS injection, which showed no further inhibitory effect upon NOT treatment. Combination of NOT and an anti-TNFα antibodies could achieve a better therapeutic effect than anti-TNFα alone in the CIA model. We therefore suggest that as a specific JAK2/3 inhibitor, the natural compound NOT ameliorates pathology of RA, which might be useful to treat other JAK2/3-related diseases.

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

Frontiers in Pharmacology ◽

10.3389/fphar.2021.727275 ◽

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.

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

10.21203/rs.3.rs-18963/v2 ◽

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.

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

Cancers ◽

10.3390/cancers13194930 ◽

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.

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

10.21203/rs.3.rs-18963/v1 ◽

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.

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Shikonin Inhibits The Proliferation of Cervical Cancer Cells Via FAK/AKT/GSK3β Signalling

10.21203/rs.3.rs-1151972/v1 ◽

2021 ◽

Author(s):

Ziyan Xu ◽

Liru Huang ◽

Tiantian Zhang ◽

Yuwei Liu ◽

Mei Gong ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Biological Activities ◽

Inhibitory Effect ◽

Dependent Manner ◽

Inhibitory Effects ◽

Cervical Cancer Cells ◽

And Migration

Abstract Cervical cancer is one of the most common female cancers worldwide, and it is one of the most lethal malignancies of the female reproductive system. Shikonin, a natural pigment of theophyllin, has a variety of biological activities and has shown significant inhibitory effects on a variety of tumours in vitro and in vivo. However, there are few studies on Shikonin in cervical cancer. In the present study, we found that Shikonin inhibited not only the proliferation but also the migration of cervical cancer cells. Our data showed that Shikonin inhibited the proliferation of HeLa and SiHa cells in a concentration- and time-dependent manner. In cervical cancer cells, Shikonin not only inhibited the phosphorylation of FAK, AKT and GSK3β but also inhibited the phosphorylation of FAK, AKT and GSK3β induced by EGF. Further exploring the mechanism, we found that Shikonin could inhibit the proliferation of cervical cancer cells by regulating the phosphorylation of the FAK/AKT/GSK3β pathway. In addition, Shikonin significantly inhibited cell migration and reduced the expression of proteins such as MTA1, TGFβ1 and VEGF. In conclusion, our study elucidated that Shikonin has an inhibitory effect on the proliferation and migration of cervical cancer cells, which may be mediated by the FAK/AKT/GSK3β signalling pathway. Our results suggest that Shikonin has the potential to become a clinical treatment for cervical cancer.

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H3 Relaxin Alleviates Migration, Apoptosis and Pyroptosis Through P2X7R-Mediated Nucleotide Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Activation in Retinopathy Induced by Hyperglycemia

Frontiers in Pharmacology ◽

10.3389/fphar.2020.603689 ◽

2020 ◽

Vol 11 ◽

Author(s):

Kelaier Yang ◽

Jiannan Liu ◽

Xiaohui Zhang ◽

Ziqi Ren ◽

Lei Gao ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Inhibitory Effect ◽

Receptor Protein ◽

Inflammasome Activation ◽

Sprague Dawley ◽

Nlrp3 Inflammasome Activation ◽

Underlying Mechanisms ◽

And Migration

Introduction: P2X7R excitation-interrelated NLRP3 inflammasome activation induced by high glucose contributes to the pathogenesis of diabetic retinopathy (DR). Relaxin-3 is a bioactive peptide with a structure similar to insulin, which has been reported to be effective in diabetic cardiomyopathy models in vivo and in vitro. However, it is not known whether relaxin-3 has a beneficial impact on DR, and the underlying mechanisms of the effect are also remain unknown.Methods and Results: The retinas of male streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rats were characterized. Human retinal microvascular endothelial cells (HRMECs) were used to evaluate the anti-inflammatory, antiapoptotic, antipyroptotic and anti-migration effects of H3 relaxin by transmission electron microscopy, wound-healing assay, transwell assay, flow cytometry, cytokine assays and western-blot analysis. After H3 relaxin treatment, changes of the ultrastructure and expression of NLRP3 inflammasome related proteins in the retinas of rats were compared with those in the diabetic group. In vitro, H3 relaxin played a beneficial role that decreased cell inflammation, apoptosis, pyroptosis and migration stimulated by advanced glycation end products (AGEs). Moreover, inhibition of P2X7R and NLRP3 inflammasome activation decreased NLRP3 inflammasome-mediated injury that similar to the effects of H3 relaxin. H3 relaxin suppressed the stimulation of apoptosis, pyroptosis and migration of HRMECs in response to AGEs mediated by P2X7R activation of the NLRP3 inflammasome.Conclusion: Our findings provide new insights into the mechanisms of the inhibitory effect of H3 relaxin on AGE-induced retinal injury, including migration, apoptosis and pyroptosis, mediated by P2X7R-dependent activation of the NLRP3 inflammasome in HRMECs.

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Oleic Acid and Insulin as Key Characteristics of T2D Promote Colorectal Cancer Deterioration in Xenograft Mice Revealed by Functional Metabolomics

Frontiers in Oncology ◽

10.3389/fonc.2021.685059 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ying Zhang ◽

Di Wang ◽

Bo Lv ◽

Xiaoying Hou ◽

Qiwei Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Oleic Acid ◽

Cyclin D1 ◽

Underlying Mechanism ◽

Inhibitory Effect ◽

Mechanism Study ◽

Functional Metabolomics ◽

And Migration

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers with high mortality worldwide. Type 2 diabetes mellitus (T2D), known as a risk factor of CRC, can promote the deterioration of CRC, but the underlying mechanism is elusive. In this study, we aimed to reveal the relationship between CRC and T2D from the perspective of small-molecule metabolism. First, a list of common dysregulated metabolites in CRC and T2D was obtained by retrieving existing metabolomics publications. Among these metabolites, oleic acid (OA) was found to be able to promote the proliferation and migration of colon carcinoma cell HCT116. Further experiments proved that insulin could significantly strengthen this promotion and showed a synergistic effect with OA. Mechanism study found that OA and insulin acted synergistically through the extracellular signal-regulated kinase (ERK)1/2/c-Myc/cyclin D1 pathway. In addition, the combination of ERK1/2 inhibitor SCH772984 and cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib showed a remarkable inhibitory effect on tumor growth in vivo. Taken together, the current study found that OA plays an important role in CRC development by using a functional metabolomics approach. More importantly, insulin and OA were confirmed to synergistically promote the deterioration of CRC in vitro and in vivo via ERK1/2/c-Myc/cyclin D1 pathway. Our findings may shed light on CRC treatment among the T2D population.

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