scholarly journals Poria cocos Regulates Cell Migration and Actin Filament Aggregation in B35 and C6 Cells by Modulating the RhoA, CDC42, and Rho Signaling Pathways

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Chia-Yu Lee ◽  
Chang-Ti Lee ◽  
I-Shiang Tzeng ◽  
Chan-Yen Kuo ◽  
Fu-Ming Tsai ◽  
...  
Keyword(s):  
Cell Migration ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Actin Filament ◽  
Neuronal Cell ◽  
Neonatal Rat ◽  
Free Calcium ◽  
C6 Cells ◽  
Migration Ability ◽  
Traditional Chinese Herbal Medicine

Poria is used as a traditional Chinese herbal medicine with anti-inflammatory, anticancer, and mood-stabilizing properties. Poria contains triterpenoids and polysaccharides, which are reported to regulate the cytoplasmic free calcium associated with the N-methyl-D-aspartate receptor and affect the cell function of neonatal rat nerve cells and hippocampal neurons. Although the modulatory effects of Poria on neuronal function have been widely reported, the molecular mechanism of these effects is unclear. Cell migration ability and the reorganization of actin filaments are important biological functions during neuronal development, and they can be regulated mainly by the Rho signaling pathway. We found that the cell migration ability and actin condensation in B35 cells enhanced by P. cocos (a water solution of P. cocos cum Radix Pini (PRP) or White Poria (WP)) might be caused by increased RhoA and CDC42 activity and increased expression of downstream ROCK1, p-MLC2, N-WASP, and ARP2/3 in B35 cells. Similar modulations of cell migration ability, actin condensation, and Rho signaling pathway were also observed in the C6 glial cell line, except for the PRP-induced regulation of RhoA and CDC42 activities. Ketamine-induced inhibition of cell migration and actin condensation can be restored by P. cocos. In addition, we observed that the increased expression of RhoA and ROCK1 or the decreased expression of CDC42 and N-WASP caused by ketamine in B35 cells could also be restored by P. cocos. The results of this study suggest that the regulatory effects of P. cocos on cell migration and actin filament aggregation are closely related to the regulation of RhoA, CDC42, and Rho signaling pathways in both B35 and C6 cells. PRP and WP have the potential to restore neuronal cell Rho signaling abnormalities involved in some mental diseases.

Flt3/ITD Enhances Hematopoietic Cell Migration Towards Chemokine CCL2 Independent of Blocking the Negative Feedback Mechanism on Rho-Associated Kinase

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3597-3597
Author(s):  
Seiji Fukuda ◽  
Chie Onishi ◽  
Tomohiro Hirade ◽  
Mariko Abe ◽  
Takeshi Taketani ◽  
...  
Keyword(s):  
Cell Migration ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Negative Feedback ◽  
Conflicts Of Interest ◽  
Feedback Mechanism ◽  
Hematopoietic Cell ◽  
Negative Feedback Mechanism ◽  
Chemokine Signaling ◽  
Qualitative Changes

Abstract Internal tandem duplication mutations in the Flt3 gene (Flt3/ITD) found in patients with AML is associated with extremely poor prognosis. Our previous report demonstrating Flt3/ITD-mediated enhancement of hematopoietic cell migration towards chemokine CXCL12 (SDF1) suggests that Flt3/ITD likely facilitates dissemination of AML cells in the patients. Following studies showed that CXCL12 transiently up-regulated the expression of Rho-associated kinase-1 (Rock1) but subsequently down-regulated Rock1 expression in the control cells, whereas this effect was abolished by Flt3/ITD. The results demonstrated that CXCL12 generates negative regulatory feedback on Rock1 expression to prevent excessive migration to CXCL12 in the control cells, whereas this mechanism is abrogated by Flt3/ITD, thereby inducing deregulated cell migration (Onishi et al. ASH 2012). However, it is not known if Flt3/ITD augments migration to other chemokines and whether Flt3/ITD-induced blockage of the negative feedback loop on Rock1 expression reflects a specific effect on CXCL12/CXCR4 signaling pathway or more global change by ITD-Flt3. We found that mRNA for CCR2, a receptor for chemokine CCL2, is expressed in human AML cells. Herein, we investigated the effect of Flt3/ITD on migration to CCL2 in hematopoietic cells. Expression of CCR2 was significantly higher in the M4 and M5 cases with AML compared to other FAB subtypes that are deposited in the public gene expression database. However, there was no difference in the mRNA level for CCR2 between Flt3/ITD+ and Flt3/ITDneg cases. Consistent with AML samples, expression of surface CCR2 protein in Ba/F3 cells transfected with Flt3/ITD is equivalent to the control cells lacking Flt3/ITD. While the control Flt3/ITDneg Ba/F3 cells failed to migrate towards 1, 5, 10 and 50ng/mL of CCL2, Flt3/ITD marginally but significantly enhanced the cell migration towards 5ng/mL of CCL2 in Ba/F3 cells within 4 hours compared to control. In the Flt3/ITDneg cells exposed to 5ng/mL of CCL2, the mRNA expression of Rock1 continued to increase without being down-regulated to the basal level within 4 hours, and did not show any biphasic changes. In the Flt3/ITD+ Ba/F3 cells, however, Rock1 expression was significantly elevated compared to Flt3/ITDneg cells prior to incubation with CCL2, but down-regulated to 50% of the original level by 5ng/mL of CCL2 within 30 minutes. In contrast, Rock1 expression was barely affected and remained elevated by CXCL12 in Flt3/ITD+ Ba/F3 cells. Elevated expression of CCR2 in the M4 and M5 AML suggests that CCR2 signaling pathways can regulate migration of AML cells with monocytic lineage. Similar to CXCL12, migration towards CCL2 was also enhanced by Flt3/ITD without up-regulating CCR2 expression, suggesting that the enhanced chemotaxis by Flt3/ITD is not specific to CXCL12 and likely attributed to qualitative changes in the CCL2/CCR2 signaling pathway rather than their quantitative increase. Down-regulation of Rock1 expression by CCL2 in Flt3/ITD+ Ba/F3 cells may represent one of the qualitative changes in the CCL2 signaling pathway. However, blocking the CXCL12-induced negative regulatory mechanism on Rock1 expression existing in the Flt3/ITD+ cells was not identified in the CCL2 signaling. These data indicate that while enhancement in cell migration to chemokines by Flt3/ITD is not specific to CXCL12, blocking the negative feedback mechanism on Rock1 expression is not necessarily used in other chemokine signaling pathways. Our data suggests that Flt3/ITD mutations regulate trafficking of AML cells by modulating various chemokine signaling, but divergent molecular mechanism is involved in regulating cell migration towards different chmeokines. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effects of Gallotannin-Enriched Extract of Galla Rhois on the Activation of Apoptosis, Cell Cycle Arrest, and Inhibition of Migration Ability in LLC1 Cells and LLC1 Tumors

2021 ◽  
Vol 27 ◽  
Author(s):  
Mi Ju Kang ◽  
Ji Eun Kim ◽  
Ji Won Park ◽  
Hyun Jun Choi ◽  
Su Ji Bae ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Migration ◽  
Cell Cycle Arrest ◽  
Signaling Pathways ◽  
Mapk Pathway ◽  
Migration Ability ◽  
Lung Carcinomas ◽  
Cycle Arrest ◽  
Anti Tumor Activity ◽  
Syngeneic Model

Gallotannin (GT) and GT-enriched extracts derived from various sources are reported to have anti-tumor activity in esophageal, colon and prostate tumors, although their anti-tumor effects have not been determined in lung carcinomas. To investigate the anti-tumor activity of GT-enriched extract of galla rhois (GEGR) against lung carcinomas, alterations in the cytotoxicity, apoptosis activation, cell cycle progression, migration ability, tumor growth, histopathological structure, and the regulation of signaling pathways were analyzed in Lewis lung carcinoma (LLC1) cells and LLC1 tumor bearing C57BL/6NKorl mice, after exposure to GEGR. A high concentration of GT (69%) and DPPH scavenging activity (IC50=7.922 µg/ml) was obtained in GEGR. GEGR treatment exerted strong cytotoxicity, cell cycle arrest at the G2/M phase and subsequent activation of apoptosis, as well as inhibitory effects on the MAPK pathway and PI3K/AKT mediated cell migration in LLC1 cells. In the in vivo syngeneic model, exposure to GEGR resulted in suppressed growth of the LLC1 tumors, as well as inhibition of NF-κB signaling and their inflammatory cytokines. Taken together, our results provide novel evidence that exposure to GEGR induces activation of apoptosis, cell cycle arrest, and inhibition of cell migration via suppression of the MAPK, NF-κB and PI3K/AKT signaling pathways in LLC1 cells and the LLC1 syngeneic model.

scholarly journals Rutaecarpine Inhibits U87 Glioblastoma Cell Migration by Activating the Aryl Hydrocarbon Receptor Signaling Pathway

2021 ◽  
Vol 14 ◽  
Author(s):  
Yiyun Liu ◽  
Yangsheng Chen ◽  
Ruihong Zhu ◽  
Li Xu ◽  
Heidi Qunhui Xie ◽  
...  
Keyword(s):  
Cell Migration ◽  
Aryl Hydrocarbon Receptor ◽  
Signaling Pathway ◽  
Dependent Manner ◽  
Glioblastoma Cell ◽  
Glioblastoma Cells ◽  
Migration Ability ◽  
Human Glioblastoma ◽  
Aryl Hydrocarbon ◽  
Human Glioblastoma Cells

Glioblastoma is the most frequent and aggressive primary astrocytoma in adults. The high migration ability of the tumor cells is an important reason for the high recurrence rate and poor prognosis of glioblastoma. Recently, emerging evidence has shown that the migration ability of glioblastoma cells was inhibited upon the activation of aryl hydrocarbon receptor (AhR), suggesting potential anti-tumor effects of AhR agonists. Rutaecarpine is a natural compound with potential tumor therapeutic effects which can possibly bind to AhR. However, its effect on the migration of glioblastoma is unclear. Therefore, we aim to explore the effects of rutaecarpine on the migration of human glioblastoma cells U87 and the involvement of the AhR signaling pathway. The results showed that: (i) compared with other structural related alkaloids, like evodiamine and dehydroevodiamine, rutaecarpine was a more potent AhR activator, and has a stronger inhibitory effect on the glioblastoma cell migration; (ii) rutaecarpine decreased the migration ability of U87 cells in an AhR-dependent manner; (iii) AhR mediated the expression of a tumor suppressor interleukin 24 (IL24) induced by rutaecarpine, and AhR-IL24 axis was involved in the anti-migratory effects of rutaecarpine on the glioblastoma. Besides IL24, other candidates AhR downstream genes both associated with cancer and migration were proposed to participate in the migration regulation of rutaecarpine by RNA-Seq and bioinformatic analysis. These data indicate that rutaecarpine is a naturally-derived AhR agonist that could inhibit the migration of U87 human glioblastoma cells mostly via the AhR-IL24 axis.

scholarly journals Fast-Acting and Receptor-Mediated Regulation of Neuronal Signaling Pathways by Copaiba Essential Oil

2020 ◽  
Vol 21 (7) ◽  
pp. 2259 ◽  
Author(s):  
Yasuyo Urasaki ◽  
Cody Beaumont ◽  
Michelle Workman ◽  
Jeffery N. Talbot ◽  
David K. Hill ◽  
...  
Keyword(s):  
Essential Oil ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Cannabinoid Receptor ◽  
Biological Activities ◽  
Chemical Constituents ◽  
Neuronal Cell ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Fast Acting

This study examined the biological activities of copaiba essential oil via measurement of its effects on signaling pathways in the SH-SY5Y neuronal cell line. Nanofluidic proteomic technologies were deployed to measure the phosphorylation of biomarker proteins within the signaling cascades. Interestingly, copaiba essential oil upregulated the pI3K/Akt/mTOR, MAPK, and JAK/STAT signaling pathways in neuronal cells. The effects of copaiba essential oil peaked at 30 min post-treatment, with a half-maximal effective concentration (EC50) of approximately 80 ng/mL. Treatment with cannabinoid receptor 2 (CB2) agonist AM1241 or the inverse agonist BML190 abrogated the regulatory effects of copaiba essential oil on the pI3K/Akt/mTOR signaling pathway. Surprisingly, copaiba essential oil also activated the apoptosis signaling pathway and reduced the viability of SH-SY5Y cells with an EC50 of approximately 400 ng/mL. Furthermore, β-caryophyllene, a principal constituent of copaiba essential oil, downregulated the pI3K/Akt/mTOR signaling pathway. Taken together, the findings indicated that copaiba essential oil upregulated signaling pathways associated with cell metabolism, growth, immunity, and apoptosis. The biological activities of copaiba essential oil were determined to be fast acting, CB2 mediated, and dependent on multiple chemical constituents of the oil. Nanofluidic proteomics provided a powerful means to assess the biological activities of copaiba essential oil.

Targeted Delivery of Natural Bioactives and Lipid-nanocargos against Signaling Pathways Involved in Skin Cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Mohammad Kashif Iqubal ◽  
Aiswarya Chaudhuri ◽  
Ashif Iqubal ◽  
Sadaf Saleem ◽  
Madan Mohan Gupta ◽  
...  
Keyword(s):  
Skin Cancer ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Targeted Delivery ◽  
Skin Pigmentation ◽  
Wnt Signaling Pathway ◽  
Human Beings ◽  
Radiation Chemical ◽  
Cell Leukemia Virus Type ◽  
Human T Cell

: At present, skin cancer is a widespread malignancy in human beings. Among diverse population types, Caucasian populations are much more prone in comparison to darker skin populations due to the comparative lack of skin pigmentation. Skin cancer is divided into malignant and non-melanoma skin cancer, which is additionally categorized as basal and squamous cell carcinoma. The exposure to ultraviolet radiation, chemical carcinogen (polycyclic aromatic hydrocarbons, arsenic, tar, etc.), and viruses (herpes virus, human papillomavirus, and human T-cell leukemia virus type-1) are major contributing factors of skin cancer. There are distinct pathways available through which skin cancer develops, such as the JAKSTAT pathway, Akt pathway, MAPKs signaling pathway, Wnt signaling pathway, to name a few. Currently, several targeted treatments are available, such as monoclonal antibodies, which have dramatically changed the line of treatment of this disease but possess major therapeutic limitations. Thus, recently many phytochemicals have been evaluated either alone or in combination with the existing synthetic drugs to overcome their limitations and have found to play a promising role in the prevention and treatment. In this review, complete tracery of skin cancer, starting from the signaling pathways involved, newer developed drugs with their targets and limitations along with the emerging role of natural products alone or in combination as potent anticancer agents and their molecular mechanism involved has been discussed. Apart from this, various nanocargos have also been mentioned here, which can play a significant role in the management and treatment of different types of skin cancer.

Biological role of AKT, and regulation of AKT signaling pathway by thymoquinone: perspectives in cancer therapeutics

2020 ◽  
Vol 20 ◽  
Author(s):  
Md. Junaid ◽  
Yeasmin Akter ◽  
Syeda Samira Afrose ◽  
Mousumi Tania ◽  
Md. Asaduzzaman Khan
Keyword(s):  
Clinical Trials ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Akt Signaling ◽  
Review Article ◽  
Therapeutic Drug ◽  
Akt Signaling Pathway ◽  
Anti Cancer

Background: AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to the carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs. Objective: In this review article, we have interpreted the role of AKT signaling pathways in cancer and natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanism. Method: We have collected the updated information and data on AKT, their role in cancer and inhibitory effect of TQ in AKT signaling pathway from google scholar, PubMed, Web of Science, Elsevier, Scopus and many more. Results: There are many drugs already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer. Conclusion: This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ’s future as a cancer therapeutic drug.

scholarly journals M2 macrophage-derived exosomal microRNAs inhibit cell migration and invasion in gliomas through PI3K/AKT/mTOR signaling pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jie Yao ◽  
Zefen Wang ◽  
Yong Cheng ◽  
Chao Ma ◽  
Yahua Zhong ◽  
...  
Keyword(s):  
Cell Migration ◽  
Western Blot ◽  
Signaling Pathway ◽  
Target Gene ◽  
Glioma Cells ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
M2 Macrophage ◽  
Mtor Signaling Pathway ◽  
Cell Migration And Invasion

Abstract Background Glioma, the most common primary brain tumor, account Preparing figures for 30 to 40% of all intracranial tumors. Herein, we aimed to study the effects of M2 macrophage-derived exosomal microRNAs (miRNAs) on glioma cells. Methods First, we identified seven differentially expressed miRNAs in infiltrating macrophages and detected the expression of these seven miRNAs in M2 macrophages. We then selected hsa-miR-15a-5p (miR-15a) and hsa-miR-92a-3p (miR-92a) for follow-up studies, and confirmed that miR-15a and miR-92a were under-expressed in M2 macrophage exosomes. Subsequently, we demonstrated that M2 macrophage-derived exosomes promoted migration and invasion of glioma cells, while exosomal miR-15a and miR-92a had the opposite effects on glioma cells. Next, we performed the target gene prediction in four databases and conducted target gene validation by qRT-PCR, western blot and dual luciferase reporter gene assays. Results The results revealed that miR-15a and miR-92a were bound to CCND1 and RAP1B, respectively. Western blot assays demonstrated that interference with the expression of CCND1 or RAP1B reduced the phosphorylation level of AKT and mTOR, indicating that both CCND1 and RAP1B can activate the PI3K/AKT/mTOR signaling pathway. Conclusion Collectively, these findings indicate that M2 macrophage-derived exosomal miR-15a and miR-92a inhibit cell migration and invasion of glioma cells through PI3K/AKT/mTOR signaling pathway.

scholarly journals The effect of dipeptidyl peptidase IV on disease-associated microglia phenotypic transformation in epilepsy

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Zhicheng Zheng ◽  
Peiyu Liang ◽  
Baohua Hou ◽  
Xin Lu ◽  
Qianwen Ma ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Neurological Diseases ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Sequencing Data ◽  
Migration Ability ◽  
Dpp4 Inhibitor ◽  
Phenotypic Transformation

Abstract Background Accumulating evidence suggests that disease-associated microglia (DAM), a recently discovered subset of microglia, plays a protective role in neurological diseases. Targeting DAM phenotypic transformation may provide new therapeutic options. However, the relationship between DAM and epilepsy remains unknown. Methods Analysis of public RNA-sequencing data revealed predisposing factors (such as dipeptidyl peptidase IV; DPP4) for epilepsy related to DAM conversion. Anti-epileptic effect was assessed by electroencephalogram recordings and immunohistochemistry in a kainic acid (KA)-induced mouse model of epilepsy. The phenotype, morphology and function of microglia were assessed by qPCR, western blotting and microscopic imaging. Results Our results demonstrated that DPP4 participated in DAM conversion and epilepsy. The treatment of sitagliptin (a DPP4 inhibitor) attenuated KA-induced epilepsy and promoted the expression of DAM markers (Itgax and Axl) in both mouse epilepsy model in vivo and microglial inflammatory model in vitro. With sitagliptin treatment, microglial cells did not display an inflammatory activation state (enlarged cell bodies). Furthermore, these microglia exhibited complicated intersections, longer processes and wider coverage of parenchyma. In addition, sitagliptin reduced the activation of NF-κB signaling pathway and inhibited the expression of iNOS, IL-1β, IL-6 and the proinflammatory DAM subset gene CD44. Conclusion The present results highlight that the DPP4 inhibitor sitagliptin can attenuate epilepsy and promote DAM phenotypic transformation. These DAM exhibit unique morphological features, greater migration ability and better surveillance capability. The possible underlying mechanism is that sitagliptin can reduce the activation of NF-κB signaling pathway and suppress the inflammatory response mediated by microglia. Thus, we propose DPP4 may act as an attractive direction for DAM research and a potential therapeutic target for epilepsy.

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