scholarly journals EDR Peptide: Possible Mechanism of Gene Expression and Protein Synthesis Regulation Involved in the Pathogenesis of Alzheimer’s Disease

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 159
Author(s):  
Vladimir Khavinson ◽  
Natalia Linkova ◽  
Ekaterina Kozhevnikova ◽  
Svetlana Trofimova
Keyword(s):  
Gene Expression ◽  
Signaling Pathway ◽  
Animal Studies ◽  
Enzyme Synthesis ◽  
In Vivo Studies ◽  
Neuronal Cultures ◽  
Ribonucleic Acids ◽  
Synthesis Regulation

The EDR peptide (Glu-Asp-Arg) has been previously established to possess neuroprotective properties. It activates gene expression and synthesis of proteins, involved in maintaining the neuronal functional activity, and reduces the intensity of their apoptosis in in vitro and in vivo studies. The EDR peptide interferes with the elimination of dendritic spines in neuronal cultures obtained from mice with Alzheimer’s (AD) and Huntington’s diseases. The tripeptide promotes the activation of the antioxidant enzyme synthesis in the culture of cerebellum neurons in rats. The EDR peptide normalizes behavioral responses in animal studies and improves memory issues in elderly patients. The purpose of this review is to analyze the molecular and genetics aspects of the EDR peptide effect on gene expression and synthesis of proteins involved in the pathogenesis of AD. The EDR peptide is assumed to enter cells and bind to histone proteins and/or ribonucleic acids. Thus, the EDR peptide can change the activity of the MAPK/ERK signaling pathway, the synthesis of proapoptotic proteins (caspase-3, p53), proteins of the antioxidant system (SOD2, GPX1), transcription factors PPARA, PPARG, serotonin, calmodulin. The abovementioned signaling pathway and proteins are the components of pathogenesis in AD. The EDR peptide can be AD.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

scholarly journals CircFAM13B promotes the proliferation of hepatocellular carcinoma by sponging miR-212, upregulating E2F5 expression and activating the P53 pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ying Xie ◽  
Xiaofeng Hang ◽  
Wensheng Xu ◽  
Jing Gu ◽  
Yuanjing Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Gene Expression Omnibus ◽  
Differentially Expressed ◽  
In Vivo Studies ◽  
Circular Rnas ◽  
Novel Target ◽  
Underlying Mechanisms

Abstract Background Most of the biological functions of circular RNAs (circRNAs) and the potential underlying mechanisms in hepatocellular carcinoma (HCC) have not yet been discovered. Methods In this study, using circRNA expression data from HCC tumor tissues and adjacent tissues from the Gene Expression Omnibus database, we identified out differentially expressed circRNAs and verified them by qRT-PCT. Functional experiments were performed to evaluate the effects of circFAM13B in HCC in vitro and in vivo. Results We found that circFAM13B was the most significantly differentially expressed circRNA in HCC tissue. Subsequently, in vitro and in vivo studies also demonstrated that circFAM13B promoted the proliferation of HCC. Further studies revealed that circFAM13B, a sponge of miR-212, is involved in the regulation of E2F5 gene expression by competitively binding to miR-212, inhibits the activation of the P53 signalling pathway, and promotes the proliferation of HCC cells. Conclusions Our findings revealed the mechanism underlying the regulatory role played by circFAM13B, miR-212 and E2F5 in HCC. This study provides a new theoretical basis and novel target for the clinical prevention and treatment of HCC.

scholarly journals Modulatory Effects of Osthole on Lipopolysaccharides-Induced Inflammation in Caco-2 Cell Monolayer and Co-Cultures with THP-1 and THP-1-Derived Macrophages

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 123
Author(s):  
Natalia K. Kordulewska ◽  
Justyna Topa ◽  
Małgorzata Tańska ◽  
Anna Cieślińska ◽  
Ewa Fiedorowicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Reaction ◽  
Wide Spectrum ◽  
Cell Monolayer ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Tnf Α

Lipopolysaccharydes (LPS) are responsible for the intestinal inflammatory reaction, as they may disrupt tight junctions and induce cytokines (CKs) secretion. Osthole has a wide spectrum of pharmacological effects, thus its anti-inflammatory potential in the LPS-treated Caco-2 cell line as well as in Caco-2/THP-1 and Caco-2/macrophages co-cultures was investigated. In brief, Caco-2 cells and co-cultures were incubated with LPS to induce an inflammatory reaction, after which osthole (150–450 ng/mL) was applied to reduce this effect. After 24 h, the level of secreted CKs and changes in gene expression were examined. LPS significantly increased the levels of IL-1β, -6, -8, and TNF-α, while osthole reduced this effect in a concentration-dependent manner, with the most significant decrease when a 450 ng/mL dose was applied (p < 0.0001). A similar trend was observed in changes in gene expression, with the significant osthole efficiency at a concentration of 450 ng/μL for IL1R1 and COX-2 (p < 0.01) and 300 ng/μL for NF-κB (p < 0.001). Osthole increased Caco-2 monolayer permeability, thus if it would ever be considered as a potential drug for minimizing intestinal inflammatory symptoms, its safety should be confirmed in extended in vitro and in vivo studies.

Integrin signaling's potential for mediating gene expression in hypertrophying skeletal muscle

2000 ◽  
Vol 88 (1) ◽  
pp. 337-343 ◽  
Author(s):  
James A. Carson ◽  
Lei Wei
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Signaling Pathway ◽  
Mechanical Load ◽  
Integrin Signaling ◽  
Mechanical Forces ◽  
Growth Factor Signaling ◽  
Muscle Gene

Overloaded skeletal muscle undergoes dramatic shifts in gene expression, which alter both the phenotype and mass. Molecular biology techniques employing both in vivo and in vitro hypertrophy models have demonstrated that mechanical forces can alter skeletal muscle gene regulation. This review's purpose is to support integrin-mediated signaling as a candidate for mechanical load-induced hypertrophy. Research quantifying components of the integrin-signaling pathway in overloaded skeletal muscle have been integrated with knowledge regarding integrins role during development and cardiac hypertrophy, with the hope of demonstrating the pathway's importance. The role of integrin signaling as an integrator of mechanical forces and growth factor signaling during hypertrophy is discussed. Specific components of integrin signaling, including focal adhesion kinase and low-molecular-weight GTPase Rho are mentioned as downstream targets of this signaling pathway. There is a need for additional mechanistic studies capable of providing a stronger linkage between integrin-mediated signaling and skeletal muscle hypertrophy; however, there appears to be abundant justification for this type of research.

scholarly journals Dickkopf-1 contributes to hepatocellular carcinoma tumorigenesis by activating the Wnt/β-catenin signaling pathway

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Rui Zhang ◽  
Hao-Ming Lin ◽  
Ruth Broering ◽  
Xiang-de Shi ◽  
Xian-huan Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Tumor Formation ◽  
In Vivo Studies ◽  
Qrt Pcr ◽  
Subsequent Investigation ◽  
Dkk1 Expression ◽  
Tumor Number

AbstractDysregulation of dickkopf-related protein 1 (DKK1) expression has been reported in a variety of human cancers. We previously reported that DKK1 was upregulated in hepatocellular carcinoma (HCC). However, the role of DKK1 in HCC remains unclear. This study aimed to investigate the clinical significance and biological functions of DKK1 in HCC. The expression of DKK1 was examined in cirrhotic and HCC tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). DKK1 was silenced or overexpressed in HCC cell lines, and in vitro and in vivo studies were performed. Immunohistochemistry revealed that DKK1 was weakly expressed in cirrhotic tissues (8/22, 36.4%) but upregulated in HCC tissues (48/53, 90.6%, cohort 1). Significant upregulation of DKK1 was observed in 57.6% (19/33, cohort 2) of HCC tissues by qRT-PCR, and the expression of DKK1 was associated with tumor size (P = 0.024) and tumor number (P = 0.019). Genetic depletion of DKK1 impaired the proliferation, colony-forming ability, invasion, and tumor formation of HCC cells (HepG2 and HUH-7). Conversely, forced expression of DKK1 increased the proliferation, colony-forming ability, and invasion of HepG2 and HUH-7 cells in vitro and enhanced tumor formation in vivo. Subsequent investigation revealed that the DKK1-mediated proliferation and tumorigenicity of HepG2 and HUH-7 cells is dependent on the Wnt/β-catenin signaling pathway. These findings indicate that DKK1 plays an oncogenic role in HCC by activating the Wnt/β-catenin signaling pathway.

scholarly journals A Review of the Role of Neurotensin and Its Receptors in Colorectal Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Shengyang Qiu ◽  
Gianluca Pellino ◽  
Francesca Fiorentino ◽  
Shahnawaz Rasheed ◽  
Ara Darzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Animal Studies ◽  
In Vivo Studies ◽  
Signalling Pathways ◽  
Diagnostic Biomarker ◽  
Gi Tract ◽  
Cellular Receptors

Neurotensin (NTS) is a physiologically occurring hormone which affects the function of the gastrointestinal (GI) tract. In recent years, NTS, acting through its cellular receptors (NTSR), has been implicated in the carcinogenesis of several cancers. In colorectal cancer (CRC), a significant body of evidence, from in vitro and in vivo studies, is available which elucidates the molecular biology of NTS/NTSR signalling and the resultant growth of CRC cells. There is growing clinical data from human studies which corroborate the role NTS/NTSR plays in the development of human CRC. Furthermore, blockade and modulation of the NTS/NTSR signalling pathways appears to reduce CRC growth in cell cultures and animal studies. Lastly, NTS/NTSR also shows potential of being utilised as a diagnostic biomarker for cancers as well as targets for functional imaging. We summarise the existing evidence and understanding of the role of NTS and its receptors in CRC.

scholarly journals In Vivo Efficacy of Anidulafungin and Caspofungin against Candida glabrata and Association with In Vitro Potency in the Presence of Sera

2007 ◽  
Vol 51 (5) ◽  
pp. 1616-1620 ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Rosie Bocanegra ◽  
Destiny Molina ◽  
Marcos Olivo ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Animal Studies ◽  
Kidney Tissue ◽  
Vitro Activity ◽  
In Vivo Studies ◽  
In Vitro Activity ◽  
In Vivo Efficacy ◽  
Fungal Burden

ABSTRACT In vitro studies have demonstrated that anidulafungin has greater potency than caspofungin against Candida glabrata. However, data from in vivo studies demonstrating that it has superior efficacy are lacking. The objective of this study was to compare the activities of anidulafungin and caspofungin against C. glabrata in a murine model of disseminated candidiasis. Two clinical C. glabrata isolates were used, including one with reduced caspofungin susceptibility. MICs were determined by broth microdilution in the presence and absence of sera. For the animal studies, mice were immunosuppressed with 5-fluorouracil one day prior to intravenous inoculation. Treatment with anidulafungin and caspofungin (0, 0.5, 1, 5, and 10 mg/kg of body weight per day) was begun 24 h later and was continued through day 7 postinoculation. The CFU were enumerated from kidney tissue. According to the standard microdilution methodology, anidulafungin had superior in vitro activity. However, this enhanced potency was attenuated by the addition of mouse and human sera. Caspofungin reduced the kidney fungal burden at lower doses compared to that achieved with anidulafungin in mice infected with the isolate with the lower MIC. Against the strain with the elevated caspofungin MIC, both anidulafungin and caspofungin were effective in reducing the kidney fungal burden at the higher doses studied. Despite the greater in vitro activity of anidulafungin in the absence of sera, both echinocandins were similarly effective in reducing the fungal burden in kidney tissue. The superior in vitro activity of anidulafungin did not confer enhanced in vivo efficacy against C. glabrata.

PDGFR-Mediated Cytomegalovirus Infection of Megakaryocytes Induces Thrombocytopenia Via Demethylation of AML1 and IEX-1 in the TPO/c-Mpl Signaling Pathway Following Allo-HSCT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3937-3937
Author(s):  
Xiao-Hui Zhang ◽  
Feng Fei-er ◽  
Qian-ming Wang ◽  
Xiao-lu Zhu ◽  
Lan-ping Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Hcmv Infection ◽  
Treated Group ◽  
In Vitro Studies ◽  
Significant Difference

Abstract Introduction: Human cytomegalovirus (HCMV) infection is a common complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is associated with high morbidity and mortality. Thrombocytopenia is one of the major hematological complications of HCMV infection. Possible causes include direct HCMV injury to hematopoietic progenitor cells and the microenvironment, as well as HCMV-related immune thrombocytopenia. Previous in vitro studies demonstrate that HCMV could directly infect megakaryocytes(MKs) and their progenitors, resulting in decreased CFU-MK and increased apoptosis, but the underlying mechanisms remain uncertain. It remains unknown whether HCMV can directly target MKs in vivo, how MK function changes after infection, why HCMV selectively infects certain patients and what inhibits MK maturation and results in apoptosis. It has been reported that patients with HCMV-related thrombocytopenia showed poor response to rhTPO, implying blockage of the TPO/c-Mpl signaling pathway. Our previous research indicated that PDGFR+CXCR4lowCCR5lowMKs are correlated with HCMV infection.We hypothesized that PDGFR+CXCR4lowCCR5lowMKs are more susceptible to HCMV infection. HCMV could directly target MKs both in vitro and in vivo, resulting in increased apoptosis and decreased MK ploidy. HCMV infection could possibly disturb the downstream TPO/c-Mpl signaling pathway, thereby inhibiting MK differentiation and maturation. Methods: We collected bone marrow from HCMV DNAemia patients post allo-HSCT for in vivo study. Transmission electron microscopy(TEM) was used to detect HCMV particles inside MKs. MKs were identified as CD41+vWF+cells by flow cytometry(FCM). To analyze the susceptibility of MKs to HCMV, expression levels of PDGFR, αvβ3, TLR2, CCR5 and CXCR4 in different groups were tested. Cell apoptosis was measured by Annexin V. MK ploidy was determined by FCM for propidium iodide (PI) staining. We also measured c-Mpl expression in MKs.In vitro study, we used plasma from HCMV-infected patients post allo-HSCT to infect MKs cultured from bone marrow CD34+ cells. We validated cell susceptibility with the same markers used in vivo. Next, inhibitors of the positive markers were co-cultured with MKs. We analyzed pp65 expression in the inhibitor-treated group and control group to explore potential prevention of HCMV infection. We investigated AML1 and IEX-1 in the downstream TPO/c-Mpl signaling pathway by PCR and Western Blot. We used bisulfite sequencing PCR (BSP) to study the methylation status in different gene expression profiles of AML1 and IEX-1. 5-ara-dC is a type of DNA methylation inhibitor. After incubation with MKs, we analyzed changes in gene expression and MKs function. Results: Using TEM, we managed to find HCMV particles in MKs from HCMV-infected patient bone marrow samples. The proportion of apoptosis markedly increased compared with HCMV-negative MKs, whereas the mean ploidy slightly decreased. C-Mpl expression showed no significant difference between the two groups. Pp65 positive cells showed elevated expression in PDGFR and reduced expression in CXCR4 and CCR5. In vitro studies revealed similar results. After treating with the PDGFR inhibitor IMC-3G3, the pp65 positive cell population was slightly decreased, but the Gleevec-treated group showed no difference. We found a decrease in both IEX-1 and AML1 on both the molecular and protein levels. Both gene promoters were hypermethylated in the HCMV-infected group. After demethylation with 5-ara-dC, IEX-1 and AML1expression levels were both up-regulated, and cell apoptosis was reduced. Conclusion: (1)HCMV inhibited megakaryocytic differentiation and maturation and reduced MKs polyploidy both in vivo and in vitro. (2)MKs positive for PDGFR and low in CXCR4 and CCR5 were more susceptible to HCMV infection. The PDGFR inhibitor IMC-3G3 protected MKs from HCMV infection. (3)The mechanism of HCMV-associated thrombocytopenia may be a disturbance of the TPO/c-Mpl signaling pathway in MKs through hypermethylation of the AML1 and IEX-1 promoters. Demethylation with 5-ara-dC could reverse cell apoptosis. Therefore, we illustrated the possible mechanism of HCMV-induced thrombocytopenia, highlighting new insights for future potential therapeutic approaches. Disclosures No relevant conflicts of interest to declare.

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