1,720,994 research outputs found
A potent ion channel blocker, hydroquinidine, exhibits strong anti-cancer activity on colon, pancreatic, and hepatocellular cancer cells
No full textBackground: Despite recent advances in drug discovery, cancer is still one of the most lethal health problems worldwide. In most cases, standard therapy methods and multi-modal treatments fail, and new therapeutic approaches are required. Ion channels are essential in multiple cellular processes regulating cell division, differentiation, and death. Recent studies on ion-channel modulators emphasize their potential to suppress tumor growth. In that regard, we reasoned that an underinvestigated potassium channel modulator, Hydroquinidine (HQ), may exhibit an anti-carcinogenic activity. Methods and results: HQ’s potential as an anti-neoplastic compound was examined using colony formation assay, wound healing assay, soft agar assay, and Annexin-V assay in the colon, pancreatic, and hepatocellular carcinomas. Our findings unveiled a remarkable anti-cancer activity of HQ by decreasing colony-forming ability, migration capacity, tumorigenicity, and proliferation and stimulating cellular death. HQ significantly reduced the formed colonies and tumorigenicity for all cells. It displayed a significant anti-migrative effect on hepatocellular carcinoma cells and promoted apoptosis in pancreatic and liver cancer cells. The altered gene expression profile upon HQ treatment was in accordance with observed cellular effects. Cells incubated with HQ downregulated the genes acting in cell division and survival, whereas the expression level of genes functioning in cell cycle arrest and apoptosis was elevated. Conclusion: Our data indicate HQ’s competency to limit cancer growth and suggest its utilization as a novel potent anti-carcinogenic agent. Future studies are necessary to provide new insights into the HQ action mechanism and to evaluate its capacity in in-vivo
Integrative analysis of axolotl gene expression data from regenerative and wound healing limb tissues
Full text linkAxolotl (Ambystoma mexicanum) is a urodele amphibian endowed with remarkable regenerative capacities manifested in scarless wound healing and restoration of amputated limbs, which makes it a powerful experimental model for regenerative biology and medicine. Previous studies have utilized microarrays and RNA-Seq technologies for detecting differentially expressed (DE) genes in different phases of the axolotl limb regeneration. However, sufficient consistency may be lacking due to statistical limitations arising from intra-laboratory analyses. This study aims to bridge such gaps by performing an integrative analysis of publicly available microarray and RNA-Seq data from axolotl limb samples having comparable study designs using the "merging" method. A total of 351 genes were found DE in regenerative samples compared to the control in data of both technologies, showing an adjusted p-value 1. Downstream analyses illustrated consistent correlations of the directionality of DE genes within and between data of both technologies, as well as concordance with the literature on regeneration related biological processes. qRT-PCR analysis validated the observed expression level differences of five of the top DE genes. Future studies may benefit from the utilized concept and approach for enhanced statistical power and robust discovery of biomarkers of regeneration
m 6 A Pathway Regulators Are Frequently Mutated in Breast Invasive Carcinoma and May Play an Important Role in Disease Pathogenesis
No full textBreast invasive carcinoma (BIC) is one of the most commonly observed and the deadliest cancer among women. Studies examining the role of epigenetics and regulation of gene expression stand to make important strides in clinical management of BIC. In this context, messenger-RNA (mRNA) modification by regulatory proteins is noteworthy. Methylation of the adenosine base on the sixth nitrogen position is termed as N6-methyladenosine (m6A) modification, and this is the most abundant mRNA modification in mammals. Using several publicly available datasets, we report, in this study, comprehensive analyses and new findings on the impact of epitranscriptome regulatory factors and genetic alterations in m6A pathway genes on BIC. Accordingly, mutation frequency, type, and expression levels were determined. Importantly, we found that VIRMA, METTL14, RBM15B, EIF3B, YTHDF1, and YTHDF3 genes hold potential significance as prognostic biomarker candidates as evidenced in particular by the overall survival analysis. Enrichment of gene ontology (GO) terms and KEGG pathways for the tumor samples with genetic alterations in the epitranscriptome regulatory pathways were investigated. Dysregulation of regulatory factors in breast cancer was associated with cell division, and survival-related pathways such as "nuclear division," and "chromosome segregation." Hence, the gained overactivity of these pathways may account for BIC's poor prognosis. In conclusion, these data underscore that m6A pathway regulators are frequently mutated in BIC and likely play a significant role in disease pathogenesis. Epitranscriptome pathway genes warrant further research attention as regulators of cancer growth and biological targets in BIC, and with an eye to personalized medicine in clinical oncology
Cellular and Molecular Comparison of Glioblastoma Multiform Cell Lines
No full textGlioblastoma multiform (GBM) is one of the most severe tumor types. It is highly invasive and characterized as a grade IV neoplastic cancer. Its resistance to chemotherapy-temozolomide (TMZ treatment)-in combination with tumor treating fields (TTFields), limits the cure of GBM. Therefore researchers are searching for new treatment options to increase the length of recurrence time and improve overall survival for GBM patients. Several cell lines have been established and are in use to understand the molecular basis of GBM and to test the developed drugs. On one hand, it is highly advantageous to utilize multiple cell lines with different genetic backgrounds to gain more insight into the characterization and treatment of the disease. However, on the other hand, characteristics of these cell lines such as proliferation rate, invasion, and colony formation capacity differ greatly among these cells. Hence, a detailed comparison concerning molecular and cellular features of commonly used cell lines is essential. In this study, cell proliferation and apoptosis rate, cell migration capacity, and gene expression profile of U87, Ln229, and SvGp12 cells have been investigated and compared
A selective androgen receptor modulator, S4, displays robust anti-cancer activity on hepatocellular cancer cells by negatively regulating PI3K/AKT/mTOR signalling pathway
No full textHepatocellular carcinoma (HCC) is a major global health problem that often correlates with poor prognosis. Due to the insufficient therapy options with limited benefits, it is crucial to identify new therapeutic approaches to overcome HCC. One of the vital signaling pathways in organ homeostasis and male sexual development is Androgen Receptor (AR) signaling. Its activity affects several genes that contribute to cancer characteristics and have essential roles in cell cycle progression, proliferation, angiogenesis, and metastasis. AR signaling has been shown to be misregulated in many cancers, including HCC, suggesting that it might contribute to hepatocarcinogenesis. Targeting AR signaling using anti-androgens, AR inhibitors, or AR-degrading molecules is a powerful and promising strategy to defeat HCC. In this study, AR signaling was targeted by a novel Selective Androgen Receptor Modulator (SARM), S4, in HCC cells to evaluate its potential anti-cancer effect. To date, S4 activity in cancer has not been demonstrated, and our data unrevealed that S4 significantly impaired HCC growth, migration, proliferation, and induced apoptosis through inhibiting PI3K/AKT/mTOR signaling. Since PI3K/AKT/mTOR signaling is frequently activated in HCC and contributes to its aggressiveness and poor prognosis, its negative regulation by the downregulation of critical components via S4 was a prominent finding. Further studies are necessary to investigate the S4 action mechanism and anti-tumorigenic capacity in in-viv
Microbiome and longevity: High abundance of longevity-linked muribaculaceae in the gut of the long-living rodentspalax leucodon
No full textWith a world population living longer as well as marked disparities in life expectancy, understanding the determinants of longevity is one of the priority research agendas in 21st century life sciences. To this end, the blind mole-rat (Spalax leucodon), a subterranean mammalian, has emerged as an exceptional model organism due to its astonishing features such as remarkable longevity, hypoxia and hypercapnia tolerance, and cancer resistance. The microbiome has been found to be a vital parameter for cellular physiology and it is safe to assume that it has an impact on life expectancy. Although the unique characteristics ofSpalaxmake it an ideal experimental model for longevity research, there is limited knowledge of the bacterial composition ofSpalaxmicrobiome, which limits its in-depth utilization. In this study, using 16S rRNA amplicon sequencing, we report the gut and skin bacterial structure ofSpalaxfor the first time. The diversity between fecal and skin samples was manifested in the distant clustering, as revealed by beta diversity analysis. Importantly, the longevity-linked Muribaculaceae bacterial family was found to be the dominating bacterial taxa inSpalaxfecal samples. These new findings contribute toward further development ofSpalaxas a model for longevity research and potential linkages between microbiome composition and longevity.National Institute of Allergy and Infectious Diseases (NIAID) Office of Cyber Infrastructure and Computational Biology (OCICB) in Bethesda, M
Downregulation of Yap1 during limb regeneration results in defective bone formation in axolotl
Full text linkThe Hippo pathway plays an imperative role in cellular processes such as differentiation, regeneration, cell migration, organ growth, apoptosis, and cell cycle. Transcription coregulator component of Hippo pathway, YAP1, promotes transcription of genes involved in cell proliferation, migration, differentiation, and suppressing apoptosis. However, its role in epimorphic regeneration has not been fully explored. The axolotl is a well-established model organism for developmental biology and regeneration studies. By exploiting its remarkable regenerative capacity, we investigated the role of Yap1 in the early blastema stage of limb regeneration. Depleting Yap1 using gene-specific morpholinos attenuated the competence of axolotl limb regeneration evident in bone formation defects. To explore the affected downstream pathways from Yap1 down-regulation, the gene expression profile was examined by employing LC-MS/MS technology. Based on the generated data, we provided a new layer of evidence on the putative roles of increased protease inhibition and immune system activities and altered ECM composition in diminished bone formation capacity during axolotl limb regeneration upon Yap1 deficiency. We believe that new insights into the roles of the Hippo pathway in complex structure regeneration were granted in this study.Science Academ
The first report on circulating microRNAs at Pre- and Post-metamorphic stages of axolotls
No full textMicroRNAs (miRNAs) are endogenously coded small RNAs, implicated in post-transcriptional gene regulation by targeting messenger RNAs (mRNAs). Circulating miRNAs are cell-free molecules, found in body fluids, such as blood and saliva, and emerged recently as potential diagnostic biomarkers. Functions of circulating miRNAs and their roles in target tissues have been extensively investigated in mammals, and the reports on circulating miRNAs in non-mammalian clades are largely missing. Salamanders display remarkable regenerative potential, and the Mexican axolotl (Ambystoma mexicanum), a critically endangered aquatic salamander, has emerged as a powerful model organism in regeneration and developmental studies. This study aimed to explore the circulating miRNA signature in axolotl blood plasma. Small RNA sequencing on plasma samples revealed 16 differentially expressed (DE) circulating miRNAs between neotenic and metamorphic stages out of identified 164 conserved miRNAs. Bioinformatics predictions provided functional annotation of detected miRNAs for both stages and enrichment of DE miRNAs in cancer-related and developmental pathways was notable. Comparison with previous reports on axolotl miRNAs unraveled common and unique members of the axolotl circulating miRNome. Overall, this work provides novel insights into non-mammalian aspects of circulating miRNA biology and expands the multi-omics toolkit for this versatile model organism
Next-generation sequencing to identify molecular regulators of regeneration after spinal cord injury in the axolotl
No full textAksolot beyin ve omurilik de dahil olmak üzere birçok organ ve uzuvlarını rejenere edebilme kapasitesi sayesinde araştırmacıların model organizma olarak kullandığı önemli bir canlıdır. Aksolotun böylesine bir rejeneratif kapasiteye sahip olmasının altında yatan moleküler mekanizmaların ne olduğu konusunda araştırmalar halen devam etmektedir. Memelilerin genel olarak rejenerasyon kapasitesinin kısıtlı olması ve özelde de merkezi sinir sistemi hasarlarını tamamen düzeltememelerine karşılık aksolotda merkezi sinir sistemi rejenerasyonu başarısını sağlayan gen ve yolaklar merak uyandırmaktadır. Transkriptom canlıların belirli bir organ, doku ya da hücre veya belirli bir zaman dilimi için ifade RNA profilinin tümüne verilen isimdir. Bu çalışmada da transkriptom analizinden faydalanarak sinir rejenerasyonunda yer alan çeşitli faktörlerin tanımlanması amaçlanmıştır. Bunun için neotenik aksolotlar kuyruk bölgesinden kesilmiş olup; 0.gün, 1.gün, 4.gün ve 7.gün örnekleri alınarak bu örnekler için RNA dizileme çalışması yapılmıştır. Tanımlanan RNA'lardan anlamlı olarak ifade edilenler, PANTHER Sınıflandırma Sistemi'yle moleküler fonksiyon, biyolojik süreç, hücresel bileşen ve protein sınıf analizi belirlenmiş, STRING veri tabanı ile de protein-protein etkileşimi analiz edilmiştir.Axolotl is a living creature, being used as a model organism through the capacity of regenaration of organs and limbs including the brain and the spinal cord. Researchs issue the underlying molecular mechanism of such a regenerative capacity have been still continuing. Despite mammals have a limited regeneration capacity and they are not able to completely fix central nerve system damages, genes and pathways ensuring central nerve system regeneration success in axolotls arouse curiosity. Transcriptome is the name for a specific organ, tissue, cell or RNA profile for a certain amount of time. This research aims to identify various factors taking place in nerve regeneration. Neotenic axolotls were cut from the queue area. Day 0,1,4 and 7 samples collected and a RNA sequence study conducted based on these samples. Those demonstrating significance among identified RNAs, molecular function by PANTHER classification system, biological process, cellular component and protein category analysis were determined. Additonally, protein-protein interaction analysis was conducted by STRING database
Hydroquinidine Displays a Significant Anti-carcinogenic Activity in Breast and Ovarian Cancer Cells via Inhibiting Cell-cycle and Stimulating Apoptosis
No full textBreast and ovarian cancers are women’s most commonly diagnosed cancers. Seeking an efficient anticarcinogenic compound is still a top priority regarding the aggressiveness of these cancers and the limited benefit of current therapies. Hydroquinidine (HQ) is a natural alkaloid used in arrhythmia and Brugada syndrome. As an ion channel blocker, HQ exhibits its activity by altering ion gradient and membrane potential. Considering the growing evidence of ion channel blockers’ antineoplastic potential, we were prompted to test HQ’s effect on breast and ovarian cancers. MCF-7 and SKOV-3 cell lines were used to inspect how HQ acts on survival, clonogenicity, migration, tumorigenicity, proliferation, and apoptosis. The molecular basis for the remarkable antiproliferative and proapoptotic effect of HQ in these cells was dissected by proteomics. CDK1, PSMB5, PSMC2, MCM2, MCM7, YWHAH, YWHAQ, and YWHAB proteins in HQ-treated MCF-7 cells, and RRM2, PSMD2, PSME2, COX2, COX4l1, and CDK6 proteins in HQ-treated SKOV-3 cells were found as low-abundant, which was noteworthy. Based on the in-depth analysis, upon HQ treatment, several cell cycle-related processes were found as suppressed, whereas apoptosis and ferroptosis pathways were found to be activated. The observed proteome alteration in cancer cells may provide mechanistic explanations for the growth-limiting effects of HQ at the cellular level
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