scholarly journals Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Charanya Sampathkumar ◽  
Yuan-Ju Wu ◽  
Mayur Vadhvani ◽  
Thorsten Trimbuch ◽  
Britta Eickholt ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Synapse Formation ◽  
Neurodevelopmental Disorder ◽  
Glutamatergic Neurons ◽  
Trkb Receptors ◽  
Wide Range ◽  
Bdnf Signaling

Mutations in the MECP2 gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re-expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons in vitro and in vivo. These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system.

scholarly journals Ways into Understanding HIF Inhibition

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 159
Author(s):  
Tina Schönberger ◽  
Joachim Fandrey ◽  
Katrin Prost-Fingerle
Keyword(s):  
Protein Interactions ◽  
Target Genes ◽  
Protein Protein Interactions ◽  
Low Oxygen ◽  
Drug Candidates ◽  
Open Questions ◽  
Wide Range ◽  
Hif Pathway

Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds.

scholarly journals The Anticancer Effects of Paeoniflorin and Its Underlying Mechanisms

2019 ◽  
Vol 14 (9) ◽  
pp. 1934578X1987640
Author(s):  
Li-Juan Deng ◽  
Yu-He Lei ◽  
Tsz-Fung Chiu ◽  
Ming Qi ◽  
Hua Gan ◽  
...  
Keyword(s):  
Recent Progress ◽  
Antitumor Effect ◽  
Molecular Mechanisms ◽  
Experimental Studies ◽  
Future Prospects ◽  
Anticancer Effects ◽  
Wide Range ◽  
Underlying Mechanisms

Paeoniflorin (PF) is an important pharmacological component of some Chinese traditional herbal formulas, such as Bai Shao, Chi Shao, and Dan Pi, which have been clinically used for centuries. Although many experimental studies have explored a wide range of pharmacological properties of PF, including anticancer, anti-inflammatory, antioxidant, immunoregulatory, and prevention of insulin resistance, there is no review to describe these reported effects systematically, especially the antitumor effect and the underlying mechanisms. In this review, we summarize the recent progress on the anticancer profiles both in vitro and in vivo of PF. Moreover, we highlight the integrated molecular mechanisms of PF and contemplate its future prospects as a potential anticancer drug.

scholarly journals Pleiotropic Biological Effects of Dietary Phenolic Compounds and their Metabolites on Energy Metabolism, Inflammation and Aging

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 596 ◽  
Author(s):  
María del Carmen Villegas-Aguilar ◽  
Álvaro Fernández-Ochoa ◽  
María de la Luz Cádiz-Gurrea ◽  
Sandra Pimentel-Moral ◽  
Jesús Lozano-Sánchez ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Phenolic Compounds ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Biological Properties ◽  
In Vivo Studies ◽  
Wide Range ◽  
High Prevalence

Dietary phenolic compounds are considered as bioactive compounds that have effects in different chronic disorders related to oxidative stress, inflammation process, or aging. These compounds, coming from a wide range of natural sources, have shown a pleiotropic behavior on key proteins that act as regulators. In this sense, this review aims to compile information on the effect exerted by the phenolic compounds and their metabolites on the main metabolic pathways involved in energy metabolism, inflammatory response, aging and their relationship with the biological properties reported in high prevalence chronic diseases. Numerous in vitro and in vivo studies have demonstrated their pleiotropic molecular mechanisms of action and these findings raise the possibility that phenolic compounds have a wide variety of roles in different targets.

scholarly journals Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Sandra Muñoz-Galván ◽  
Blanca Felipe-Abrio ◽  
Eva M. Verdugo-Sivianes ◽  
Marco Perez ◽  
Manuel P. Jiménez-García ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Hippo Pathway ◽  
Ovarian Tumors ◽  
Tumor Resistance ◽  
Functional Link ◽  
The Hippo Pathway

Abstract Background Ovarian cancer is one of the most common and malignant cancers, partly due to its late diagnosis and high recurrence. Chemotherapy resistance has been linked to poor prognosis and is believed to be linked to the cancer stem cell (CSC) pool. Therefore, elucidating the molecular mechanisms mediating therapy resistance is essential to finding new targets for therapy-resistant tumors. Methods shRNA depletion of MYPT1 in ovarian cancer cell lines, miRNA overexpression, RT-qPCR analysis, patient tumor samples, cell line- and tumorsphere-derived xenografts, in vitro and in vivo treatments, analysis of data from ovarian tumors in public transcriptomic patient databases and in-house patient cohorts. Results We show that MYPT1 (PPP1R12A), encoding myosin phosphatase target subunit 1, is downregulated in ovarian tumors, leading to reduced survival and increased tumorigenesis, as well as resistance to platinum-based therapy. Similarly, overexpression of miR-30b targeting MYPT1 results in enhanced CSC-like properties in ovarian tumor cells and is connected to the activation of the Hippo pathway. Inhibition of the Hippo pathway transcriptional co-activator YAP suppresses the resistance to platinum-based therapy induced by either low MYPT1 expression or miR-30b overexpression, both in vitro and in vivo. Conclusions Our work provides a functional link between the resistance to chemotherapy in ovarian tumors and the increase in the CSC pool that results from the activation of the Hippo pathway target genes upon MYPT1 downregulation. Combination therapy with cisplatin and YAP inhibitors suppresses MYPT1-induced resistance, demonstrating the possibility of using this treatment in patients with low MYPT1 expression, who are likely to be resistant to platinum-based therapy.

scholarly journals TRA1, a Novel mRNA Highly Expressed in Leukemogenic Mouse Monocytic Sublines But Not in Nonleukemogenic Sublines

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2975-2985 ◽  
Author(s):  
Takashi Kasukabe ◽  
Junko Okabe-Kado ◽  
Yoshio Honma
Keyword(s):  
Amino Acids ◽  
Cdna Library ◽  
Molecular Mechanisms ◽  
Bone Marrow Cells ◽  
S2 Cells ◽  
Normal Tissues ◽  
Wide Range ◽  
P Cells

Abstract Mouse monocytic Mm-A, Mm-P, Mm-S1, and Mm-S2 cells are sublines of mouse monocytic and immortalized Mm-1 cells derived from spontaneously differentiated, mouse myeloblastic M1 cells. Although these subline cells retain their monocytic characteristics in vitro, Mm-A and Mm-P cells are highly leukemogenic to syngeneic SL mice and athymic nude mice, whereas Mm-S1 and Mm-S2 cells are not or are only slightly leukemogenic. To better understand the molecular mechanisms of these levels of leukemogenicity, we investigated putative leukemogenesis-associated genes or oncogenes involved in the maintenance of growth, especially in vivo, by means of differential mRNA display. We isolated a fragment clone (15T01) from Mm-P cells. The mRNA probed with 15T01 was expressed at high levels in leukemogenic Mm-P and Mm-A cells but not in nonleukemogenic Mm-S1 and Mm-S2 cells. The gene corresponding to 15T01, named TRA1, was isolated from an Mm-P cDNA library. The longest open reading frame of the TRA1 clone predicts a peptide containing 204 amino acids with a calculated molecular weight of 23,049 D. The predicted TRA1 protein is cysteine-rich and contains multiple cysteine doublets. A putative normal counterpart gene, named NOR1, was also isolated from a normal mouse kidney cDNA library and sequenced. NOR1 cDNA predicts a peptide containing 234 amino acids. The sequence of 201 amino acids from the C-terminal NOR1 was completely identical to that of TRA1, whereas the remaining N-terminal amino acids (33 amino acids) were longer than that (3 amino acids) of TRA1 and the N-terminus of NOR1 protein contained proline-rich sequence. A similarity search against current nucleotide and protein sequence databases indicated that the NOR1/TRA1 gene(s) is conserved in a wide range of eukaryotes, because apparently homologous genes were identified in Caenorhabditis elegans and Saccharomyces cerevisiae genomes. Northern blotting using TRA1-specific and NOR1-specific probes indicated that TRA1 mRNA is exclusively expressed in leukemogenic but not in nonleukemogenic Mm sublines and normal tissues and also indicated that NOR1 mRNA is expressed in normal tissues, especially in kidney, lung, liver, and bone marrow cells but not in any Mm sublines. After leukemogenic Mm-P cells were induced to differentiate into normal macrophages by sodium butyrate, the normal counterpart, NOR1, was expressed, whereas the TRA1 level decreased. Furthermore, transfection of TRA1 converted nonleukemogenic Mm-S1 cells into leukemogenic cells. These results indicate that the TRA1 gene is associated at least in part with the leukemogenesis of monocytic Mm sublines.

scholarly journals Apigenin Inhibits the Growth of Hepatocellular Carcinoma Cells by Affecting the Expression of microRNA Transcriptome

2021 ◽  
Vol 11 ◽  
Author(s):  
Shou-Mei Wang ◽  
Pei-Wei Yang ◽  
Xiao-Jun Feng ◽  
Yi-Wei Zhu ◽  
Feng-Jun Qiu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Dependent Manner ◽  
Regulatory Pathways ◽  
The Core ◽  
Huh7 Cells

BackgroundApigenin, as a natural flavonoid, has low intrinsic toxicity and has potential pharmacological effects against hepatocellular carcinoma (HCC). However, the molecular mechanisms involving microRNAs (miRNAs) and their target genes regulated by apigenin in the treatment of HCC have not been addressed.ObjectiveIn this study, the molecular mechanisms of apigenin involved in the prevention and treatment of HCC were explored in vivo and in vitro using miRNA transcriptomic sequencing to determine the basis for the clinical applications of apigenin in the treatment of HCC.MethodsThe effects of apigenin on the proliferation, cell cycle progression, apoptosis, and invasion of human hepatoma cell line Huh7 and Hep3B were studied in vitro, and the effects on the tumorigenicity of Huh7 cells were assessed in vivo. Then, a differential expression analysis of miRNAs regulated by apigenin in Huh7 cells was performed using next-generation RNA sequencing and further validated by qRT-PCR. The potential genes targeted by the differentially expressed miRNAs were identified using a curated miRTarBase miRNA database and their molecular functions were predicted using Gene Ontology and KEGG signaling pathway analysis.ResultsCompared with the control treatment group, apigenin significantly inhibited Huh7 cell proliferation, cell cycle, colony formation, and cell invasion in a concentration-dependent manner. Moreover, apigenin reduced tumor growth, promoted tumor cell necrosis, reduced the expression of Ki67, and increased the expression of Bax and Bcl-2 in the xenograft tumors of Huh7 cells. Bioinformatics analysis of the miRNA transcriptome showed that hsa-miR-24, hsa-miR-6769b-3p, hsa-miR-6836-3p, hsa-miR-199a-3p, hsa-miR-663a, hsa-miR-4739, hsa-miR-6892-3p, hsa-miR-7107-5p, hsa-miR-1273g-3p, hsa-miR-1343, and hsa-miR-6089 were the most significantly up-regulated miRNAs, and their key gene targets were MAPK1, PIK3CD, HRAS, CCND1, CDKN1A, E2F2, etc. The core regulatory pathways of the up-regulated miRNAs were associated with the hepatocellular carcinoma pathway. The down-regulated miRNAs were hsa-miR-181a-5p and hsa-miR-148a-3p, and the key target genes were MAPK1, HRAS, STAT3, FOS, BCL2, SMAD2, PPP3CA, IFNG, MET, and VAV2, with the core regulatory pathways identified as proteoglycans in cancer pathway.ConclusionApigenin can inhibit the growth of HCC cells, which may be mediated by up-regulation or down-regulation of miRNA molecules and their related target genes.

RNAi-based gene therapy provides a wide variety of applications. Safe, biodegradable nano delivery vectors are still needed

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Clinical Trials ◽  
Target Genes ◽  
Endosomal Escape ◽  
Cell Uptake ◽  
Clinical Investigations ◽  
Wide Range ◽  
Production Techniques ◽  
High Degree

The considerable influence of siRNA and shRNA in controlling CRC by activating apoptosis and preventing CRC formation has been proven in vitro and in vivo research. Furthermore, the combined actions of inhibitors and RNAi-mediated gene knockdown may result in novel cancer therapy approaches.RNAi-based approaches give a wide range of prospective applications and a high degree of freedom to manipulate heretofore "unhackable" targets. However, in clinical investigations, RNAi medications are a major challenge to overcome. Furthermore, compared to other cancers such as melanoma, colon cancer has seen fewer clinical trials due to its tissue complexity. While new delivery strategies and materials are being investigated to increase distribution efficiency, randomized controlled trials must be done before treatment recommendations utilize RNAi. Safe, biodegradable and biocompatible NP delivery systems are still needed. Repeatable and simple batch production techniques for clinical trials and regulatory evaluations need to be created. Since unmodified siRNAs have limited cell uptake, they must be conjugated or complexed with suitable carrier systems. Furthermore, by combining siRNAs with adaptive and biocompatible nonviral carriers, the short half-life of siRNAs may be regulated due to their quick plasma and cell cytoplasm breakdown. Clinical trials should be explored with improved techniques to enhance RNAi medication encapsulation in lipid-based NPs such as liposomes or biodegradable polymers such as PLGA, cellular uptake and endosomal escape in mCRC cells. Advances in nanotechnology and medicinal chemistry may help address these issues, and adoption of RNAi-based therapeutics may increase.Another crucial part of employing RNAi-based therapeutics is finding suitable targets. Besides knowing target genes and pathways for CRC advancement, understanding modifying genes that compensate for the effect of target gene loss function and the degree of gene silence necessary is crucial.

scholarly journals miR-139 Functions as An Antioncomir to Repress Glioma Progression Through Targeting IGF-1 R, AMY-1, and PGC-1β

2016 ◽  
Vol 16 (4) ◽  
pp. 497-511 ◽  
Author(s):  
Hong Wang ◽  
Xi Yan ◽  
Li-Ya Ji ◽  
Xi-Tuan Ji ◽  
Ping Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Epigenetic Modification ◽  
Negative Control ◽  
Peroxisome Proliferator ◽  
Insulin Like Growth Factor ◽  
Peroxisome Proliferator Activated Receptor

Gliomas are the most common primary malignant brain tumor with poor prognosis, characterized by a highly heterogeneous cell population, extensive proliferation, and migration. A lot of molecular mechanisms regulate gliomas development and invasion, including abnormal expression of oncogenes and variation of epigenetic modification. MicroRNAs could affect cell growth and functions. Several reports have demonstrated that miR-139 plays multifunctions in kinds of solid tumors through different pathways. However, the antitumor mechanisms of this miR-139 are not unveiled in detail. In this study, we not only validated the low expression level of miR-139 in glioma tissues and cell lines but also detected the effect of miR-139 on modulating gliomas proliferation and invasion both in vitro and in vivo. We identified insulin-like growth factor 1 receptor, associate of Myc 1, and peroxisome proliferator-activated receptor γ coactivator 1β as direct targets of miR-139 and the levels of them were all inversely correlated with miR-139 in gliomas. Insulin like growth factor 1 receptor promoted gliomas invasion through Akt signaling and increased proliferation in the peroxisome proliferator-activated receptor γ coactivator 1β-dependent way. Associate of Myc 1 also facilitated gliomas progression by activating c-Myc pathway. Overexpression of the target genes could retrieve the antitumor function of miR-139, respectively, in different degrees. The nude mice transplantation tumor experiment displayed that glioma cells stably expressed miR-139 growth much slower in vivo than the negative control cells. Taken together, these findings suggested miR-139 acted as a favorable factor against gliomas progression and uncovered a novel regulatory mechanism, which may provide a new evidenced prognostic marker and therapeutic target for gliomas.

scholarly journals Thrombopoietin (TPO) Induces Hematopoietic Differentiation of Mouse ES Cells Via HIF-1 Alpha-Dependent Activation of a BMP4 Autoregulatory Loop

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1186-1186
Author(s):  
Azadeh Zahabi ◽  
Tatsuya Morishima ◽  
Andri Pramono ◽  
Dan Lan ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Es Cells ◽  
Embryonic Stem ◽  
Efficient Production ◽  
Hematopoietic Differentiation ◽  
Hematopoietic Stem

Abstract Understanding the molecular mechanisms underlying hematopoietic differentiation of embryonic stem (ES) cells may help to ascertain the optimal conditions for the production of hematopoietic cells as a source for transplantation or experimental use. Previously, we found that patients with congenital amegakaryocytic thrombocytopenia (CAMT), who develop pancytopenia early after birth, harbor mutations within the thrombopoietin (TPO) receptor, c-mpl. This knowledge, together with observations in vitro and in animal models in vivo, suggests that TPO/c-mpl signaling promotes early hematopoiesis. However, the downstream mechanisms underlying TPO signaling are not fully elucidated. Here, we describe for the first time a direct connection between the TPO and bone morphogenetic protein 4 (BMP4) signaling pathways in the hematopoietic fate decision of ES cells. BMP4 is a classical morphogen and a well-known inducer of early hematopoietic differentiation of ES cells. Treatment of ES cells with TPO induced the autocrine production of BMP4 by ES cells with concomitant upregulation of the BMP receptor, BMPR1A, phosphorylation of Smad1, 5, and 8 and activation of the specific target genes, Id1, 2, and 3, and Msx1 and 2. This was mediated by TPO-dependent binding of the HIF-1α transcription factor to the BMP4 gene promoter, resulting in further activation of the BMP4-autoregulatory loop. Treatment of ES cells with the BMP antagonist noggin substantially reduced TPO-dependent hematopoietic differentiation of ES cell. Taken together, our findings contribute to the understanding the mechanisms of hematopoietic differentiaiton of ES cells and might help to establish new methods for the efficient production of hematopoietic stem cells in vitro. Disclosures No relevant conflicts of interest to declare.

Cnidium monnieri: A Review of Traditional Uses, Phytochemical and Ethnopharmacological Properties

2015 ◽  
Vol 43 (05) ◽  
pp. 835-877 ◽  
Author(s):  
Yi-Min Li ◽  
Min Jia ◽  
Hua-Qiang Li ◽  
Nai-Dan Zhang ◽  
Xian Wen ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Herbal Medicines ◽  
In Vivo Studies ◽  
Active Constituent ◽  
Active Constituents ◽  
Traditional Uses ◽  
Male Impotence ◽  
Wide Range

Cnidium monnieri (L.) Cuss., an annual plant of the Umbelliferae species is one of the most widely used traditional herbal medicines and its fruits have been used to treat a variety of diseases in China, Vietnam, and Japan. The aim of this review is to provide an up-to-date and comprehensive analysis of the botany, traditional uses, phytochemistry, pharmacology, toxicity and contraindication of Cnidium monnieri (L.) Cuss. and to provide future directions of research on this plant. To date, 350 compounds have been isolated and identified from Cnidium monnieri (L.) Cuss., including the main active constituent, coumarins. In vitro and in vivo studies suggest that osthole and other coumarin compounds possess wide range of pharmacological properties for the treatment of female genitals, male impotence, frigidity, skin-related diseases, and exhibit strong antipruritic, anti-allergic, antidermatophytic, antibacterial, antifungal, anti-osteoporotic effects. Although coumarins have been identified as the main active constituents responsible for the observed pharmacological effects, the molecular mechanisms of their actions are still unknown. Therefore, further studies are still required to reveal the structure–activity relationship of these active constituents. In addition, toxicological and clinical studies are also required to provide further data for pharmaceutical use.

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