scholarly journals RIP1 Perturbation Induces Chondrocyte Necroptosis and Promotes Osteoarthritis Pathogenesis via Targeting BMP7

2021 ◽  
Vol 9 ◽  
Author(s):  
Jin Cheng ◽  
Xiaoning Duan ◽  
Xin Fu ◽  
Yanfang Jiang ◽  
Peng Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cartilage Degradation ◽  
Vital Role ◽  
Interacting Protein ◽  
Downstream Target ◽  
Disease Modifying Therapy ◽  
Morphogenetic Protein ◽  
Joint Disorder

Osteoarthritis (OA) is a highly prevalent and debilitating joint disorder that characterized by progressive destruction of articular cartilage. There is no effective disease-modifying therapy for the condition due to limited understanding of the molecular mechanisms on cartilage maintenance and destruction. Receptor-interacting protein kinase 1 (RIP1)-mediated necroptosis plays a vital role in various diseases, but the involvement of RIP1 in OA pathogenesis remains largely unknown. Here we show that typical necrotic cell morphology is observed within human OA cartilage samples in situ, and that RIP1 is significantly upregulated in cartilage from both OA patients and experimental OA rat models. Intra-articular RIP1 overexpression is sufficient to induce structural and functional defects of cartilage in rats, highlighting the crucial role of RIP1 during OA onset and progression by mediating chondrocyte necroptosis and disrupting extracellular matrix (ECM) metabolism homeostasis. Inhibition of RIP1 activity by its inhibitor necrostatin-1 protects the rats from trauma-induced cartilage degradation as well as limb pain. More importantly, we identify bone morphogenetic protein 7 (BMP7) as a novel downstream target that mediates RIP1-induced chondrocyte necroptosis and OA manifestations, thereby representing a non-canonical regulation mode of necroptosis. Our study supports a model whereby the activation of RIP1-BMP7 functional axis promotes chondrocyte necroptosis and subsequent OA pathogenesis, thus providing a new therapeutic target for OA.

scholarly journals The role of m6A modification in the biological functions and diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiulin Jiang ◽  
Baiyang Liu ◽  
Zhi Nie ◽  
Lincan Duan ◽  
Qiuxia Xiong ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Rna Modification ◽  
Biological Functions ◽  
Rna Methylation ◽  
Downstream Target ◽  
Different Types ◽  
M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

Nutrigenomics and Life Style Facet- A Modulatory Molecular Evidence in Progression of Breast and Colon Cancer with Emerging Importance

2021 ◽  
Vol 21 ◽  
Author(s):  
Suman Kumar Ray ◽  
Sukhes Mukherjee
Keyword(s):  
Colon Cancer ◽  
Molecular Mechanisms ◽  
Health Management ◽  
Vital Role ◽  
Molecular Evidence ◽  
Nutritional Interventions ◽  
Phenotypic Alteration ◽  
The Individual ◽  
Supplement Intake

: Legitimate nutrition assumes a significant role in preventing diseases and, in this way, nutritional interventions establish vital strategies in the area of public health. Nutrigenomics centres on the different genes and diet in an individual and how an individual’s genes influence the reaction to bioactive foodstuff. It targets considering the genetic and epigenetic interactions with nutrients to lead to a phenotypic alteration and consequently to metabolism, differentiation, or even apoptosis. Nutrigenomics and lifestyle factors play a vital role in health management and represent an exceptional prospect for the improvement of personalized diets to the individual at risk of developing diseases like cancer. Concerning cancer as a multifactorial genetic ailment, several aspects need to be investigated and analysed. Various perspectives should be researched and examined regarding the development and prognosis of breast and colon cancer. Malignant growth occurrence is anticipated to upsurge in the impending days, and an effective anticipatory strategy is required. The effect of dietary components, basically studied by nutrigenomics, looks at gene expression and molecular mechanisms. It also interrelates bioactive compounds and nutrients because of different 'omics' innovations. Several preclinical investigations demonstrate the pertinent role of nutrigenomics in breast and colon cancer, and change of dietary propensities is conceivably a successful methodology for reducing cancer risk. The connection between the genomic profile of patients with breast or colon cancer and their supplement intake, it is conceivable to imagine an idea of personalized medicine, including nutrition and medicinal services.

scholarly journals Transcriptome-Wide Analyses Provide Insights into Development of the Hedychium Coronarium Flower, Revealing Potential Roles of PTL

2020 ◽  
Author(s):  
Tong Zhao ◽  
Alma Piñeyro-Nelson ◽  
Qianxia Yu ◽  
Xiaoying Hu ◽  
Huanfang Liu ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Flower Development ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Floral Organ ◽  
Mrna In Situ Hybridization ◽  
Hedychium Coronarium ◽  
Organ Identity

Abstract Background:The flower of Hedychium coronarium possesses highly specialized floral organs: a synsepalous calyx, petaloid staminodes and a labellum. The formation of these organs is controlled by two gene categories: floral organ identity genes and organ boundary genes, which may function individually or jointly during flower development. Although the floral organogenesis of H. coronarium has been studied at the morphological level, the underlying molecular mechanisms involved in its floral development still remain poorly understood. In addition, previous works analyzing the role of MADS-box genes in controlling floral organ specification in some Zingiberaceae did not address the molecular mechanisms involved in the formation of particular organ morphologies that emerge later in flower development, such as the synsepalous calyx formed through intercalary growth of adjacent sepals. Results:Here, we used comparative transcriptomics combined with Real-time quantitative PCR and mRNA in situ hybridization to investigate gene expression patterns of ABC-class genes in H. coronarium flowers, as well as the homolog of the organ boundary gene PETAL LOSS (HcPTL). qRT-PCR detection showed that HcAP3 and HcAG were expressed in both the petaloid staminode and the fertile stamen. mRNA in situ hybridization showed that HcPTL was expressed in developing meristems, including cincinnus primordia, floral primordia, common primordia and almost all new initiating floral organ primordia.Conclusions:Our studies found that stamen/petal identity or stamen fertility in H. coronarium was not necessarily correlated with the differential expression of HcAP3 and HcAG. We also found a novel spatio-temporal expression pattern for HcPTL mRNA, suggesting it may have evolved a lineage-specific role in the morphogenesis of the Hedychium flower. Our study provides a new transcriptome reference and a functional hypothesis regarding the role of a boundary gene in organ fusion that should be further addressed through phylogenetic analyzes of this gene, as well as functional studies.

scholarly journals Chaperone-mediated hierarchical control in targeting misfolded proteins to aggresomes

2011 ◽  
Vol 22 (18) ◽  
pp. 3277-3288 ◽  
Author(s):  
Xingqian Zhang ◽  
Shu-Bing Qian
Keyword(s):  
Protein Folding ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Hierarchical Control ◽  
Dominant Negative ◽  
Misfolded Proteins ◽  
Interacting Protein ◽  
Aggresome Formation

Protein misfolding is a common event in living cells. Molecular chaperones not only assist protein folding; they also facilitate the degradation of misfolded polypeptides. When the intracellular degradative capacity is exceeded, juxtanuclear aggresomes are formed to sequester misfolded proteins. Despite the well-established role of chaperones in both protein folding and degradation, how chaperones regulate the aggregation process remains controversial. Here we investigate the molecular mechanisms underlying aggresome formation in mammalian cells. Analysis of the chaperone requirements for the fate of misfolded proteins reveals an unexpected role of heat shock protein 70 (Hsp70) in promoting aggresome formation. This proaggregation function of Hsp70 relies on the interaction with the cochaperone ubiquitin ligase carboxyl terminal of Hsp70/Hsp90 interacting protein (CHIP). Disrupting Hsp70–CHIP interaction prevents the aggresome formation, whereas a dominant-negative CHIP mutant sensitizes the aggregation of misfolded protein. This accelerated aggresome formation also relies on the stress-induced cochaperone Bcl2-associated athanogene 3. Our results indicate that a hierarchy of cochaperone interaction controls different aspects of the intracellular protein triage decision, extending the function of Hsp70 from folding and degradation to aggregation.

scholarly journals The Role of Non-Coding RNAs in the Sorafenib Resistance of Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Xinyao Hu ◽  
Hua Zhu ◽  
Yang Shen ◽  
Xiaoyu Zhang ◽  
Xiaoqin He ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Vital Role ◽  
Circular Rnas ◽  
First Line ◽  
Advanced Hcc ◽  
Chemotherapy Agent ◽  
Development Of Resistance ◽  
Non Coding Rnas

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Sorafenib is approved by the U.S. Food and Drug Administration to be a first-line chemotherapy agent for patients with advanced HCC. A portion of advanced HCC patients can benefit from the treatment with sorafenib, but many patients ultimately develop sorafenib resistance, leading to a poor prognosis. The molecular mechanisms of sorafenib resistance are sophisticated and indefinite. Notably, non-coding RNAs (ncRNAs), which include long ncRNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs), are critically participated in the occurrence and progression of tumors. Moreover, growing evidence has suggested that ncRNAs are crucial regulators in the development of resistance to sorafenib. Herein, we integrally and systematically summarized the molecular mechanisms and vital role of ncRNAs impact sorafenib resistance of HCC, and ultimately explored the potential clinical administrations of ncRNAs as new prognostic biomarkers and therapeutic targets for HCC.

scholarly journals DDX10 Promotes the Proliferation and Metastasis of Colorectal Cancer Cells via Splicing RPL35

2021 ◽  
Author(s):  
Xin Zhou ◽  
Zhihong Liu ◽  
Cuifeng Zhang ◽  
Manman Jiang ◽  
Yuxiao Jin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Migration And Invasion ◽  
Ppi Network ◽  
Interacting Protein ◽  
Network Analyses ◽  
Potential Biomarker

Abstract Background: Colorectal cancer (CRC) has become the second deadliest cancer in the world and severely threatens human health. An increasing number of studies have focused on the role of the RNA helicase DEAD-box (DDX) family in CRC. However, the mechanism of DDX10 in CRC has not been elucidated.Methods: In our study, we analysed the expression data of CRC samples from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Subsequently, we performed cytological experiments and animal experiments to explore the role of DDX10 in CRC cells. Furthermore, we performed Gene Ontology (GO)/ Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction (PPI) network analyses. Finally, we predicted the interacting protein of DDX10 by LC-MS/MS and verified it by coimmunoprecipitation (Co-IP) and qPCR.Results: In the present study, we identified that DDX10 mRNA was extremely highly expressed in CRC tissues compared with normal colon tissues in the TCGA and GEO databases. The protein expression of DDX10 was measured by immunochemistry (IHC) in 17 CRC patients. The biological roles of DDX10 were explored via cell and molecular biology experiments in vitro and in vivo and cell cycle assays. We found that DDX10 knockdown markedly reduced CRC cell proliferation, migration and invasion. Then, we constructed a PPI network with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). GO and KEGG enrichment analysis and gene set enrichment analysis (GSEA) showed that DDX10 was closely related to RNA splicing and E2F targets. Using LC-MS/MS and Co-IP assays, we discovered that RPL35 is the interacting protein of DDX10. In addition, we hypothesize that RPL35 is related to the E2F pathway and the immune response in CRC.Conclusions: In conclusion, provides a better understanding of the molecular mechanisms of DDX10 in CRC and provides a potential biomarker for the diagnosis and treatment of CRC.

Regulation of hemidesmosome dynamics and cell signaling by integrin α6β4

2021 ◽  
Vol 134 (18) ◽  
Author(s):  
Lisa te Molder ◽  
Jose M. de Pereda ◽  
Arnoud Sonnenberg
Keyword(s):  
Signal Transduction ◽  
Extracellular Matrix ◽  
Cell Adhesion ◽  
Epithelial Cells ◽  
Basement Membrane ◽  
Molecular Mechanisms ◽  
Vital Role ◽  
Cellular Processes ◽  
Integrin Α6β4

ABSTRACT Hemidesmosomes (HDs) are specialized multiprotein complexes that connect the keratin cytoskeleton of epithelial cells to the extracellular matrix (ECM). In the skin, these complexes provide stable adhesion of basal keratinocytes to the underlying basement membrane. Integrin α6β4 is a receptor for laminins and plays a vital role in mediating cell adhesion by initiating the assembly of HDs. In addition, α6β4 has been implicated in signal transduction events that regulate diverse cellular processes, including proliferation and survival. In this Review, we detail the role of α6β4 in HD assembly and beyond, and we discuss the molecular mechanisms that regulate its function.

Abstract 16626: Endothelial Zinc Transporter Zip8 Regulates Ventricular Trabeculation and Compaction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jihyun Jang ◽  
Deqiang Li
Keyword(s):  
Notch Signaling ◽  
Molecular Mechanisms ◽  
Left Ventricular ◽  
Zinc Transporter ◽  
Late Gestation ◽  
Downstream Target ◽  
Conditional Deletion ◽  
Developing Heart ◽  
Morphogenetic Protein ◽  
Downstream Target Gene

Trabeculation and subsequent compaction of the ventricular wall are essential for normal heart morphogenesis. In human, excessive trabeculation and impaired myocardial compaction during earlyheart development lead to left ventricular non compaction (LVNC), a third most common cardiomyopathies after dilated and hypertrophic cardiomyopathies. LVNC is also associated with cardiac arrhythmia and sudden cardiac death. The etiology of LVNC is poorly understood. Recently our group identified that Zip8, a Zinc transporter, implicated in ventricular trabeculation and compaction (JCI, 2018,PMID: 29337306). However, it remains elusive how Zip8 regulates these processes through cellular and molecular mechanisms. We conditionally ablated Zip8 in the endothelial cells, epicardial cells and cardiomyocytes in the developing heart respectively. Strikingly, deletion of Zip8 in the endothelial cellsgave rise to LVNC phenotypes, identical to cardiac phenotypes from the global Zip8 knockouts. Incontrast, hearts with deletions of Zip8 in either epicardium or myocardium developed normally. Further,we found only conditional deletion of Zip8 in the endothelium in the early developing hearts (at E8.5)generated LVNC but not in the late gestation stage (E13.5), suggesting that Zip8 plays critical roles during the initial trabeculation stage. Interestingly, we found that endocardial Zip8 deficiency resulted inthe upregulation of Notch signaling, as evidenced by the increase of intracellular domain of notch protein(NICD) and its downstream target gene, bone morphogenetic protein 10 (BMP10). When the notch signaling is inhibited in the endothelial Zip8 knockout hearts either by DAPI, a γ secretase inhibitor, or by genetic deletion of Rbpj, the LVNC cardiac phenotypes are partially rescued. These results suggest thatZip8 orchestrates myocardial trabeculation and compaction by regulating notch signaling.Collectively, our study provides novel insights into the mechanisms of LVNC, suggesting that genetic mutations in Zip8 or zinc deficiency may contribute to LNVC in humans.

Role of medicinal plants against neurodegenerative diseases

2021 ◽  
Vol 22 ◽  
Author(s):  
Ritika Luthra ◽  
Arpita Roy
Keyword(s):  
Medicinal Plants ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Environmental Changes ◽  
Inflammatory Responses ◽  
Vital Role ◽  
Significant Loss ◽  
Therapeutic Interventions ◽  
Inflammatory Stress

: Diseases with a significant loss of neurons, structurally and functionally are termed as neurodegenerative diseases. Due to the present therapeutic interventions and progressive nature of diseases, a variety of side effects have risen up, thus leading the patients to go for an alternative medication. The role of medicinal plants in such cases has been beneficial because of their exhibition via different cellular and molecular mechanisms. Alleviation in inflammatory responses, suppression of the functionary aspect of pro-inflammatory cytokines like a tumor, improvement in antioxidative properties is among few neuroprotective mechanisms of traditional plants. Variation in transcription and transduction pathways play a vital role in the preventive measures of plants in such diseases. Neurodegenerative diseases are generally caused by depletion of proteins, oxidative and inflammatory stress, environmental changes and so on, with aging being the most important cause. Natural compounds can be used in order to treat neurodegenerative diseases Medicinal plants such as Ginseng, Withania somnifera, Bacopa monnieri, Ginkgo biloba, etc. are some of the medicinal plants for prevention of neurological symptoms. This review deals with the use of different medicinal plants for the prevention of neurodegenerative diseases.

Pharmacological Inhibition of Lck is Able to Revert Glucocorticoid Resistance in Pediatric T-ALL

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 838-838
Author(s):  
Valentina Serafin ◽  
Giorgia Capuzzo ◽  
Gloria Milani ◽  
Silvia Bresolin ◽  
Marica Pinazza ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Survival ◽  
Molecular Mechanisms ◽  
Active Form ◽  
Resistant Cell ◽  
Poor Responders ◽  
Downstream Target ◽  
Blast Cells ◽  
Approved Drugs

Abstract The AIEOP-BFM group has traditionally used the peripheral blood blast cells count after a 7-day glucocorticoids (GC) prephase to classify patients as Prednisone Good Responders (PGR) or Prednisone Poor Responders (PPR). As described by Schrappe M. in 2011, PPR patients tend to have a worse prognosis, despite the fact that all of them are assigned to the High Risk protocol. Little is known about the molecular mechanisms that lead to GC resistance, guiding our research to the identification of new specific molecular targets in order to develop new approaches to improve therapy efficacy in these patients. To this end, we performed a Reverse Phase Protein Analysis (RPPA) of 54 PGR and 33 PPR pediatric T-ALL patients at diagnosis, and studied the activation or expression of 87 proteins involved in key cellular signaling pathways. Interestingly, we found a higher expression of LCK phosphorylated at Y505 (inhibited form) in PGR patients (p=0.001), together with a higher phosphorylation of SRC Y416 (active form) in PPR patients (p=0.01). Total LCK and LCK RNA expression were not differentially expressed in the two subgroups of patients, suggesting an increased activation of LCK in PPR patients. Indeed, in agreement with these results, also LCK downstream target PLCɣ, phosphorylated at Y783, resulted hyperactivated in PPR compared to PGR patients (p=0.05), confirmed also by a positive correlation between PLCɣ Y783 and SRC Y416 (r=0.51, p=0.01). Taken together, these results indicate a hyperactivation of the LCK pathway in PPR patients compared to PGR ones. LCK is part of the TCR multiprotein complex together with the GC receptor. In normal T lymphocytes, after GC treatment the complex is disrupted, LCK activation is decreased and downstream prosurvival signaling inhibited, thus leading to cell death. In this light, in GC resistant patients hyperactivated LCK might sustain cell survival regardless of GC activity. We then tested if FDA-approved or recently developed LCK inhibitors would revert GC resistance in T-ALL cells. GC resistant cell lines ALL-SIL, T-ALL1 and CEM were treated with Dasatinib, Bosutinib, Nintedanib and WH-4-023 alone or in combination with Dexamethasone (Dex). All four inhibitors alone are able to decrease cell survival, and all of them strongly synergize with Dex, bringing to the sensitization of these cells to GC treatment. We also tested these compounds alone or in combination with Dex in 4 PPR T-ALL patients cells derived from xenograft mice. Also in these cases we observed an enhanced sensitization of cells to GC treatment. Finally, corroborating the crucial role of LCK in GC resistance, we observed a strong decrease in cell viability after specific LCK gene silencing and Dex treatment in ALL-SIL cells, together with an increased GC resistance following LCK hyperactivation in P12-ICHIKAWA GC sensitive cells. Thus, our results strongly suggest that the inhibition of LCK using clinically approved drugs could represent a promising new additional therapeutic strategy to revert drug resistance in high-risk pediatric T-ALL patients. Disclosures Indraccolo: OncoMed Pharmaceuticals, Inc.: Research Funding.

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