scholarly journals DICER1 regulates antibacterial function of epididymis by modulating transcription of β-defensins

2018 ◽  
Vol 11 (5) ◽  
pp. 408-420 ◽  
Author(s):  
Chunhua Tang ◽  
Minjie Ni ◽  
Shengsong Xie ◽  
Yao Zhang ◽  
Chaobao Zhang ◽  
...  
Keyword(s):  
Male Fertility ◽  
Antibacterial Properties ◽  
Mouse Line ◽  
Targeted Disruption ◽  
Independent Manner ◽  
Antibacterial Ability ◽  
Principal Cells ◽  
Key Enzyme

Abstract DICER1 is a key enzyme responsible for the maturation of microRNAs. Recent evidences suggested that DICER1 and microRNAs expressed in epididymis were involved in the control of male fertility. However, the exact mechanism remains to be elucidated. Here, we created a mouse line by targeted disruption of Dicer1 gene in the principal cells of distal caput epididymis. Our data indicated that a set of β-defensin genes were downregulated by DICER1 rather than by microRNAs. Moreover, DICER1 was significantly enriched in the promoter of β-defensin gene and controlled transcription. Besides, the antibacterial ability of the adult epididymis significantly declined upon Dicer1 deletion both in vitro and in vivo. And a higher incidence of reproductive defect was observed in middle-aged Dicer1−/− males. These results suggest that DICER1 plays an important role in transcription of β-defensin genes, which are associated with the natural antibacterial properties in a microRNA-independent manner, and further impacts the male fertility.

scholarly journals Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor

2002 ◽  
Vol 157 (2) ◽  
pp. 303-314 ◽  
Author(s):  
Masaki Kato ◽  
Millan S. Patel ◽  
Regis Levasseur ◽  
Ivan Lobov ◽  
Benny H.-J. Chang ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Osteoblast Proliferation ◽  
Targeted Disruption ◽  
Independent Manner ◽  
Wnt Proteins ◽  
Density Lipoprotein Receptor ◽  
And Function

The low-density lipoprotein receptor–related protein (Lrp)-5 functions as a Wnt coreceptor. Here we show that mice with a targeted disruption of Lrp5 develop a low bone mass phenotype. In vivo and in vitro analyses indicate that this phenotype becomes evident postnatally, and demonstrate that it is secondary to decreased osteoblast proliferation and function in a Cbfa1-independent manner. Lrp5 is expressed in osteoblasts and is required for optimal Wnt signaling in osteoblasts. In addition, Lrp5-deficient mice display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis. These results implicate Wnt proteins in the postnatal control of vascular regression and bone formation, two functions affected in many diseases. Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation.

scholarly journals Designing P. aeruginosa synthetic phages with reduced genomes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Diana P. Pires ◽  
Rodrigo Monteiro ◽  
Dalila Mil-Homens ◽  
Arsénio Fialho ◽  
Timothy K. Lu ◽  
...  
Keyword(s):  
Galleria Mellonella ◽  
Antibacterial Properties ◽  
Genetically Engineered ◽  
In Vivo Studies ◽  
Infection Model ◽  
Promising Therapeutic Approach ◽  
Genes Encoding ◽  
First Time

AbstractIn the era where antibiotic resistance is considered one of the major worldwide concerns, bacteriophages have emerged as a promising therapeutic approach to deal with this problem. Genetically engineered bacteriophages can enable enhanced anti-bacterial functionalities, but require cloning additional genes into the phage genomes, which might be challenging due to the DNA encapsulation capacity of a phage. To tackle this issue, we designed and assembled for the first time synthetic phages with smaller genomes by knocking out up to 48% of the genes encoding hypothetical proteins from the genome of the newly isolated Pseudomonas aeruginosa phage vB_PaeP_PE3. The antibacterial efficacy of the wild-type and the synthetic phages was assessed in vitro as well as in vivo using a Galleria mellonella infection model. Overall, both in vitro and in vivo studies revealed that the knock-outs made in phage genome do not impair the antibacterial properties of the synthetic phages, indicating that this could be a good strategy to clear space from phage genomes in order to enable the introduction of other genes of interest that can potentiate the future treatment of P. aeruginosa infections.

scholarly journals Hypoxia promotes the metastasis of pancreatic cancer through regulating NOX4/KDM5A-mediated histone methylation modification changes in a HIF1A-independent manner

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Hongzhen Li ◽  
Chunyan Peng ◽  
Chenhui Zhu ◽  
Shuang Nie ◽  
Xuetian Qian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Nadph Oxidase ◽  
Western Blot ◽  
Cancer Progression ◽  
Histone Methylation ◽  
Invasion And Metastasis ◽  
Independent Manner ◽  
Nadph Oxidase 4

Abstract Background Hypoxia is a characteristic of the tumor microenvironments within pancreatic cancer (PC), which has been linked to its malignancy. Recently, hypoxia has been reported to regulate the activity of important carcinogenic pathways by changing the status of histone modification. NOX4, a member of NADPH oxidase (NOX), has been found to be activated by hypoxia and promote cancer progression in several cancers. But whether it is involved in the epigenetic changes of tumor cells induced by hypoxia is still unclear, and its biological roles in PC also need to be explored. Methods A hypoxic-related gene signature and its associated pathways in PC were identified by analyzing the pancreatic cancer gene expression data from GEO and TCGA database. Candidate downstream gene (NOX4), responding to hypoxia, was validated by RT-PCR and western blot. Then, we evaluated the relationship between NOX4 expression and clinicopathologic parameters in 56 PC patients from our center. In vitro and in vivo assays were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for a detailed mechanism. Results We quantified hypoxia and developed a hypoxia signature, which was associated with worse prognosis and elevated malignant potential in PC. Furthermore, we found that NADPH oxidase 4 (NOX4), which was induced by hypoxia and upregulated in PC in a HIF1A-independent manner, caused inactivation of lysine demethylase 5A (KDM5A), increased the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). This served to promote the invasion and metastasis of PC. NOX4 deficiency repressed hypoxia-induced EMT, reduced expression of H3K4ME3 and impaired the invasion and metastasis of PC cells; however, knockdown of KDM5A reversed the poor expression of H3KEME3 induced by NOX4 deficiency, thereby promoting EMT. Conclusions This study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.

scholarly journals USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Oncogenesis ◽  
2021 ◽  
Vol 10 (7) ◽  
Author(s):  
Ruize Gao ◽  
David Buechel ◽  
Ravi K. R. Kalathur ◽  
Marco F. Morini ◽  
Mairene Coto-Llerena ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcriptional Activity ◽  
Kinase Inhibitor ◽  
Aerobic Glycolysis ◽  
Hypoxia Inducible Factor ◽  
Aberrant Expression ◽  
Key Enzyme ◽  
Hcc Cells

AbstractUnderstanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1α and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1α, which directly deubiquitylates and stabilizes HIF1α and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1α is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1α transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1α, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

scholarly journals A Possible Role of Allatostatin C in Inhibiting Ecdysone Biosynthesis Revealed in the Mud Crab Scylla paramamosain

2021 ◽  
Vol 8 ◽  
Author(s):  
An Liu ◽  
Wenyuan Shi ◽  
Dongdong Lin ◽  
Haihui Ye
Keyword(s):  
Scylla Paramamosain ◽  
Dependent Manner ◽  
Mud Crab ◽  
Methyl Farnesoate ◽  
Independent Manner ◽  
Wide Range ◽  
Negative Effect

C-type allatostatins (C-type ASTs) are a family of structurally related neuropeptides found in a wide range of insects and crustaceans. To date, the C-type allatostatin receptor in crustaceans has not been deorphaned, and little is known about its physiological functions. In this study, we aimed to functionally define a C-type ASTs receptor in the mud crab, Scylla paramamosian. We showed that C-type ASTs receptor can be activated by ScypaAST-C peptide in a dose-independent manner and by ScypaAST-CCC peptide in a dose-dependent manner with an IC50 value of 6.683 nM. Subsequently, in vivo and in vitro experiments were performed to investigate the potential roles of ScypaAST-C and ScypaAST-CCC peptides in the regulation of ecdysone (20E) and methyl farnesoate (MF) biosynthesis. The results indicated that ScypaAST-C inhibited biosynthesis of 20E in the Y-organ, whereas ScypaAST-CCC had no effect on the production of 20E. In addition, qRT-PCR showed that both ScypaAST-C and ScypaAST-CCC significantly decreased the level of expression of the MF biosynthetic enzyme gene in the mandibular organ, suggesting that the two neuropeptides have a negative effect on the MF biosynthesis in mandibular organs. In conclusion, this study provided new insight into the physiological roles of AST-C in inhibiting ecdysone biosynthesis. Furthermore, it was revealed that AST-C family peptides might inhibit MF biosynthesis in crustaceans.

scholarly journals THE EFFECT OF ESSENTIAL OILS ON MICROORGANISMS CAUSING CARIES AND PERIODONTITIS

2020 ◽  
Vol 20 (2) ◽  
pp. 253-259
Author(s):  
N.M. Devyatkina ◽  
N.O. Bobrova ◽  
E.M. Vazhnichaya
Keyword(s):  
Essential Oils ◽  
Dental Treatment ◽  
Therapeutic Potential ◽  
Oral Care ◽  
Antibacterial Properties ◽  
Herbal Medicines ◽  
Oral Streptococci ◽  
Tea Tree

The oral cavity contains a large number of bacteria, some of which are involved in the development of caries and periodontitis (S. mutans, S. sobrinus, Lactobacilli spp, P. intermedia, P. gingivalis, and T. forythus). The disadvantages of existing antiseptics used in dentistry necessitate the study of antibacterial properties of herbal medicines, and, in particular, of essential oils. The aim of this review is to provide the analysis of literature sources from PubMed and Google Scholar databases related to the effects of essential oils of cloves, mint, thyme, eucalyptus, tea tree and their components on cariogenic and periodontopathic microflora. It was found out that the most in vitro studies evaluated the effects of essential oils or isolated compounds (eugenol, menthol, thymol, carvacrol, eucalyptol, and terpinene-4-ol) on S. mutans, which is considered to be the most cariogenic of oral streptococci, and the researchers limited to defining the susceptibility of the microorganism and effects on biofilm formation. Only in a few studies, the effects of essential oils on the virulence factors of oral pathogens, in particular glycosyl transferase, are represented. Clinical trials of essential oils, their components and combinations confirm the therapeutic potential of these agents in vivo, but raise the question of their effectiveness, taking into account the short-term action, which does not exceed the potency of chlorhexidine. Essential oils of cloves, mint, thyme, eucalyptus, tea tree and their components should be used for treating caries and periodontitis. They are also promising when used as agents of the oral care products, preservatives of the dental medicinal forms, and as remedies for halitosis. With a rational prescription, essential oils can be useful in improving the quality of dental treatment and preventive procedures.

scholarly journals TNFα Potently Activates Osteoclasts, through a Direct Action Independent of and Strongly Synergistic with RANKL

Endocrinology ◽  
2002 ◽  
Vol 143 (3) ◽  
pp. 1108-1118 ◽  
Author(s):  
Karen Fuller ◽  
Chiho Murphy ◽  
Barrie Kirstein ◽  
Simon W. Fox ◽  
Timothy J. Chambers
Keyword(s):  
Direct Action ◽  
Ring Formation ◽  
Actin Ring ◽  
Independent Manner ◽  
Low Concentrations ◽  
Order Of Magnitude ◽  
Extreme Sensitivity ◽  
Osteoclastic Differentiation

Abstract TNFα is pivotal to the pathogenesis of inflammatory and possibly postmenopausal osteolysis. Much recent work has clarified mechanisms by which TNFα promotes osteoclastogenesis, but the means by which it activates osteoclasts to resorb bone remain uncertain. We found that very low concentrations of TNFα promoted actin ring formation, which correlates with functional activation in osteoclasts, both in osteoclasts formed in vitro and extracted from newborn rats. TNFα was equipotent with RANKL for this action. Activation by TNFα was unaffected by blockade of RANKL by OPG, its soluble decoy receptor, suggesting that this was due to a direct action on osteoclasts. Bone resorption was similarly directly and potently stimulated, in a RANKL-independent manner in osteoclasts, whether these were formed in vitro or in vivo. Interestingly, TNFα promoted actin ring formation at concentrations an order of magnitude below those required for osteoclastic differentiation. Moreover, TNFα strongly synergized with RANKL, such that miniscule concentrations of TNFα were sufficient to substantially augment osteoclast activation. The extreme sensitivity of osteoclasts to activation by TNFα suggests that the most sensitive osteolytic response of bone to TNFα is through activation of existing osteoclasts; and the strong synergy with RANKL provides a mechanism whereby increased osteolysis can be achieved without disturbance to the underlying pattern of osteoclastic localization.

Abstract 140: Anti-inflammatory and Anti-atherogenic Role of Bmp Receptor II In Endothelial Cells

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Chanwoo Kim ◽  
Hannah Song ◽  
Sandeep Kumar ◽  
Douglas Nam ◽  
Hyuk Sang Kwon ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Intracellular Signaling ◽  
Independent Manner ◽  
Disturbed Flow ◽  
Bmp Receptors ◽  
Endothelial Inflammation ◽  
Anti Inflammatory

Atherosclerosis is a multifactorial disease that arises from a combination of endothelial dysfunction and inflammation, occurring preferentially in arterial regions exposed to disturbed flow. Bone morphogenic protein-4 (BMP4) produced by disturbed flow induces inflammation, endothelial dysfunction and hypertension, suggesting the importance of BMPs in vascular biology and disease. BMPs bind to two different types of BMP receptors (BMPRI and II) to instigate intracellular signaling. Increasing evidences suggest a correlative role of BMP4 and atherosclerosis, but the role of BMP receptors especially BMPRII in atherosclerosis is still unclear and whether knockdown of BMPRII is the cause or the consequence of atherosclerosis is still not known. It is therefore, imperative to investigate the mechanisms by which BMPRII expression is modulated and its ramifications in atherosclerosis. Initially, we expected that knockdown of BMPRII will result in loss of pro-atherogenic BMP4 signaling and will thereby prevent atherosclerosis. Contrarily, we found that loss of BMPRII expression causes endothelial inflammation and atherosclerosis. Using BMPRII siRNA and BMPRII +/- mice, we found that BMPRII knockdown induces endothelial inflammation in a BMP-independent manner via mechanisms involving reactive oxygen species (ROS), NFκB, and NADPH oxidases. Further, BMPRII +/- ApoE -/- mice develop accelerated atherosclerosis compared to BMPRII +/+ ApoE -/- mice, suggesting loss of BMPRII may induce atherosclerosis. Interestingly, we found that multiple pro-atherogenic stimuli such as hypercholesterolemia, disturbed flow, pro-hypertensive angiotensin II, and pro-inflammatory cytokine, TNFα, downregulate BMPRII expression in endothelium, while anti-atherogenic stimuli such as stable flow and statin treatment upregulate its expression, both in vivo and in vitro . Moreover, we found that BMPRII expression is significantly diminished in human coronary advanced atherosclerotic lesions. These results suggest that BMPRII is a critical, anti-inflammatory and anti-atherogenic protein that is commonly targeted by multiple pro- and anti-atherogenic factors. BMPRII could be used as a novel diagnostic and therapeutic target in atherosclerosis.

scholarly journals Graphene Family Nanomaterials: Properties and Potential Applications in Dentistry

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Ziyu Ge ◽  
Luming Yang ◽  
Fang Xiao ◽  
Yani Wu ◽  
Tingting Yu ◽  
...  
Keyword(s):  
Biomedical Applications ◽  
Current Knowledge ◽  
Antibacterial Properties ◽  
Biological Properties ◽  
New Materials ◽  
Clinical Reality ◽  
Comprehensive Literature Review ◽  
Potential Applications

Graphene family nanomaterials, with superior mechanical, chemical, and biological properties, have grabbed appreciable attention on the path of researches seeking new materials for future biomedical applications. Although potential applications of graphene had been highly reviewed in other fields of medicine, especially for their antibacterial properties and tissue regenerative capacities, in vivo and in vitro studies related to dentistry are very limited. Therefore, based on current knowledge and latest progress, this article aimed to present the recent achievements and provide a comprehensive literature review on potential applications of graphene that could be translated into clinical reality in dentistry.

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