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6
Authors: Zhu Liang, Andreas Damianou, Elena Di Daniel, Benedikt M. Kessler
Published: Feb 2021
Authors: Zhu Liang, Andreas Damianou, Elena Di Daniel, Benedikt M. Kessler
Published: Feb 2021
Abstract Controlling the activation of the NLRP3 inflammasome by post-translational modifications (PTMs) of critical protein subunits has emerged as a key determinant in inflammatory processes as well as in pathophysiology. In this review, we put into context the kinases, ubiquitin processing and other PTM enzymes that modify NLRP3, ASC/PYCARD and caspase-1, leading to inflammasome regulation, activation and signal termination. Potential target therapeutic entry points for a number of inflammatory diseases focussed on PTM enzyme readers, writers and erasers, leading to the regulation of inflammasome function, are discussed.
1
Authors: Jones, Dakota L., et al
Published: Feb 2021
Authors: Jones, Dakota L., et al
Published: Feb 2021
Matrix stiffness is a central regulator of fibroblast function. However, the transcriptional mechanisms linking matrix stiffness to changes in fibroblast phenotype are incompletely understood. Here, we evaluated the effect of matrix stiffness on genome-wide chromatin accessibility in freshly isolated lung fibroblasts using ATAC-seq. We found higher matrix stiffness profoundly increased global chromatin accessibility relative to lower matrix stiffness, and these alterations were in close genomic proximity to known profibrotic gene programs. Motif analysis of these regulated genomic loci identified ZNF416 as a putative mediator of fibroblast stiffness responses. Genome occupancy analysis using ChIP-seq confirmed that ZNF416 occupies a broad range of genes implicated in fibroblast activation and tissue fibrosis, with relatively little overlap in genomic occupancy with other mechanoresponsive and profibrotic transcriptional regulators. Using loss- and gain-of-function studies, we demonstrated that ZNF416 plays a critical role in fibroblast proliferation, extracellular matrix synthesis, and contractile function. Together, these observations identify ZNF416 as novel mechano-activated transcriptional regulator of fibroblast biology.
1
Authors: Chauhan, Madhu, et al
Published: Feb 2021
Authors: Chauhan, Madhu, et al
Published: Feb 2021
Abstract Effect of fms-like tyrosine kinase (sFLT-1) and angiotensin2 (Ang2) on the function of calcitonin gene-related peptide (CALCB), adrenomedullin (ADM) and adrenomedullin2 (ADM2) in vascular smooth muscle cell, and the effect of preeclampsia (PE) on the sensitivity of omental artery (OA) for these peptides is not known in human pregnancy. Objective: Identify the effect of sFLT-1 and Ang2 on the function of CALCB family peptides in OA smooth muscle cells (OASMC) and assess the sensitivity of OA for these peptides in PE and normotensive pregnancy. Methods: Peptide function was assessed by cAMP assays and wire myograph; mRNA expression by PCR and protein–protein interaction by proximity ligation assay and co-immunoprecipitation. Findings: All 3 peptides increased cAMP synthesis in the order of efficacy CALCB>ADM = ADM2 and VEGF mRNA in OASMC (p < 0.05); sFLT-1 mediated decrease in cAMP synthesis (p < 0.05) is differentially rescued by all 3 CALCB family peptides in OASMC (P < 0.005); sFLT-1 decreased receptor activity modifying protein (RAMP)1 and RAMP2 mRNA expression (p < 0.05); Ang2 decreased the expression of CALCRL and RAMP1 mRNA and desensitized CALCB and ADM2 receptors in OASMC (p < 0.05); sFLT-1 increased RAMP1and Ang2 type 1 receptor (AT1R) interaction in OASMC which is inhibited in presence of all 3 peptides; and all 3 peptides relax OA in PE with enhanced ADM2 response (p < 0.05). Conclusion: sFLT-1 and Ang2 impair OASMC mediated functional responses of CALCB family peptides which can be inhibited by respective peptide treatment. The sensitivity of OA for CALCB, ADM and ADM2-mediated relaxation is retained in PE.
1
Authors: A Komsky-Elbaz, D Kalo, Z Roth
Published: Feb 2021
Authors: A Komsky-Elbaz, D Kalo, Z Roth
Published: Feb 2021
Abstract Atrazine (ATZ) is an extensively used herbicide and ubiquitous environmental contaminant. ATZ and its metabolite, diaminochlorotriazine (DACT), cause several cellular and functional alterations in spermatozoa. We aimed to examine the effect of ATZ/DACT on spermatozoon DNA integrity, fertilization competence, embryonic development and transcriptome profile of in-vitro-produced embryos derived from fertilization with pre-exposed sperm. Bovine spermatozoa exposed to ATZ (0.1 or 1 μM) or DACT (1 or 10 μM) during in-vitro capacitation were used for in-vitro fertilization of untreated oocytes. Cleavage and blastocyst-formation rates were evaluated 42 h and 7 days post-fertilization, respectively. The association between DNA fragmentation and apoptosis (annexin V kit) was determined. Fertilization competence of annexin-positive (AV+) and annexin-negative (AV-) spermatozoa was examined. Microarray analysis was performed for 7-day blastocysts. Intracytoplasmic sperm injection was performed with control (AV+, AV-) and DACT (AV+, AV-) spermatozoa. Cleavage rates did not differ between groups and blastocyst formation tended to be higher for AV- vs. AV+ in both control and DACT groups, suggesting that acrosome reaction, rather than DNA fragmentation, underlies the reduced cleavage. Transcriptomic analysis revealed 139 and 230 differentially expressed genes in blastocysts derived from ATZ- and DACT-exposed spermatozoa, respectively, relative to controls. Proteomic analysis shown differential expression of proteins in ATZ- or DACT-treated spermatozoa, in particular proteins related to cellular processes and biological pathways. Therefore, we assume that factors delivered by the spermatozoa, regardless of DNA fragmentation, are also involved. Overall, the current study reveals a deleterious carryover effect of ATZ/DACT from the spermatozoa to the developing embryo.
1
Authors: Jeremy R Egbert, Jerid W Robinson, Tracy F Uliasz, Lincoln R Potter, Laurinda A Jaffe
Published: Feb 2021
Authors: Jeremy R Egbert, Jerid W Robinson, Tracy F Uliasz, Lincoln R Potter, Laurinda A Jaffe
Published: Feb 2021
Cyclic AMP elevation links luteinizing hormone receptor signaling to dephosphorylation and inactivation of the NPR2 guanylyl cyclase in preovulatory mouse follicles.
1
Authors: Edward M. Rogers, S. Colby Allred, Mark Peifer
Published: Feb 2021
Authors: Edward M. Rogers, S. Colby Allred, Mark Peifer
Published: Feb 2021
Abstract Background The non-receptor tyrosine kinase Abelson (Abl) is a key player in oncogenesis, with kinase inhibitors serving as paradigms of targeted therapy. Abl also is a critical regulator of normal development, playing conserved roles in regulating cell behavior, brain development and morphogenesis. Drosophila offers a superb model for studying Abl’s normal function, because, unlike mammals, there is only a single fly Abl family member. In exploring the mechanism of action of multi-domain scaffolding proteins like Abl, one route is to define the roles of their individual domains. Research into Abl’s diverse roles in embryonic morphogenesis revealed many surprises. For instance, kinase activity, while important, is not crucial for all Abl activities, and the C-terminal F-actin binding domain plays a very modest role. This turned our attention to one of Abl’s least understood features—the long intrinsically-disordered region (IDR) linking Abl’s kinase and F-actin binding domains. The past decade revealed unexpected, important roles for IDRs in diverse cell functions, as sites of posttranslational modifications, mediating multivalent interactions and enabling assembly of biomolecular condensates via phase separation. Previous work deleting conserved regions in Abl’s IDR revealed an important role for a PXXP motif, but did not identify any other essential regions. Methods Here we extend this analysis by deleting the entire IDR, and asking whether Abl∆IDR rescues the diverse roles of Abl in viability and embryonic morphogenesis in Drosophila . Results This revealed that the IDR is essential for embryonic and adult viability, and for cell shape changes and cytoskeletal regulation during embryonic morphogenesis, and, most surprisingly, revealed a role in modulating protein stability. Conclusion Our data provide new insights into the role of the IDR in an important signaling protein, the non-receptor kinase Abl, suggesting that it is essential for all aspects of protein function during embryogenesis, and revealing a role in protein stability. These data will stimulate new explorations of the mechanisms by which the IDR regulates Abl stability and function, both in Drosophila and also in mammals. They also will stimulate further interest in the broader roles IDRs play in diverse signaling proteins.
1
Authors: Schürmann, Matthias, et al
Published: Feb 2021
Authors: Schürmann, Matthias, et al
Published: Feb 2021
Abstract Background Cholesteatoma disease is an expanding lesion in the middle ear. Hearing loss and facial paralysis alongside with other intracranial complications are found. No pharmaceutical treatment is available today and recurrence after surgical extraction occurs. We investigated possible TLR4-based mechanisms promoting recurrence and explore possible treatments strategies. Methods We isolated fibroblasts and epidermal stem cells from cholesteatoma tissue and healthy auditory canal skin. Subsequently, their expression under standard culture conditions and after stimulation with LPS was investigated by RT-qPCR. Cell metabolism and proliferation were analysed upon LPS treatment, with and without TLR4 antagonist. An indirect co-culture of fibroblasts and epidermal stem cells isolated from cholesteatoma tissue was utilized to monitor epidermal differentiation upon LPS treatment by RT-qPCR and immunocytochemistry. Results Under standard culture conditions, we detected a tissue-independent higher expression of IL-1β and IL-8 in stem cells, an upregulation of KGF and IGF-2 in both cell types derived from cholesteatoma and higher expression of TLR4 in stem cells derived from cholesteatoma tissue. Upon LPS challenge, we could detect a significantly higher expression of IL-1α, IL-1β, IL-6 and IL-8 in stem cells and of TNF-a, GM-CSF and CXCL-5 in stem cells and fibroblasts derived from cholesteatoma. The expression of the growth factors KGF, EGF, EREG, IGF-2 and HGF was significantly higher in fibroblasts, particularly when derived from cholesteatoma. Upon treatment with LPS the metabolism was elevated in stem cells and fibroblasts, proliferation was only enhanced in fibroblasts derived from cholesteatoma. This could be reversed by the treatment with a TLR4 antagonist. The cholesteatoma fibroblasts could be triggered by LPS to promote the epidermal differentiation of the stem cells, while no LPS treatment or LPS treatment without the presence of fibroblasts did not result in such a differentiation. Conclusion We propose that cholesteatoma recurrence is based on TLR4 signalling imprinted in the cholesteatoma cells. It induces excessive inflammation of stem cells and fibroblasts, proliferation of perimatrix fibroblasts and the generation of epidermal cells from stem cells thru paracrine signalling by fibroblasts. Treatment of the operation site with a TLR4 antagonist might reduce the chance of cholesteatoma recurrence.
1
Authors: Lv, Chao, et al
Published: Feb 2021
Authors: Lv, Chao, et al
Published: Feb 2021
Abstract The zona pellucida (ZP) plays vital roles in reproductive processes including oogenesis, fertilization and preimplantation development. Both human and rat ZP consist of four glycoproteins, called ZP1, ZP2, ZP3 and ZP4. Our previous research reported a novel Zp1 mutation in cases of human infertility, associated with an abnormal phenotype involving the absence of the zona pellucida. Here, we developed a homologous rat strain to investigate the pathogenic effect. The ovaries of homozygous (Zp1MT/MT) females possessed both growing and fully grown oocytes; the oocytes completely lacked a zona pellucida, but ZP1 was detectable inside the cytoplasm. Only 1-2 eggs were recovered from oviducts of superovulated Zp1MT/MT females, while ≈ 21 eggs were recovered from superovulated Zp1WT/WT females. The eggs of Zp1MT/MT females were not surrounded by a zona pellucida and lost their fertilization capacity in vitro. Zp1MT/MT females mated with wild-type males failed to become pregnant. Studies in 293 T cells showed that mutant Zp1 resulted in a truncated ZP1 protein, which might be intracellularly sequestered and interact with wild-type ZP3 or ZP4. Our results suggest that the Zp1 point mutation led to infertility and loss of the ZP in oocytes in rats.
1
Authors: Smita Eknath Desale, Subashchandrabose Chinnathambi
Published: Feb 2021
Authors: Smita Eknath Desale, Subashchandrabose Chinnathambi
Published: Feb 2021
Abstract Alzheimer’s disease is one of the neurodegenerative diseases, characterized by the accumulation of abnormal protein deposits, which disrupts signal transduction in neurons and other glia cells. The pathological protein in neurodegenerative diseases, Tau and amyloid-β contribute to the disrupted microglial signaling pathways, actin cytoskeleton, and cellular receptor expression. The important secondary messenger lipids i.e., phosphatidylinositols are largely affected by protein deposits of amyloid-β in Alzheimer’s disease. Phosphatidylinositols are the product of different phosphatidylinositol kinases and the state of phosphorylation at D3, D4, and D5 positions of inositol ring. Phosphatidylinositol 3,4,5-triphosphate (PI 3, 4, 5-P3) involves in phagocytic cup formation, cell polarization, whereas Phosphatidylinositol 4,5-bisphosphate (PI 4, 5-P2)-mediates the process of phagosomes formation and further its fusion with early endosome.. The necessary activation of actin-binding proteins such as Rac, WAVE complex, and ARP2/3 complex for the actin polymerization in the process of phagocytosis, migration is regulated and maintained by PI 3, 4, 5-P3 and PI 4, 5-P2. The ratio and types of fatty acid intake can influence the intracellular secondary lipid messengers along with the cellular content of phaphatidylcholine and phosphatidylethanolamine. The Amyloid-β deposits and extracellular Tau seeds disrupt phosphatidylinositides level and actin cytoskeletal network that hamper microglial-signaling pathways in AD. We hypothesize that being a lipid species intracellular levels of phosphatidylinositol would be regulated by dietary fatty acids. Further we are interested to understand phosphoinositide-based signaling cascades in phagocytosis and actin remodeling.
1
Authors: Korkmaz-Icöz, Sevil, et al
Published: Feb 2021
Authors: Korkmaz-Icöz, Sevil, et al
Published: Feb 2021
Abstract Background Brain death (BD) has been suggested to induce coronary endothelial dysfunction. Ischemia/reperfusion (IR) injury during heart transplantation may lead to further damage of the endothelium. Previous studies have shown protective effects of conditioned medium (CM) from bone marrow-derived mesenchymal stem cells (MSCs) against IR injury. We hypothesized that physiological saline-supplemented CM protects BD rats’ vascular grafts from IR injury. Methods The CM from rat MSCs, used for conservation purposes, indicates the presence of 23 factors involved in apoptosis, inflammation, and oxidative stress. BD was induced by an intracranial-balloon. Controls were subjected to a sham operation. After 5.5 h, arterial pressures were measured in vivo. Aortic rings from BD rats were harvested and immediately mounted in organ bath chambers (BD group, n  = 7) or preserved for 24 h in 4 °C saline-supplemented either with a vehicle (BD-IR group, n  = 8) or CM (BD-IR+CM group, n  = 8), prior to mounting. Vascular function was measured in vitro. Furthermore, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) have been performed. Results BD in donors was associated with significantly impaired hemodynamic parameters and higher immunoreactivity of aortic myeloperoxidase (MPO), nitrotyrosine, caspase-3, caspase-8, caspase-9, and caspase-12 compared to sham-operated rats. In organ bath experiments, impaired endothelium-dependent vasorelaxation to acetylcholine in the BD-IR group compared to BD rats was significantly improved by CM (maximum relaxation to acetylcholine: BD 81 ± 2% vs. BD-IR 50 ± 3% vs. BD-IR + CM 72 ± 2%, p  < 0.05). Additionally, the preservation of BD-IR aortic rings with CM significantly lowered MPO, caspase-3, caspase-8, and caspase-9 immunoreactivity compared with the BD-IR group. Furthermore, increased mRNA expression of vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in the aortas from the BD-IR rats compared to BD group were significantly decreased by CM. Conclusions The preservation of BD rats’ vascular grafts with CM alleviates endothelial dysfunction following IR injury, in part, by reducing levels of inflammatory response and caspase-mediated apoptosis.
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