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The Journal of Pathology Jan 2021Most cancer cells are exposed to altered extracellular environments, such as an increase in extracellular matrix (ECM) stiffness and soluble signals consisting of growth...
Most cancer cells are exposed to altered extracellular environments, such as an increase in extracellular matrix (ECM) stiffness and soluble signals consisting of growth factors and cytokines. It is therefore conceivable that changes in tumor extracellular environments affect tumor cell behavior. The Hippo pathway reportedly responds to the extracellular environment and regulates the nuclear localization of the transcription co-activator, yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ). Inactivation of the Hippo pathway with nuclear translocation of YAP/TAZ stimulates cell proliferation. Its pathway also regulates gene expression, but the precise molecule(s) meditating the cell-proliferating effect of YAP signaling on oral squamous cell carcinoma (OSCC) is unclear. First, we examined the effects of YAP signaling on OSCC tumorigenesis. Loss-of-function experiments using siRNA or an inhibitor, and immunohistochemical analyses of tissue specimens obtained from OSCC patients demonstrated that YAP signaling was involved in OSCC cell proliferation. Second, we identified Piezo-type mechanosensitive ion channel component 1 (PIEZO1), a Ca channel, as a transcriptional target of YAP signaling and showed that elevated PIEZO1 was required for PIEZO1 agonist-dependent Ca entry and cell proliferation in OSCC cells. Experiments using three-dimensional and suspension culture revealed that PIEZO1 was involved in OSCC cellular growth. Finally, YAP overexpression in the nucleus and/or cytoplasm was immunohistochemically detected in tumor lesions with frequent expression of both PIEZO1 and Ki-67, but not in non-tumor regions of OSCC specimens. These results suggest that the YAP/PIEZO1 axis promotes OSCC cell growth. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Calcium; Calcium Signaling; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Ion Channels; Male; Middle Aged; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck; Transcription Factors; YAP-Signaling Proteins
PubMed: 32985688
DOI: 10.1002/path.5553 -
The European Respiratory Journal Mar 2023Pulmonary hypertension (PH) is a life-threatening disease featuring pulmonary vessel remodelling and perivascular inflammation. The effect, if any, of eosinophils (EOS)...
BACKGROUND
Pulmonary hypertension (PH) is a life-threatening disease featuring pulmonary vessel remodelling and perivascular inflammation. The effect, if any, of eosinophils (EOS) on the development of PH remains unclear.
METHODS
EOS infiltration and chemotaxis were investigated in peripheral blood and lung tissues from pulmonary arterial hypertension (PAH) patients without allergic history and from sugen/hypoxia-induced PH mice. The role of EOS deficiency in PH development was investigated using deletion (ΔdblGATA) mice and anti-interleukin 5 antibody-treated mice and rats. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was conducted to identify the critical oxylipin molecule(s) produced by EOS. Culture supernatants and lysates of EOS were collected to explore the mechanisms in co-culture cell experiments.
RESULTS
There was a lower percentage of EOS in peripheral blood but higher infiltration in lung tissues from PAH patients and PH mice. PAH/PH lungs showed increased EOS-related chemokine expression, mainly C-C motif chemokine ligand 11 derived from adventitial fibroblasts. EOS deficiency aggravated PH in rodents, accompanied by increased neutrophil and monocyte/macrophage infiltration. EOS highly expressed arachidonate 15-lipoxygenase (ALOX15). 14-hydroxy docosahexaenoic acid (14-HDHA) and 17-HDHA were critical downstream oxylipins produced by EOS, which showed anti-inflammatory effects on recruitment of neutrophils and monocytes/macrophages through N-formyl peptide receptor 2. They also repressed pulmonary artery smooth muscle cell (PASMC) proliferation by activating peroxisome proliferator-activated receptor γ and blunting Stat3 phosphorylation.
CONCLUSIONS
In PH development without external stimuli, peripheral blood exhibits a low EOS level. EOS play a protective role by suppressing perivascular inflammation and maintaining PASMC homeostasis 14/17-HDHA.
Topics: Rats; Mice; Animals; Hypertension, Pulmonary; Eosinophils; Tandem Mass Spectrometry; Mice, Knockout; Pulmonary Arterial Hypertension; Pulmonary Artery; Familial Primary Pulmonary Hypertension; Inflammation; Myocytes, Smooth Muscle; Cell Proliferation; Cells, Cultured; Hypoxia
PubMed: 36423907
DOI: 10.1183/13993003.00582-2022 -
Microbiome Jan 2021Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to...
BACKGROUND
Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota.
RESULTS
The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice.
CONCLUSIONS
Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. Video abstract.
Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Disease Progression; Dopaminergic Neurons; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Infusions, Parenteral; Male; Mice; Neuroprotective Agents; Osteocalcin; Oxidopamine; Parkinson Disease; Propionates; Receptors, G-Protein-Coupled
PubMed: 33517890
DOI: 10.1186/s40168-020-00988-6 -
Cellular and Molecular Life Sciences :... Mar 2021As a naturally occurring class of gene regulators, microRNAs (miRNAs) have attracted much attention as promising targets for therapeutic development. However, RNAs... (Review)
Review
As a naturally occurring class of gene regulators, microRNAs (miRNAs) have attracted much attention as promising targets for therapeutic development. However, RNAs including miRNAs have long been considered undruggable, and most efforts have been devoted to using synthetic oligonucleotides to regulate miRNAs. Encouragingly, recent findings have revealed that miRNAs can also be drugged with small molecules that directly target miRNAs. In this review paper, we give a summary of recently emerged small-molecule inhibitors (SMIs) and small-molecule degraders (SMDs) for miRNAs. SMIs are small molecules that directly bind to miRNAs to inhibit their biogenesis, and SMDs are bifunctional small molecules that upon binding to miRNAs induce miRNA degradation. Strategies for discovering SMIs and developing SMDs were summarized. Applications of SMIs and SMDs in miRNA inhibition and cancer therapy were also introduced. Overall, SMIs and SMDs introduced here have high potency and specificity in miRNA inhibition. We envision that these small molecules will pave the way for developing novel therapeutics toward miRNAs that were previously considered undruggable.
Topics: Animals; Gene Expression Regulation; High-Throughput Screening Assays; Humans; MicroRNAs; Molecular Structure; Nucleic Acid Conformation; RNA Stability; Small Molecule Libraries
PubMed: 33052435
DOI: 10.1007/s00018-020-03676-8 -
IUCrData Feb 2023The title compound, CHNOSi·0.5CHCl, crystallizes in the the triclinic space group with two host mol-ecules and one chloro-form mol-ecule in the asymmetric unit. The...
The title compound, CHNOSi·0.5CHCl, crystallizes in the the triclinic space group with two host mol-ecules and one chloro-form mol-ecule in the asymmetric unit. The core of the mol-ecule consists of a urea unit bound to a 3-amino-acryloyl group. These units are almost planar in both mol-ecules [average deviation from plane of 0.05 (6) Å in mol-ecule and 0.04 (5) Å in mol-ecule ]. The main difference between mol-ecules and involves the dihedral angles of the phenyl groups. One phenyl ring makes dihedral angles of 71.14 (6)° (mol-ecule ) and 82.81 (7)° (mol-ecule ) with respect to the core (CNO) of the mol-ecule [14.56 (9)° (mol-ecule ) and 5.7 (1)° (mol-ecule ) for the other phenyl ring]. Another prominent feature is the intra-molecular N-H⋯O hydrogen bond present in both crystallographically independent mol-ecules.
PubMed: 36911080
DOI: 10.1107/S2414314623001177 -
Molecules (Basel, Switzerland) Aug 2022Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively... (Review)
Review
Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.
Topics: Drug Development; Immunotherapy; Neoplasms; Proteolysis
PubMed: 36080223
DOI: 10.3390/molecules27175439 -
Acta Pharmaceutica Sinica. B Dec 2022Immunotherapy has led to a paradigm shift in the treatment of cancer. Current cancer immunotherapies are mostly antibody-based, thus possessing advantages in regard to... (Review)
Review
Immunotherapy has led to a paradigm shift in the treatment of cancer. Current cancer immunotherapies are mostly antibody-based, thus possessing advantages in regard to pharmacodynamics (., specificity and efficacy). However, they have limitations in terms of pharmacokinetics including long half-lives, poor tissue/tumor penetration, and little/no oral bioavailability. In addition, therapeutic antibodies are immunogenic, thus may cause unwanted adverse effects. Therefore, researchers have shifted their efforts towards the development of small molecule-based cancer immunotherapy, as small molecules may overcome the above disadvantages associated with antibodies. Further, small molecule-based immunomodulators and therapeutic antibodies are complementary modalities for cancer treatment, and may be combined to elicit synergistic effects. Recent years have witnessed the rapid development of small molecule-based cancer immunotherapy. In this review, we describe the current progress in small molecule-based immunomodulators (inhibitors/agonists/degraders) for cancer therapy, including those targeting PD-1/PD-L1, chemokine receptors, stimulator of interferon genes (STING), Toll-like receptor (TLR), etc. The tumorigenesis mechanism of various targets and their respective modulators that have entered clinical trials are also summarized.
PubMed: 36562003
DOI: 10.1016/j.apsb.2022.11.007 -
Circulation Apr 2023Myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlying molecular mechanisms remain unclear. Recent studies demonstrate that the...
Nitrative Modification of Caveolin-3: A Novel Mechanism of Cardiac Insulin Resistance and a Potential Therapeutic Target Against Ischemic Heart Failure in Prediabetic Animals.
BACKGROUND
Myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlying molecular mechanisms remain unclear. Recent studies demonstrate that the diabetic heart is resistant to other cardioprotective interventions, including adiponectin and preconditioning. The "universal" resistance to multiple therapeutic interventions suggests impairment of the requisite molecule(s) involved in broad prosurvival signaling cascades. Cav (Caveolin) is a scaffolding protein coordinating transmembrane signaling transduction. However, the role of Cav3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown.
METHODS
Wild-type and gene-manipulated mice were fed a normal diet or high-fat diet for 2 to 12 weeks and subjected to myocardial ischemia and reperfusion. Insulin cardioprotection was determined.
RESULTS
Compared with the normal diet group, the cardioprotective effect of insulin was significantly blunted as early as 4 weeks of high-fat diet feeding (prediabetes), a time point where expression levels of insulin-signaling molecules remained unchanged. However, Cav3/insulin receptor-β complex formation was significantly reduced. Among multiple posttranslational modifications altering protein/protein interaction, Cav3 (not insulin receptor-β) tyrosine nitration is prominent in the prediabetic heart. Treatment of cardiomyocytes with 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride reduced the signalsome complex and blocked insulin transmembrane signaling. Mass spectrometry identified Tyr as the Cav3 nitration site. Phenylalanine substitution of Tyr (Cav3) abolished 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride-induced Cav3 nitration, restored Cav3/insulin receptor-β complex, and rescued insulin transmembrane signaling. It is most important that adeno-associated virus 9-mediated cardiomyocyte-specific Cav3 reexpression blocked high-fat diet-induced Cav3 nitration, preserved Cav3 signalsome integrity, restored transmembrane signaling, and rescued insulin-protective action against ischemic heart failure. Last, diabetic nitrative modification of Cav3 at Tyr also reduced Cav3/AdipoR1 complex formation and blocked adiponectin cardioprotective signaling.
CONCLUSIONS
Nitration of Cav3 at Tyr and resultant signal complex dissociation results in cardiac insulin/adiponectin resistance in the prediabetic heart, contributing to ischemic heart failure progression. Early interventions preserving Cav3-centered signalsome integrity is an effective novel strategy against diabetic exacerbation of ischemic heart failure.
Topics: Mice; Animals; Prediabetic State; Caveolin 3; Insulin Resistance; Adiponectin; Chlorides; Myocardial Reperfusion Injury; Myocytes, Cardiac; Heart Failure
PubMed: 36883479
DOI: 10.1161/CIRCULATIONAHA.122.063073 -
Reumatologia 2022Systemic lupus erythematosus is a connective disease in which all vitally important organs may be affected. The etiology of the disease is largely unknown and almost all... (Review)
Review
Systemic lupus erythematosus is a connective disease in which all vitally important organs may be affected. The etiology of the disease is largely unknown and almost all immunological mechanisms have been proposed as the pathophysiological background of the disease. Among them, endothelial damage and dysfunction seem to play a pivotal role. Endothelial damage can be accurately measured using adhesion molecules such asintercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), platelet endothelial cell adhesion molecule (PECAM) and selectins. In this review we discuss the role of well-known cellular adhesion molecules as pathogenic factors in disease development as well as disease activity biomarkers.
PubMed: 35782027
DOI: 10.5114/reum.2022.115664 -
Trends in Immunology Jul 2020How innate immunity gave rise to adaptive immunity in vertebrates remains unknown. We propose an evolutionary scenario beginning with pathogen-associated molecular... (Review)
Review
How innate immunity gave rise to adaptive immunity in vertebrates remains unknown. We propose an evolutionary scenario beginning with pathogen-associated molecular pattern(s) (PAMPs) being presented by molecule(s) on one cell to specific receptor(s) on other cells, much like MHC molecules and T cell receptors (TCRs). In this model, mutations in MHC-like molecule(s) that bound new PAMP(s) would not be recognized by original TCR-like molecule(s), and new MHC-like gene(s) would be lost by neutral drift. Integrating recombination activating gene (RAG) transposon(s) in a TCR-like gene would result in greater recognition diversity, with new MHC-like variants recognized and selected, along with a new RAG/TCR-like system. MHC genes would be selected to present many peptides, through multigene families, allelic polymorphism, and peptide-binding promiscuity.
Topics: Adaptive Immunity; Animals; DNA Transposable Elements; Evolution, Molecular; Genes, RAG-1; Immunity, Innate; Major Histocompatibility Complex; Receptors, Antigen, T-Cell
PubMed: 32467030
DOI: 10.1016/j.it.2020.05.002