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Molecules (Basel, Switzerland) Aug 2014Allicin (diallylthiosulfinate) is a defence molecule from garlic (Allium sativum L.) with a broad range of biological activities. Allicin is produced upon tissue damage... (Review)
Review
Allicin (diallylthiosulfinate) is a defence molecule from garlic (Allium sativum L.) with a broad range of biological activities. Allicin is produced upon tissue damage from the non-proteinogenic amino acid alliin (S-allylcysteine sulfoxide) in a reaction that is catalyzed by the enzyme alliinase. Current understanding of the allicin biosynthetic pathway will be presented in this review. Being a thiosulfinate, allicin is a reactive sulfur species (RSS) and undergoes a redox-reaction with thiol groups in glutathione and proteins that is thought to be essential for its biological activity. Allicin is physiologically active in microbial, plant and mammalian cells. In a dose-dependent manner allicin can inhibit the proliferation of both bacteria and fungi or kill cells outright, including antibiotic-resistant strains like methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, in mammalian cell lines, including cancer cells, allicin induces cell-death and inhibits cell proliferation. In plants allicin inhibits seed germination and attenuates root-development. The majority of allicin's effects are believed to be mediated via redox-dependent mechanisms. In sub-lethal concentrations, allicin has a variety of health-promoting properties, for example cholesterol- and blood pressure-lowering effects that are advantageous for the cardio-vascular system. Clearly, allicin has wide-ranging and interesting applications in medicine and (green) agriculture, hence the detailed discussion of its enormous potential in this review. Taken together, allicin is a fascinating biologically active compound whose properties are a direct consequence of the molecule's chemistry.
Topics: Animals; Anti-Infective Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Arabidopsis; Disulfides; Germination; Humans; Oxidation-Reduction; Plant Roots; Sulfinic Acids
PubMed: 25153873
DOI: 10.3390/molecules190812591 -
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 -
Annual Review of Microbiology Sep 2016The ability of bacteria to recognize kin provides a means to form social groups. In turn these groups can lead to cooperative behaviors that surpass the ability of the... (Review)
Review
The ability of bacteria to recognize kin provides a means to form social groups. In turn these groups can lead to cooperative behaviors that surpass the ability of the individual. Kin recognition involves specific biochemical interactions between a receptor(s) and an identification molecule(s). Recognition specificity, ensuring that nonkin are excluded and kin are included, is critical and depends on the number of loci and polymorphisms involved. After recognition and biochemical perception, the common ensuing cooperative behaviors include biofilm formation, quorum responses, development, and swarming motility. Although kin recognition is a fundamental mechanism through which cells might interact, microbiologists are only beginning to explore the topic. This review considers both molecular and theoretical aspects of bacterial kin recognition. Consideration is also given to bacterial diversity, genetic relatedness, kin selection theory, and mechanisms of recognition.
Topics: Bacteria; Bacterial Physiological Phenomena; Bacterial Proteins; Gene Expression Regulation, Bacterial
PubMed: 27359217
DOI: 10.1146/annurev-micro-102215-095325 -
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 -
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 -
Frontiers in Genetics 2022The collagen- and calcium-binding EGF-like domains 1 (CCBE1) is a secreted protein extensively described as indispensable for lymphangiogenesis during development... (Review)
Review
The collagen- and calcium-binding EGF-like domains 1 (CCBE1) is a secreted protein extensively described as indispensable for lymphangiogenesis during development enhancing VEGF-C signaling. In human patients, mutations in have been found to cause Hennekam syndrome, an inherited disease characterized by malformation of the lymphatic system that presents a wide variety of symptoms such as primary lymphedema, lymphangiectasia, and heart defects. Importantly, over the last decade, an essential role for CCBE1 during heart development is being uncovered. In mice, expression was initially detected in distinct cardiac progenitors such as first and second heart field, and the proepicardium. More recently, expression was identified in the epicardium and sinus venosus (SV) myocardium at E11.5-E13.5, the stage when SV endocardium-derived (VEGF-C dependent) coronary vessels start to form. Concordantly, CCBE1 is required for the correct formation of the coronary vessels and the coronary artery stem in the mouse. Additionally, was found to be enriched in mouse embryonic stem cells (ESC) and revealed as a new essential gene for the differentiation of ESC-derived early cardiac precursor cell lineages. Here, we bring an up-to-date review on the role of CCBE1 in cardiac development, function, and human disease implications. Finally, we envisage the potential of this molecule's functions from a regenerative medicine perspective, particularly novel therapeutic strategies for heart disease.
PubMed: 35222551
DOI: 10.3389/fgene.2022.836694 -
International Journal of Nanomedicine 2022Bioavailability is an eternal topic that cannot be circumvented by peroral drug delivery. Adequate blood drug exposure after oral administration is a prerequisite for... (Review)
Review
Bioavailability is an eternal topic that cannot be circumvented by peroral drug delivery. Adequate blood drug exposure after oral administration is a prerequisite for effective treatment. Nanovesicles as pleiotropic oral vehicles can solubilize, encapsulate, stabilize an active ingredient and promote the payload absorption via various mechanisms. Vesicular systems with nanoscale size, such as liposomes, niosomes and polymersomes, provide a versatile platform for oral delivery of drugs with distinct nature. The amphiphilicity of vesicles in structure allows hydrophilic and lipophilic molecule(s) either or both to be loaded, being encapsulated in the aqueous cavity or the inner core, respectively. Depending on high oral transport efficiency based on their structural flexibility, gastrointestinal stability, biocompatibility, and/or intestinal epithelial affinity, nanovesicles can markedly augment the oral bioavailability of various poorly absorbed drugs. Vesicular drug delivery systems (VDDSs) demonstrate a lot of preferences and are becoming more prominent of late years in biomedical applications. Equally, these systems can potentiate a drug's therapeutic index by ameliorating the oral absorption. This review devotes to comment on various VDDSs with special emphasis on the peroral drug delivery. The classification of nanovesicles, preparative processes, intestinal transport mechanisms, in vivo fate, and design rationale were expounded. Knowledge on vesicles-mediated oral drug delivery for bioavailability enhancement has been properly provided. It can be concluded that VDDSs with many merits will step into an energetic arena in oral drug delivery.
Topics: Biological Availability; Liposomes; Administration, Oral; Hydrophobic and Hydrophilic Interactions; Excipients
PubMed: 36262189
DOI: 10.2147/IJN.S382192 -
Pharmaceutics Nov 2022Chemical warfare or terrorism attacks with organophosphates may place intoxicated subjects under immediate life-threatening and psychologically demanding conditions....
Chemical warfare or terrorism attacks with organophosphates may place intoxicated subjects under immediate life-threatening and psychologically demanding conditions. Antidotes, such as the oxime HI-6, which must be formulated as a powder for reconstitution reflecting the molecule's light sensitivity and instability in aqueous solutions, dramatically improve recovery-but only if used soon after exposure. Muscle tremors, anxiety, and loss of consciousness after exposure jeopardize proper administration, translating into demanding specifications for the dissolution of HI-6. Reflecting the patients' catastrophic situation and anticipated desire to react immediately to chemical weapon exposure, the dissolution should be completed within ten seconds. We are developing multi-dose and single-dose autoinjectors to reliably meet these dissolution requirements. The temporal and spatial course of dissolution within the various autoinjector designs was profiled colorimetrically. Based on these colorimetric insights with model dyes, we developed experimental setups integrating online conductometry to push experiments toward the relevant molecule, HI-6. The resulting blueprints for autoinjector designs integrated small-scale rotor systems, boosting dissolution across a wide range of viscosities, and meeting the required dissolution specifications driven by the use of these drug products in extreme situations.
PubMed: 36432735
DOI: 10.3390/pharmaceutics14112544