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Malaria caused by P. falciparum, has been recognized as one of the major infectious diseases causing the death of several patients as per the reports from the World Health Organization. In search of effective therapeutic agents against malaria, several research groups have started working on the design and development of novel heterocycles as anti-malarial agents. Heterocycles have been recognized as the pharmacophoric features for the different types of medicinally important activities. Among all these heterocycles, nitrogen containing aza-heterocycles should not be underestimated owing to their wide therapeutic window. Amongst the aza-heterocycles, indoles and fused indoles such as marinoquinolines, isocryptolepines and their regioisomers, manzamines, neocryptolenines, and indolones have been recognized as anti-malarial agents active against P. falciparum. The present work unleashes the synthetic attempts of anti-malarial indoles and fused indoles through cyclocondensation, Fischer-indole synthesis, etc. along with the brief discussions on structure-activity relationships, in vitro or in vivo studies for the broader interest of these medicinal chemists, working on their design and development as potential anti-malarial agents.
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INTRODUCTION: Rhododendron arboreum Sm. flowers grow in the Himalayan region and have traditionally been used in beverages and food. These wild edible Himalayan flowers are known for their sweet-sour flavor and beautiful scarlet red color. The primary pigments responsible for the scarlet red color of these flowers are anthocyanins. OBJECTIVE: In the present study, we conducted chemo-profiling and elucidated the chromatic characteristics of R. arboreum flower petals growing in the wild in different altitudinal areas. METHODOLOGY: The content of anthocyanins, phenolics, and other flavonoids was determined in R. arboreum flower petals collected from 38 different locations in two provinces in India (Himachal Pradesh and Uttarakhand) to obtain a distinguishable chemical index. A UHPLC method has also been developed and validated for the quantitative analysis. Besides, the color characteristics of each collected floral sample were also analyzed. RESULTS: Chemometric analysis (principal component analysis [PCA] and heatmap analysis) revealed that floral samples collected from different altitudes exhibited similar chemical diversity, whereas statistical analysis (bivariate linear correlation) revealed a positive correlation between the color parameter a*/b* and cyanidin glycosides. Besides, non-targeted metabolomics analysis was carried out, which resulted in the tentative identification of 150 metabolites. CONCLUSION: The results revealed that there is a direct influence of accumulated anthocyanins to color parameter a*/b* values in the floral samples irrespective of altitude.
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Altitude , Antocianinas , Flores , Polifenóis , Análise de Componente Principal , Rhododendron , Rhododendron/química , Flores/química , Polifenóis/análise , Cromatografia Líquida de Alta Pressão , Antocianinas/análise , Cor , Flavonoides/análiseRESUMO
Strong light-matter coupling offers a way to tailor the optoelectronic properties of materials. Energy transfer between strongly coupled donor-acceptor pairs shows remarkable efficiency beyond the Förster distance via coupling through a confined photon. This long-range energy transfer is facilitated through the collective nature of polaritonic states. Here, the cooperative, strong coupling of a donor (MoS2 monolayer) and an acceptor (BRK) generates mixed polaritonic states. The photocurrent spectrum of the MoS2 monolayer is measured in a field effect transistor while coupling the two oscillators to the confined cavity mode. The strongly coupled system shows efficient energy transfer, which is observed through the photoresponsivity even the donor and acceptor are physically separated by 500 Å. These studies are further correlated with the Hopfield coefficients and the overlap integral of the lower polaritonic and uncoupled/dark states. Cavity detuning and distance-dependent studies support the above evidence. These observations open new avenues for using long-range interaction of polaritonic states in optoelectronic devices.
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Glycogen synthase kinase-3 (GSK-3) is a multitasking protein kinase that regulates numerous critical cellular functions. Not surprisingly, elevated GSK-3 activity has been implicated in a host of diseases including pathological inflammation, diabetes, cancer, arthritis, asthma, bipolar disorder, and Alzheimer's. Therefore, reagents that inhibit GSK-3 activity provide a means to investigate the role of GSK-3 in cellular physiology and pathophysiology and could become valuable therapeutics. Finding a potent inhibitor of GSK-3 that can selectively target this kinase, among over 500 protein kinases in the human genome, is a significant challenge. Thus there remains a critical need for the identification of selective inhibitors of GSK-3. In this work, we introduce a novel small organic compound, namely COB-187, which exhibits potent and highly selective inhibition of GSK-3. Specifically, this study 1) utilized a molecular screen of 414 kinase assays, representing 404 unique kinases, to reveal that COB-187 is a highly potent and selective inhibitor of GSK-3; 2) utilized a cellular assay to reveal that COB-187 decreases the phosphorylation of canonical GSK-3 substrates indicating that COB-187 inhibits cellular GSK-3 activity; and 3) reveals that a close isomer of COB-187 is also a selective and potent inhibitor of GSK-3. Taken together, these results demonstrate that we have discovered a region of chemical design space that contains novel GSK-3 inhibitors. These inhibitors will help to elucidate the intricate function of GSK-3 and can serve as a starting point for the development of potential therapeutics for diseases that involve aberrant GSK-3 activity.
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Compostos de Bifenilo/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Animais , Compostos de Bifenilo/síntese química , Desenho de Fármacos , Ensaios Enzimáticos , Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Fosforilação , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/genética , Células RAW 264.7 , Relação Estrutura-Atividade , Especificidade por Substrato , Células THP-1 , Acetato de Tetradecanoilforbol/farmacologia , Tiadiazóis/química , Tiadiazóis/farmacologiaRESUMO
Here, we report the catalytic effect of vibrational strong coupling (VSC) on the solvolysis of para-nitrophenyl acetate (PNPA), which increases the reaction rate by an order of magnitude. This is observed when the microfluidic Fabry-Perot cavity in which the VSC is generated is tuned to the C=O vibrational stretching mode of both the reactant and solvent molecules. Thermodynamic experiments confirm the catalytic nature of VSC in the system. The change in the reaction rate follows an exponential relation with respect to the coupling strength of the solvent, indicating a cooperative effect between the solvent molecules and the reactant. Furthermore, the study of the solvent kinetic isotope effect clearly shows that the vibrational overlap of the C=O vibrational bands of the reactant and the strongly coupled solvent molecules is critical for the catalysis in this reaction. The combination of cooperative effects and cavity catalysis confirms the potential of VSC as a new frontier in chemistry.
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In autoimmune patients, regulatory T cells (Tregs) are increasingly found to be unable to suppress patient-derived T cells, an outcome referred to as Treg resistance. In this study, we show that CD4 T cells from patients with multiple sclerosis resist suppression by patient-derived or healthy donor-derived ex vivo Tregs. Importantly, we report that granzyme B (GzmB) contributes to this Treg resistance via a novel, apoptosis-independent mechanism. We show that memory CD4(+)CD127(lo)FOXP3(+) Treg subsets do not express GzmB, whereas activated, nonregulatory CD4 T cells isolated from patients with multiple sclerosis express higher levels of GzmB than do cells from healthy donors. In contrast to the intracellular GzmB that mediates apoptosis, GzmB can be found in extracellular fluids where it is hypothesized to regulate other cellular processes. In this study, we show that providing extracellular GzmB strongly inhibits Treg suppression, without altering Treg viability. However, when GzmB and GzmB-specific inhibitor are both provided to the cocultures, Treg suppression occurs. Thus, these data suggest that a novel activity of extracellular GzmB is to regulate Treg suppression. Additionally, we find that the suppression-abrogating cytokine IL-6 augments GzmB expression by human CD4 T cells, and it inhibits Treg suppression via this nonapoptotic GzmB-mediated mechanism. Lastly, in examining the mechanism whereby GzmB inhibits Treg function, we show that extracellular GzmB reduces Treg expression of CD39 and programmed death ligand 1. Collectively, these data indicate that extracellular GzmB plays an unexpected, nonapoptotic role in regulating Treg suppression and suggest that inactivation of specifically the extracellular activity of GzmB may be an efficacious therapeutic in autoimmunity.
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Granzimas/imunologia , Antígenos HLA-DR/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucina-6/farmacologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Granzimas/genética , Granzimas/farmacologia , Antígenos HLA-DR/genética , Humanos , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/patologia , Cultura Primária de Células , Transdução de Sinais , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologiaRESUMO
OBJECTIVE AND DESIGN: Atherosclerosis (ATH) is a chronic inflammatory disease that involves cascades of signaling events mediated by various effector proteins. Here we sought to determine if the expression of Wnt5a, a secreted glycoprotein, is altered in discrete regions of the arterial plaque. METHODS: Atherosclerotic plaque tissues from 14 human subjects undergoing elective carotid endarterectomy were used in this study. Immunohistochemistry and laser capture microdissection combined with quantitative real-time PCR were used to determine the expression of Wnt5a and Toll-like receptors (TLRs) in different sections of the arterial lesions. Atherosclerotic serum samples (n = 30) and serum from healthy subjects (n = 16) were quantified for Wnt5a using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The data analysis revealed that Wnt5a transcripts and protein were elevated in advanced arterial lesions relative to less advanced arterial lesions; that Wnt5a expression correlated with the presence of TLR4 and TLR2 transcripts; and that the average amount of Wnt5a protein present in atherosclerotic patient serum was significantly higher compared to healthy controls. CONCLUSIONS: This study is the first to provide evidence that the expression of Wnt5a increases as the disease progresses to a more advanced stage, and that this expression is coincident with that of TLR2 and TLR4. In addition, we found that the average Wnt5a levels in the serum of atherosclerotic patients are elevated relative to healthy controls, which is consistent with the hypothesis that Wnt5a plays a role in ATH.
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Aterosclerose/genética , Proteínas Proto-Oncogênicas/genética , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Proteínas Wnt/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/sangue , Aterosclerose/metabolismo , Aterosclerose/patologia , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/sangue , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/metabolismo , Proteínas Wnt/sangue , Proteínas Wnt/metabolismo , Proteína Wnt-5aRESUMO
Preclinical Research Phenylmethimazole (C10) is an inhibitor of Toll-like receptor (TLR3 and TLR4) expression and signaling. In this study, we carried out a detailed investigation of the effect of C10 on TLR4 and its molecular signaling products in RAW 264.7 macrophages using quantitative real-time polymerase chain reaction (PCR), ELISA and cell toxicity assays, a set of in vitro assays that may be used to screen future C10 analogs. C10 exhibited an inhibitory effect on TLR4 MyD88-dependent and MyD88-independent pathways. Within the TLR4 pathway, C10 inhibited the expression of cytokines, cytokine receptors, kinases, adapter molecules and transcription factors, suggesting a pathway-wide inhibitory effect. We also found that C10 dose-dependently inhibited the expression of TLR4 signaling products, specifically IL-6, inducible nitric oxide (NO) synthase and IFNß. Additionally, pre-treatment of RAW 264.7 cells with C10 resulted in protection from lipopolysaccharide (LPS) insults, suggesting C10 may be bound to the target thus exhibiting activity during/following LPS stimulation. Also, dimethyl sulfoxide, the solvent for C10 exhibited inhibitory effect on TLR4 signaling products independent from the effects of C10. Combined, this study enhances understanding of the actions of C10 on the TLR4 signaling pathway providing a path for the development of new C10 analogs for inhibiting TLR expression and signaling [corrected].
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Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Metimazol/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Tionas/farmacologia , Receptor 4 Toll-Like/genética , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/citologia , Metimazol/farmacologia , Camundongos , Receptor 4 Toll-Like/metabolismoRESUMO
We leveraged strong light-matter coupling, a quantum process generating hybridized states, to prepare phototransistors using donor-acceptor pairs that transfer energy via Rabi oscillations. In a prototype experiment, we used a cyanine J-aggregate (TDBC; donor) and MoS2 monolayer (acceptor) in a field effect transistor cavity to study photoresponsivity. Energy migrates through the newly formed polaritonic ladder, with enhanced device efficiency when the cavity is resonant with donors. A theoretical model based on the time-dependent Schrödinger equation helped interpret results, with polaritonic states acting as a strong energy funnel to the MoS2 monolayer. These findings suggest novel applications of strong light-matter coupling in quantum materials.
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This paper presents the demographics, dynamics, and attitudes of dog ownership across three states in India. The background of this research is set against the increasing significance of pet ownership in urban Indian contexts, with a particular focus on understanding the variations in dog-ownership patterns and their implications for public health and animal welfare. We employed a survey-based approach, gathering quantitative survey data from dog owners (n = 563) and non-dog-owners (n = 9282) across different socioeconomic and geographic backgrounds in seven Indian settlements. The results reveal notable differences in dog-ownership patterns, influenced by regional state. In particular, settlements in Gujarat were found to have significantly fewer dog-owning households than those in Tamil Nadu, with no differences found according to settlement size. Dog ownership was found to be more common in households of higher socioeconomic standing, and settlements in Uttarakhand were found more frequently to possess dogs for reasons other than companionship. Data from Ahmedabad and Vadodara, specifically, also indicate rapidly increasing rates of pet ownership. Sterilisation and rabies vaccination proportions were typically low and high, respectively, across all settlements, with few significant differences found among settlements. Confinement of owned dogs at night was significantly lower in Nainital than all other settlements. Differences in attitudes towards roaming dogs between dog owners and non-dog-owners were also examined, with the results indicating both positive and negative trends accordingly. Our results emphasise the need for region-specific strategies in public health and animal welfare policies, acknowledging the diverse nature of pet ownership in India. This research provides valuable insight for policymakers and animal welfare organisations, underlining the importance of tailored approaches to address the unique challenges and opportunities in the Indian context.
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ETHNOPHARMACOLOGICAL RELEVANCE: Swertia chirayita (Roxb.) H. Karst. is a traditionally used, well-recognized medicinal plant of the family Gentianaceae with significant therapeutic potential. It has been traditionally used to cure various ailments such as fever, vomiting, jaundice, digestive disorders, heart diseases, diabetes, malaria, scorpion bite, and skin diseases. AIM OF REVIEW: The present review emphasized the traditional uses, phytochemistry, pharmacology, toxicology, chemical profiling, and structural identification of isolated compounds by analytical and spectroscopic techniques. This review demonstrates the possibility of advanced ethnopharmacological research. MATERIALS AND METHODS: The literature on S. chirayita was obtained from bibliographic databases like Web of Science, PubMed, Science-Direct, American Chemical Society (ACS), Google Scholar, and SciFinder. The compiled review is covered up until March 2022. RESULTS: Approximately, 123 specialized metabolites including xanthones, seco-iridoids, terpenoids, alkaloids, and flavonoids have been isolated and characterized from S. chirayita. The extract and isolated compounds exhibited a wide spectrum of pharmacological effects such as anti-inflammatory, antioxidant, antitumor, hepatoprotective, antiviral, antimalarial, and antibacterial offering scientific evidence for traditional claims of this medicinal plant. In addition, various analytical methods using HPTLC, UPLC, HPLC, LC-MS, and GC-MS have also been documented to determine the phytochemicals of S. chirayita. CONCLUSION: The current article provides information on traditional usage, phytochemistry, chemical profiling, structure elucidation, pharmacological efficacy, toxicity, and future prospects of S. chirayita. This plant has long been traditionally used in a variety of ways by indigenous people. Numerous phytoconstituents and several pharmacological activities have been reported in S. chirayita. However, there are still some scientific gaps such as identification of bioactive compounds, structure-activity relationship and mechanistic action of isolated bioactive compounds, development of effective analytical methods for comprehensive quality control, and safety profiles that need to be addressed.
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Antimaláricos , Plantas Medicinais , Swertia , Xantonas , Antibacterianos/uso terapêutico , Antimaláricos/uso terapêutico , Antioxidantes , Antivirais , Etnofarmacologia , Flavonoides , Humanos , Iridoides , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , TerpenosRESUMO
Strong light-matter interaction of functional materials is emerging as a promising area of research. Recent experiments suggest that material properties like charge transport can be controlled by coupling to a vacuum electromagnetic field. Here, we explored the design of a Fabry-Perot cavity in a field-effect transistor configuration and studied the charge transport in two-dimensional materials. The optical and electrical measurements of strongly coupled WS2 suggest an enhancement of electron transport at room temperature. Electron mobility is enhanced more than 50 times at ON resonance conditions. Similarly, Ion/Ioff ratio of the device increased by 2 orders of magnitude without chemical modification of the active layer. Cavity tuning and coupling strength-dependent studies support the evidence of modifying the electronic properties of the coupled system. A clear correlation in the effective mass of the polaritonic state and Schottky barrier height indicates a collective nature of light-matter interaction.
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A series of novel 1,2,4-oxadiazole, phthalimide, amide and other derivatives of ISO-1 were synthesized and probed for inhibition of macrophage migration inhibitory factor (MIF) activity. Several compounds inhibited MIF enzymatic activity at levels better than ISO-1. Of note, compounds 7, 22, 23, 24, 25 and 27 inhibited the spontaneous secretion/release/recognition of MIF from freshly isolated human peripheral blood mononuclear cells and, more importantly, inhibited the MIF-induced production of interleukin-6 (IL-6) and/or interleukin-1beta (IL-1beta) significantly better than ISO-1.
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Anti-Inflamatórios/síntese química , Isoxazóis/química , Receptores Imunológicos/antagonistas & inibidores , Amidas/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Linhagem Celular , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Isoxazóis/síntese química , Isoxazóis/farmacologia , Oxidiazóis/química , Ftalimidas/química , Receptores Imunológicos/metabolismoRESUMO
A series of novel cyanopyridyl based molecules (1-14) were designed, synthesized and probed for inhibition of mammalian target of rapamycin (mTOR) activity. Compound 14 was found to be a potent inhibitor of mTOR activity as assessed by enzyme-linked immunoassays and Western blot analysis. Most importantly, systemic application (intraperitoneal; ip) of compound 14 significantly suppressed macroscopic and histological abnormalities associated with chemically-induced murine colitis.
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Nitrilas/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/metabolismo , Piridinas/síntese química , Acrilamidas/síntese química , Acrilamidas/farmacocinética , Acrilamidas/uso terapêutico , Animais , Linhagem Celular Tumoral , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Camundongos , Nitrilas/química , Nitrilas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/química , Piridinas/farmacocinética , Piridinas/uso terapêutico , Serina-Treonina Quinases TORRESUMO
BACKGROUND AND OBJECTIVE: Oral submucous fibrosis (OSMF) is a precancerous condition. It is widespread in the Asian subcontinent, with India bearing most of the burden. It is characterized by mucosal rigidity of varying intensity due to the fibroelastic changes of the juxta epithelial layer, resulting in a progressive inability to open the mouth. Early recognition with accurate staging of the disease and appropriate treatment planning is of utmost importance to prevent the malignant transformation and to improve the quality of life of the patient. In the present study, an attempt is made to clinically evaluate the condition and correlate it with the histopathological findings according to standard criteria. MATERIALS AND METHODS: A hospital-based study was conducted on sixty OSMF patients. Detailed history was recorded, and functional staging was given depending on mouth opening. Punch biopsy was performed, and histological stages were given based on standard criteria. The data so received were mathematically evaluated to determine whether any correlation exists between the stages using Chi-square test. RESULTS: The sixty patients were in the age range of 16-50 years. Male-to-female ratio was that of 97:3. The statistical analysis using Chi-square test showed statistically significant association (P < 0.001) between the functional and histologic stages. CONCLUSION: There is a definite correlation between functional and histological stages of OSMF which suggests that clinically advanced OSMF has extensive fibrosis histologically.
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OBJECTIVE: Brain damage, long-term disability and death are the dreadful consequences of ischemic stroke. It causes imbalance in the biochemical constituents that distorts the brain dynamics. Understanding the sub-cellular alterations associated with the stroke will contribute to deeper molecular understanding of brain plasticity and recovery. Current routine approaches examining lipid and protein biochemical changes post stoke can be difficult. Fourier Transform Infrared (FTIR) imaging spectroscopy can play a vital role in detecting these molecular alterations on a sub-cellular level due to its high spatial resolution, accuracy and sensitivity. This study investigates the biochemical and molecular changes in peri-infract zone (PIZ) (contiguous area not completely damaged by stroke) and ipsi-lesional white matter (WM) (right below the stroke and PIZ regions) nine weeks post photothrombotic ischemic stroke in rats. MATERIALS AND METHODS: FTIR imaging spectroscopy and transmission electron microscopy (TEM) techniques were applied to investigate brain tissue samples while hematoxylin and eosin (H&E) stained images of adjacent sections were prepared for comparison and examination the morphological changes post stroke. RESULTS: TEM results revealed shearing of myelin sheaths and loss of cell membrane, structure and integrity after ischemic stroke. FTIR results showed that ipsi-lesional PIZ and WM experienced reduction in total protein and total lipid content compared to contra-lesional hemisphere. The lipid/protein ratio reduced in PIZ and adjacent WM indicated lipid peroxidation, which results in lipid chain fragmentation and an increase in olefinic content. Protein structural change is observed in PIZ due to the shift from random coli and α-helical structures to ß-sheet conformation. CONCLUSION: FTIR imaging bio-spectroscopy provide novel biochemical information at sub-cellular levels that be difficult to be obtained by routine approaches. The results suggest that successful therapeutic strategy that is based on administration of anti-oxidant therapy, which could reduce and prevent neurotoxicity by scavenging the lipid peroxidation products. This approach will mitigate tissue damage in chronic ischemic period. FTIR imaging bio-spectroscopy can be used as a powerful tool and offer new approach in stroke and neurodegenerative diseases research.
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OBJECTIVE: The objective of this article is to review the current literature on Wnt5a and its signaling mechanism, along with its role in atherosclerosis. In addition, the significance of Wnt5a as a diagnostic marker and a potential therapeutic target is reviewed. Wnt5a, a secreted glycoprotein, belongs to a family of highly conserved proteins that regulate important processes such as cell fate specification, embryonic development, cell proliferation, migration, and differentiation in a variety of organisms. The complexity of Wnt5a signaling lies in the fact that Wnt5a can bind to different classes of frizzled receptors, receptor tyrosine kinase-like orphan receptor 2, as well as co-receptors such as low density lipoprotein receptor-related protein 5/6. Wnt5a signals primarily through the non-canonical pathway, where it mediates cell proliferation, adhesion, and movement. However, the role of Wnt5a in canonical signaling is still unresolved. Depending on the receptor availability, Wnt5a can serve to activate or inhibit the canonical Wnt signaling pathway. Due to the promiscuous nature of Wnt5a, it has been extremely difficult to fully understand its signaling mechanism. Wnt5a has recently emerged as a macrophage effector molecule that triggers inflammation. Perturbations in Wnt5a signaling have been reported in several inflammatory diseases, particularly in sepsis, rheumatoid arthritis, and atherosclerosis. CONCLUSION: Both existing and emerging evidence suggests that the expression of Wnt5a is always up-regulated in these, and possibly other inflammatory disorders. This knowledge can be useful for targeting Wnt5a and/or its receptor and downstream signaling molecules for therapeutic intervention in inflammatory disorders.
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Aterosclerose/metabolismo , Inflamação/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Wnt/fisiologia , Animais , Artrite Reumatoide/metabolismo , Biomarcadores/metabolismo , Diferenciação Celular , Linhagem da Célula , Humanos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Macrófagos/metabolismo , Camundongos , Transdução de Sinais , Proteína Wnt-5aRESUMO
Fibrosarcoma is a malignant mesenchymal neoplasm of fibroblasts that rarely affects the oral cavity and can cause local recurrences or metastasis. Fibrosarcomas account for 15% of all soft tissue sarcomas, which represent only 1% of all malignant tumors of the head and neck region. The clinical behavior of the fibrosarcoma is characterized by a high local recurrence rate, and low incidence of loco regional lymph node and/or distant hematogenous metastasis. The etiology for fibrosarcoma has no definite cause but is thought to occur from preexisting lesions or in previously irradiated areas of bone lesions. Immunosuppression associated with HIV infection and acquired immune deficiency syndrome (AIDS) has been consistently linked to various cancers, including Kaposi's sarcoma, non-Hodgkin's lymphoma, and invasive cervical cancer. Rare neoplasms like Hodgkin's disease, anal cancer, leukemia, basal cell carcinoma, and squamous cell carcinoma have also been demonstrated. This paper presents one such a rare incidence of an intraosseous fibrosarcoma occurring in an HIV-positive patient.
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Fibrossarcoma/complicações , Infecções por HIV/complicações , Neoplasias Maxilares/complicações , Adulto , Feminino , Fibrossarcoma/diagnóstico por imagem , Fibrossarcoma/metabolismo , Fibrossarcoma/patologia , Humanos , Hospedeiro Imunocomprometido , Imuno-Histoquímica , Neoplasias Maxilares/diagnóstico por imagem , Neoplasias Maxilares/metabolismo , Neoplasias Maxilares/patologia , Radiografia PanorâmicaRESUMO
OBJECTIVE: Wnt5a is a secreted glycoprotein highly present in atherosclerotic lesions. Uptake of oxidized-low density lipoprotein (ox-LDL) by monocytes/macrophages plays a critical role in atherosclerosis. The objective of this study was to determine if Wnt5a mRNA expression correlates with the severity of atherosclerotic lesions, and if, ox-LDL can induce Wnt5a mRNA in macrophages. METHODS: Wnt5a mRNA in tissue sections from carotid arteries of patients undergoing endarterectomy was quantified via RT-PCR and correlated with plaque severity. Human monocyte-derived macrophages and differentiated THP-1 cells, a human monocytic cell line, were treated with ox-LDL or native-LDL. Subsequently, Wnt5a transcripts were quantified by RT-PCR. RESULTS: Regions of the arteries with more severe plaques had detectable and significant levels of Wnt5a mRNA, while regions of the arteries containing less vulnerable plaques had low or non-detectable Wnt5a. Ox-LDL, but not native-LDL, induced Wnt5a mRNA in both human monocyte-derived macrophages and differentiated THP-1 cells. CONCLUSION: Our results demonstrate that the expression of Wnt5a correlates with the severity of atherosclerotic lesions, and that ox-LDL induces Wnt5a mRNA expression in human macrophages. These findings are consistent with the hypothesis that Wnt5a plays a critical role in atherosclerosis progression and that a source of Wnt5a is ox-LDL stimulated macrophages.
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Pathological inflammation and endothelial dysfunction in atherosclerosis causes endothelial cell detachment from affected vasculature giving rise to circulating endothelial cells (CECs). A blood-based assay that can detect and characterize CECs in atherosclerosis could serve as a valuable diagnostic. Thus, we sought to develop a prototypic assay that detects and characterizes the inflammatory state of endothelial cells present in blood. For this purpose, we spiked resting and inflamed human umbilical vein endothelial cells (HUVEC) into separate samples of whole blood. RNA was harvested and analyzed via quantitative real-time PCR (qPCR) using melanoma cell adhesion molecule (MCAM), as an endothelial marker, and vascular cell adhesion molecule (VCAM-1), which is increased on inflamed endothelium. We found that MCAM mRNA levels correlated with the number of HUVEC spiked into the blood. VCAM-1 mRNA levels were elevated, and correlated with the number of HUVEC, in blood spiked with inflamed HUVEC but not in blood spiked with resting HUVEC. VCAM-1 and MCAM mRNA levels were converted into numerical indices that indicate the inflammatory state of the HUVEC. Combined, the blood spiking studies demonstrate that a VCAM-1/MCAM qPCR assay can successfully detect inflamed endothelial cells in whole blood thus providing proof-of-concept for a diagnostic based on a coupled-phenotypic qPCR assay.