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Multidrug-resistant yeast Candida auris is a serious threat to public health with documented survival in various hospital niches. The dynamics of this survival benefit and its trade off with drug resistance are still unknown for this pathogen. In this study we investigate the oxidative stress response (OSR) in fluconazole-resistant C. auris and compare its relative fitness with fluconazole-susceptible strains. A total of 351 C. auris clinical isolates (61 fluconazole-susceptible and 290 fluconazole-resistant) were screened for stress tolerance by spot assay and 95.08 % fluconazole-susceptible isolates were hyper-resistant to oxidative stress while majority (94.5 %) fluconazole-resistant isolates had lower oxidative tolerance. Expression of Hog1 and Cta1 gene transcript levels and cellular catalase levels were significantly higher in fluconazole-susceptible isolates and a corresponding higher intracellular reactive oxygen species level (iROS) was accumulated in the fluconazole-resistant isolates. Biofilm formation and cell viability under oxidative stress revealed higher biofilm formation and better viability in fluconazole-susceptible isolates. Fluconazole-resistant isolates had higher basal cell wall chitin. On comparison of virulence, the % cytotoxicity in A549 cell line was higher in fluconazole-susceptible isolates and the median survival of the infected larvae in G. mellonella infection model was higher in fluconazole-resistant (5; IQR:4.5-5 days) vs. fluconazole-susceptible C. auris (2; IQR:1.5-2.5 days). All organisms evolve with changes in their environmental conditions, to ensure an optimal balance between proliferation and survival. Development of tolerance to a certain kind of stress example antifungal exposure in yeast can leads to a compensatory decrease in tolerance for other stresses. This study provides useful insights into the comparative fitness and antifungal susceptibility trade off in C. auris. We report a negative association between H2O2 tolerance and fluconazole susceptibility. Using in-vitro cell cytotoxicity and in-vivo survival assays we also demonstrate the higher virulence potential of fluconazole-susceptible C. auris isolates corroborating the negative correlation between susceptibility and pathogen survival or virulence. These findings could also be translated to clinical practice by investigating the possibility of using molecules targeting stress response and fitness regulating pathways for management of this serious infection.
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Thorium-232 (Th-232) is a promising fuel for advanced nuclear reactors. However, in case of internal human exposure to Th, there is currently no effective modality for its removal from liver and skeleton or for mitigating its effect. The FDA-approved agent, diethylenetriaminepentaacetate (DTPA), can remove Th and other actinides from blood circulation only. For the first time, a rationally-selected polyherbal hepatoprotective i.e. Liv52® (L52S), was evaluated in-combination with DTPA for its Th decorporation ability in Swiss mice. Inductively-coupled plasma mass spectroscopic analysis showed that oral administration of L52S in conjunction with DTPA significantly decreased Th burden from liver (20 %) and skeleton (33 %) as well as enhanced Th excretion (â¼2.5 folds) through urine in comparison to DTPA or L52S alone. The combinatorial therapy was found to be complementary in-action, ameliorating Th-induced tissue damage in liver, spleen, and bone more effectively than monotherapy. Furthermore, markers of liver function (alanine transaminase) and liver inflammation and fibrosis (NF-κB & keratin) further validated the beneficial effect of L52S. The human consumption of L52S for various liver disorders further supports its clinical application for Th decorporation and mitigation of its health effects.
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Fígado , Ácido Pentético , Tório , Animais , Tório/toxicidade , Ácido Pentético/química , Camundongos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Masculino , Quelantes/farmacologia , Quelantes/química , Baço/efeitos dos fármacos , Baço/metabolismoRESUMO
Sundarban, a Ramsar site of India, has been encountering an ecological threat due to the presence of microplastic (MP) wastes generated from different anthropogenic sources. Clibanarius longitarsus, an intertidal hermit crab of Sundarban Biosphere Reserve, resides within the abandoned shell of a gastropod mollusc, Telescopium telescopium. We characterized and estimated the MP in the gills and gut of hermit crab, as well as in the water present in its occupied gastropod shell. The average microplastic abundance in sea water, sand and sediment were 0.175 ± 0.145 MP L-1, 42 ± 15.03 MP kg-1 and 67.63 ± 24.13 MP kg-1 respectively. The average microplastic load in hermit crab was 1.94 ± 0.59 MP crab-1, with 33.89 % and 66.11 % in gills and gut respectively. Gastropod shell water exhibited accumulation of 1.69 ± 1.43 MP L-1. Transparent and fibrous microplastics were documented as the dominant polymers of water, sand and sediment. Shell water exhibited the prevalence of green microplastics followed by transparent ones. Microscopic examination revealed microplastics with 100-300 µm size categories were dominant across all abiotic compartments. ATR-FTIR and Raman spectroscopy confirmed polyethylene and polypropylene as the prevalent polymers among the five identified polymers of biotic and abiotic components. The target group index indicated green and black as the preferable microplastics of crab. The ecological risk analysis indicated a considerable level of environmental pollution risk in Sundarban and its inhabiting organisms. This important information base may facilitate in developing a strategy of mitigation to limit the MP induced ecological risk at Sundarban Biosphere Reserve.
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Anomuros , Monitoramento Ambiental , Sedimentos Geológicos , Microplásticos , Água do Mar , Poluentes Químicos da Água , Animais , Poluentes Químicos da Água/análise , Microplásticos/análise , Monitoramento Ambiental/métodos , Sedimentos Geológicos/química , Índia , Medição de Risco , Água do Mar/química , AreiaRESUMO
We report an environmentally benign recycling approach for large-capacity nickel manganese cobalt (NMC) batteries through the electrochemical concentration of lithium on the anode and subsequent recovery with only water. Cycling of the NMC pouch cells indicated the potential for maximum lithium recovery at a 5C charging rate. The anodes extracted from discharged and disassembled cells were submerged in deionized water, resulting in lithium dissolution and graphite recovery from the copper foils. A maximum of 13 mg of lithium salts per 100 mg of the anode, copper current collector, and separator was obtained from NMC pouch cell cycled at a 4C charging rate. The lithium salts extracted from batteries cycled at low C-rates were richer in lithium carbonate, while the salts from batteries cycled at high C-rates were richer in lithium oxides and peroxides, as determined by X-Ray photoelectron spectroscopy. The present method can be successfully used to recover all the pouch cell components: lithium, graphite, copper, and aluminum current collectors, separator, and the cathode active material.
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Fontes de Energia Elétrica , Lítio , Lítio/química , Água/química , Eletrodos , Solventes/química , Cobalto/química , Reciclagem , Níquel/química , Manganês/química , Grafite/química , Cobre/químicaRESUMO
The burgeoning interest in the field of molecular magnetism is to perceive the high magnetic anisotropy in different geometries of metal complexes and hence to draw a magneto-structural correlation. Despite a handful of examples to exemplify the magnetic anisotropy in various coordination geometries of mononuclear complexes, the magnetic anisotropies for two different coordination geometries are underexplored. Employing an appropriate synthetic strategy utilizing the ligand LH2 [2,2'-{(1E,1'E)-pyridine2,6-diyl-bis(methaneylylidine)}-bis(azaneylylidine)diphenol] and cobalt halide salts in a 1 : 2 stoichiometric ratio in the presence of triethylamine allowed us to report a new family of dinuclear cobalt complexes [CoII2X2(L)(P)(Q)]·S with varying terminal halides [X = Cl, P = CH3CN, Q = H2O, S = H2O (1), X = Br, P = CH3CN, Q = H2O, S = H2O (2), X = I, P = CH3CN, and Q = CH3CN (3)]. All these complexes are characterized through single crystal X-ray crystallography, which reveals their crystallization in the monoclinic system P21/n space group with nearly identical structural features. These complexes share vital components, including Co(II) centers, a fully deprotonated ligand [L]2-, halide ions, and solvent molecules. The [L]2- ligand contains two Co(II) centers, where phenolate oxygen atoms bridge the Co(II) centers, forming a Co2O2 four-membered ring. Co1 demonstrates a distorted pentagonal-bipyramidal geometry with axial positions for solvent molecules, while Co2 displays a distorted tetrahedral geometry involving phenolate oxygen atoms and halide ions. Temperature-dependent dc magnetic susceptibility measurements were conducted on 1-3 within a range of 2 to 300 K at 1 kOe. The χmT vs. T plots exhibit similar trends, with χmT values at 300 K higher than the spin-only value, signifying a significant orbital contribution. As the temperature decreases, χmT decreases smoothly in all the complexes; however, no clear saturation at low temperatures is observed. Field-dependent magnetization measurements indicate a rapid increase below 20 kOe, with no hysteresis and a low magnetic blocking temperature. DFT and CASSCF/NEVPT2 theoretical calculations were performed to perceive the magnetic interaction and single-ion anisotropies of Co(II) ions in various ligand-field environments.
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Objective First responders' mandatory reports of mental health episodes requiring emergency hospital care contain rich information about patients and their needs. In Queensland (Australia) much of the information contained in Emergency Examination Authorities (EEAs) remains unused. We propose and demonstrate a methodology to extract and translate vital information embedded in reports like EEAs and to use it to investigate the extreme propensity of incidence of serious mental health episodes. Methods The proposed method integrates clinical, demographic, spatial and free text information into a single data collection. The data is subjected to exploratory analysis for spatial pattern recognition leading to an observational epidemiology model for the association of maximum spatial recurrence of EEA episodes. Results Sentiment analysis revealed that among EEA presentations hospital and health service (HHS) region #4 had the lowest proportion of positive sentiments (18 %) compared to 33 % for HHS region #1 pointing to spatial differentiation of sentiments immanent in mandated free text which required more detailed analysis. At the postcode geographical level, we found that variation in maximum spatial recurrence of EEAs was significantly positively associated with spatial range of sentiments (0.29, p < 0.001) and the postcode-referenced sex ratio (0.45, p = 0.01). The volatility of sentiments significantly correlated with extremes of recurrence of EEA episodes. The predicted (probabilistic) incidence rate when mapped reflected this correlation. Conclusions The paper demonstrates the efficacy of integrating, machine extracted, human sentiments (as potential surrogates) with conventional exposure variables for evidence-based methods for mental health spatial epidemiology. Such insights from informatics-driven epidemiological observations may inform the strategic allocation of health system resources to address the highest levels of need and to improve the standard of care for mental patients while also enhancing their safe and humane treatment and management.
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Saúde Mental , Humanos , Transtornos Mentais/terapia , Transtornos Mentais/epidemiologia , Queensland/epidemiologia , Masculino , FemininoRESUMO
NADPH oxidase 5 (NOX5) catalyzes the production of superoxide free radicals and regulates physiological processes from sperm motility to cardiac rhythm. Overexpression of NOX5 leads to cancers, diabetes, and cardiovascular diseases. NOX5 is activated by intracellular calcium signaling, but the underlying molecular mechanism of which - in particular, how calcium triggers electron transfer from NADPH to FAD - is still unclear. Here we capture motions of full-length human NOX5 upon calcium binding using single-particle cryogenic electron microscopy (cryo-EM). By combining biochemistry, mutagenesis analyses, and molecular dynamics (MD) simulations, we decode the molecular basis of NOX5 activation and electron transfer. We find that calcium binding to the EF-hand domain increases NADPH dynamics, permitting electron transfer between NADPH and FAD and superoxide production. Our structural findings also uncover a zinc-binding motif that is important for NOX5 stability and enzymatic activity, revealing modulation mechanisms of reactive oxygen species (ROS) production.
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Cálcio , NADPH Oxidase 5 , NADP , Humanos , Sítios de Ligação , Cálcio/metabolismo , Microscopia Crioeletrônica , Transporte de Elétrons , Ativação Enzimática , Flavina-Adenina Dinucleotídeo/metabolismo , Simulação de Dinâmica Molecular , NADP/metabolismo , NADPH Oxidase 5/metabolismo , NADPH Oxidase 5/genética , NADPH Oxidase 5/química , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Zinco/metabolismoRESUMO
The structural stability and therapeutic activity of Stem Bromelain (BM) have been explored by unravelling the interaction of stem BM in presence of two different types of anionic surfactants namely, bile salts, NaC and NaDC and the conventional anionic surfactants, SDDS and SDBS, below, at and above the critical micelle concentration (cmc) in aqueous phosphate buffer of pH 7. Different physicochemical parameters like, surface excess (Γcmc), minimum area of surfactants at air water interface (Amin) etc. are calculated from tensiometry both in absence and presence of BM. Several inflection points (C1, C2 and C3) have been found in tensiometry profile of surfactants in presence of BM due to the conformational change of BM assisted by surfactants. Similar observation also found in isothermal titration calorimetry (ITC) profiles where the enthalpy of micellization (ΔH0obs) of surfactants in absence and presence of BM have calculated. Further, steady state absorption and fluorescence spectra monitoring the tryptophan (Trp) emission of free BM and in presence of all the surfactants at three different temperatures (288.15 K, 298.15 K, and 308.15 K) reveal the nature of fluorescence quenching of BM in presence of bile salts/surfactants. Time resolved fluorescence studies at room temperature also support to determine the several quenching parameters. The binding constant (Kb) of BM with all the surfactants and free energy of binding (∆G0 of bile salts/surfactants with BM at different temperatures have been calculated exploiting steady state fluorescence technique. It is observed that, the binding of NaC with BM is greater as compared to other surfactants while Stern-Volmer quenching constant (KSV) is found greater in presence of SDBS as compared with others which supports the surface tension and ITC data with the fact that surface activity of surfactant(s) is decreasing with the binding of the surfactants at the core or binding pocket of BM. Circular Dichroism (CD) study shows the stability of secondary structure of BM in presence of NaC and NaDC below C3, while BM lost its structural stability even at very low surfactant concentration of SDDS and SDBS which also supports the more involvement of bile salts in binding rather than surfactants. The molecular docking studies have also been substantiated for better understanding the several experimental investigations interaction of BM with the bile salts/surfactants.
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Bromelaínas , Micelas , Simulação de Acoplamento Molecular , Tensoativos , Termodinâmica , Bromelaínas/química , Bromelaínas/metabolismo , Tensoativos/química , Concentração de Íons de Hidrogênio , Ânions/química , Espectrometria de Fluorescência , Soluções TampãoRESUMO
BACKGROUND: Diabetes mellitus, a hyperglycemic condition associated with multitudinous organ dysfunction, is a hallmark of the metabolic disorder. This life-threatening condition affects millions of individuals globally, harming them financially, physically and psychologically in the course of therapy. PURPOSES: The course therapy for illnesses has undergone ground-breaking transformations due to recent technical advances and insights. Alternatively, the administration of hyperglycemia-reducing agents results in several complications, including severe cardiovascular disease, kidney failure, hepatic problems, and several dermatological conditions. Consideration of alternate diabetic therapy having minimal side effects or no adverse reactions has been driven by such problems. STUDY DESIGN: An extensive literature study was conducted in authoritative scientific databases such as PubMed, Scopus, and Web of Science to identify the studies elucidating the bioactivities of terpenoids in diabetic conditions. METHODS: Keywords including 'terpenoids', 'monoterpenes', 'diterpenes', 'sesquiterpenes', 'diabetes', 'diabetes mellitus', 'clinical trials', 'preclinical studies', and 'increased blood glucose' were used to identify the relevant research articles. The exclusion criteria, such as English language, duplication, open access, abstract only, and studies not involving preclinical and clinical research, were set. Based on these criteria, 937 relevant articles were selected for further evaluation. RESULTS: Triterpenes can serve as therapeutic agents for diabetic retinopathy, peripheral neuropathy, and kidney dysfunction by inhibiting several pathways linked to hyperglycemia and its complications. Therefore, it is essential to draw special attention to these compounds' therapeutic effectiveness and provide scientific professionals with novel data. CONCLUSION: This study addressed recent progress in research focussing on mechanisms of terpenoid, its by-products, physiological actions, and therapeutic applications, particularly in diabetic and associated disorders.
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Diabetes Mellitus , Hipoglicemiantes , Terpenos , Humanos , Terpenos/farmacologia , Terpenos/uso terapêutico , Animais , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Fitoterapia , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêuticoRESUMO
Road dust is a demonstrated source of urban air pollution. Given this, the implementation of street sweeping strategies that effectively limit road dust accumulation and resuspension should be a public health priority. Research examining the effectiveness of street sweeping for road dust removal in support of good air quality has been limited to date. To address this, the study aimed to assess the use of a regenerative-air street sweeper to efficiently remove road dust particles and metal(loid)s in size fractions relevant for respiratory exposure in Toronto, Canada. As part of this, the mass amounts, particle size distribution and elemental concentrations of bulk road dust before and after sweeping at five arterial sites were characterized. Sweeping reduced the total mass amount of thoracic-sized (<10 µm) road dust particles by 76 % on average. A shift in the size distribution of remaining particles toward finer fractions was observed in post-sweeping samples, together with an enrichment in many metal(loid)s such as Co, Ti and S. Overall, the mass amounts of metal(loid)s of respiratory health concern like Cu and Zn were greatly reduced with sweeping. Traffic volume and road surface quality were predictors of dust loadings and elemental concentrations. Road surface quality was also found to impact street sweeping efficiencies, with larger mass amounts per unit area collected post-sweeping where street surfaces were distressed. This study demonstrates that street sweeping using advanced technology can be highly effective for road dust removal, highlighting its potential to support air quality improvement efforts. The importance of tailoring sweeping service levels and technologies locally as per the quality of road surface and traffic patterns is emphasized. Continued efforts to mitigate non-exhaust emissions that pose a respiratory health risk at their source is essential.
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Poluentes Atmosféricos , Poeira , Metais , Tamanho da Partícula , Poeira/análise , Poluentes Atmosféricos/análise , Metais/análise , Poluição do Ar/prevenção & controle , Cidades , Monitoramento Ambiental/métodos , Humanos , Material Particulado/análise , Emissões de Veículos/análiseRESUMO
Thorium-232 (Th), the most abundant naturally occurring nuclear fuel, has been identified as a sustainable source of energy. In view of its large-scale utilization and human evidence of lung disorders and carcinogenicity, it is imperative to understand the effect of Th exposure on lung cells. The present study investigated the effect of Th-dioxide (1-100 µg/mL, 24-48 h) on expression of surfactant proteins (SPs) (SP-A, SP-B, SP-C, and SP-D, which are essential to maintain lung's surface tension and host-defense) in human lung cells (WI26 and A549), representative of alveolar cell type-I and type-II, respectively. Results demonstrated the inhibitory effect of Th on transcriptional expression of SP-A, SP-B, and SP-C. However, Th promoted the mRNA expression of SP-D in A549 and reduced its expression in WI26. To a significant extent, the effect of Th on SPs was found to be in accordance with their protein levels. Moreover, Th exposure altered the extracellular release of SP-D/A from A549, which remained unaltered in WI26. Our results suggested the differential role of oxidative stress and ATM and HSP90 signaling in Th-induced alterations of SPs. These effects of Th were found to be consistent in lung tissues of mice exposed to Th aerosols, suggesting a potential role of SPs in Th-associated lung disorders.
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Células Epiteliais Alveolares , Tório , Humanos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Camundongos , Animais , Células A549 , Proteínas Associadas a Surfactantes Pulmonares/metabolismoRESUMO
Glycosmis pentaphylla, a member of the Rutaceae family, has been extensively studied for its pharmacological activities, focusing mainly on the cytotoxic properties of its roots and stems. Conversely, limited researched has been done in terms of the phytochemical composition of the fruits. The objective of this study is to isolate and identify the bioactive compounds found in the fruits of G. pentaphylla and then evaluate their potential for anti-cancer activity in oral cancer CAL 27 cell lines. The extraction of bioactive compounds from fruits was done by maceration, and the isolation of alkaloids and volatile oil fractions (F1-F5) was performed by column chromatography. The alkaloids, such as 3-O-methoxyglycocitrine II, noracronycine, 1-hydroxy-3-methoxy-10-methyl-9-acridone and kokusaginine, were first isolated from the fruits of G. pentaphylla. Additionally, GC-MS analysis identified 78 metabolites. The isolated compounds and identified volatile oil fractions were explored for their anti-cancer activity by cell viability assay. Results demonstrated that isolated compounds were found inactive, while the volatile fraction F1 was found active in CAL 27 cell line. Fraction F1 impeded wound healing in CAL 27 cells by scratch assay, and significantly inhibited colony formation in colony formation assay. In cell cycle analysis, treatment with fraction F1 redistributed cells to the S and G2 phases of the cell cycle. α-elemol (2) is the major metabolite identified from the F1 fraction by GC-MS, which could be responsible for the anti-cancer activity. There is potential for future work to further isolate volatile oil metabolites and evaluate their anti-cancer activity through in-vivo techniques.
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Alcaloides , Antineoplásicos Fitogênicos , Frutas , Cromatografia Gasosa-Espectrometria de Massas , Óleos Voláteis , Compostos Fitoquímicos , Rutaceae , Frutas/química , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Rutaceae/química , Linhagem Celular Tumoral , Alcaloides/farmacologia , Alcaloides/isolamento & purificação , Humanos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Estrutura MolecularRESUMO
To study the effect of diamagnetic ions on magnetic interactions, utilizing a compartmental ligand (Z)-2-(hydroxymethyl)-4-methyl-6-((quinolin-8-ylimino)methyl)phenol (LH2), two different series of ZnII-LnIII complexes, namely the trinuclear series of [DyZn2(L)2(µ2-OAc)2(CH3OH)2]·NO3·MeOH (1), [TbZn2(L)2(µ2-OAc)2(CH3OH)2]·NO3·5MeOH·H2O (2), and [GdZn2(L)2(µ2-OAc)2(CH3OH)2]·NO3·MeOH·CHCl3 (3) and the tetranuclear series of [Dy2Zn2(LH)4(NO3)4(µ2OAc)]·NO3·MeOH·H2O (4), [Tb2Zn2(LH)4(NO3)4(µ2-OAc)]·NO3·MeOH·2H2O (5), and [Gd2Zn2(LH)4(NO3)4(µ2-OAc)]·NO3·MeOH·2H2O (6), were synthesized. Trinuclear ZnII-LnIII complexes 1-3 consist of one LnIII ion sandwiched between two peripheral ZnII ions forming a bent type ZnII-DyIII-ZnII array with an angle of 110.64°. Tetranuclear ZnII-LnIII complexes 4-6 are basically a combination of two dinuclear moieties of [LnZn(LH)2(NO3)2]+ connected by one bidentate bridging acetate ion in µ2-OAc coordination mode. The detailed magnetic analysis reveals that complexes 1 and 4 are single molecule magnets having energy barriers of 34.98 K and 46.71 K with relaxation times (τ0) of 5.05 × 10-4 s and 5.24 × 10-4 s, respectively. Ab initio calculations were employed to analyze the magnetic anisotropy and magnetic exchange interaction between the ZnII and LnIII centers with the aim of gaining better insights into the magnetic dynamics of complexes 1-6.
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Triple negative breast carcinoma (TNBC) accounts for 15-20 % of all incident breast cancers (BC) and is known to be highly invasive, has fewer treatment options, and tends to have a worse prognosis. However, due to its biological heterogeneity and diverse clinical and epidemiological behaviors, TNBC lacks a tumor-specific targeted therapy. In the present work we have developed a TNBC-specific targeted nano-delivery agent comprising of a cRGD labeled magneto-liposome (T-LMD) co-encapsulated with oleic acid coated iron oxide nanoparticles (MN-OA) and doxorubicin (Dox) in the liposome bilayer and core, respectively. T-LMD was found to show enhanced uptake and induction of ferroptotic cell death in MDA-MB-231, a TNBC model cell line. Additionally, T-LMD induced ferroptosis was found to be accompanied by release of HMGB1, an immunogenic cell death marker, suggesting its immunogenicity for augmenting the activation of anti-tumor immunity in TNBC. The strategic placement of IONPs in the liposome bilayer of T-LMD facilitates the sensitization of MDA-MB-231 cells to undergo ferroptosis; predominantly via the activation of the iron/lipid metabolism pathway, as validated by use of small molecule ferroptosis inhibitor (ferrostatin-1) and iron chelator (deferoxamine). Activation of ferroptotic cell death was also corroborated by ferroptosis specific-ultrastructural alterations in the shape/size of cellular mitochondria and cell ballooning as observed by transmission electron microscopy and bright field imaging, respectively. Thus, our ferroptosis nano-inducer (T-LMD) can efficiently kill TNBC cells via enhanced LPO and ROS generation leading to membrane damage and consequent release of LDH and HMGB1, induce mitochondrial alterations and enhanced DNA double strand breaks. Altogether, our results suggest significant implications of T-LMD for treatment of TNBC.
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Doxorrubicina , Ferroptose , Lipossomos , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Ferroptose/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Lipossomos/química , Feminino , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Proteína HMGB1/metabolismo , Nanopartículas Magnéticas de Óxido de Ferro/químicaRESUMO
Advanced spectroscopic techniques have been utilized to study the interaction between the laser dye coumarin 153 (C153) and graphene oxide (GO) nanoparticles. GO was synthesized using a modified Hummers' method and characterized by UV-vis spectroscopy, Raman laser spectroscopy, FTIR-ATR spectroscopy, FESEM, HR-TEM, and XRD techniques. The GO@C153 composite was formed by mixing two aqueous solutions of GO and C153 due to their strong interaction through stacking and hydrophobic interactions. In this case, GO acts as an effective fluorescence quencher for C153 molecules, which undergo H-type aggregation in the presence of GO. The Stern-Volmer equation and time-dependent fluorescence studies were utilized to analyse the mechanism of fluorescence quenching. According to the findings, both static and dynamic quenching processes are responsible for the reduction in fluorescence intensity. The effect of surfactants (both cetyltrimethylammonium p-toluenesulfonate (CTAT) and synthesized N,N'-dihexadecyl-N,N,N',N'-tetramethyl-N,N'-but-2-ynediyl-di-ammonium chloride (16-4-16)) on the aggregation and photophysical properties of the dye was investigated using surface tensiometry, conductometry, UV-vis absorption spectroscopy, steady-state fluorescence measurements, DLS, and time-dependent fluorescence spectroscopy. Surfactants change the microenvironment of the C153 dye, leading to spectrum shifting and a higher quantum yield, which causes a rapid rise in fluorescence intensity in the micellar medium. It has been noted that in a micellar medium rather than in an aqueous one, the luminous intramolecular charge transfer (ICT) state of C153 stabilises. Lastly, we investigated the photophysical behavior of the GO-C153-micelle ternary system and discovered that, in the presence of a micellar medium, the quenched and blue-shifted (H-type aggregation) fluorescence peak of C153 (in the presence of GO) began to intensify once more. The main goal of this work is to create an effective and fairly cost powerful fluorescence sensor. Additionally, the ternary system (GO-C153-micelle) analytical idea can be employed to identify the onset of micelle formation. In wastewater treatment analysis, the GO-C153-surfactant ternary system concept can also be used to regenerate the adsorbent (in this case, GO) from dye molecules by allowing the dye molecules to exit the adsorbent and enter the micellar medium.
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Triple negative breast cancer (TNBC) is an aggressive form of tumor, more prevalent in younger women resulting in poor survival rate (2nd in cancer deaths) because of its asymptomatic existence. The most popular and convenient approach for the treatment of TNBC is chemotherapy which is associated with several limitations. Considering the importance of nanotechnology in health care system, in the present manuscript, we have designed and developed a simple, efficient, cost effective, and ecofriendly method for the synthesis of copper nitroprusside analogue nanoparticles (Cu[Fe(CN)5NO] which is abbreviated as CuNPANP that may be the potential anti-cancer nanomedicine for the treatment of TNBC. Copper (present in CuNPANP) is used because of its affordability, nutritional value and various biomedical applications. The CuNPANP are thoroughly characterized using several analytical techniques. The in vitro cell viability (in normal cells) and the ex vivo hemolysis assay reveal the biocompatible nature of CuNPANP. The anti-cancer activity of the CuNPANP is established in TNBC cells (MDA-MB-231 and 4T1) through several in vitro assays along with plausible mechanisms. The intraperitoneal administration of CuNPANP in orthotopic breast tumor model by transplanting 4T1 cells into the mammary fat pad of BALB/c mouse significantly inhibits the growth of breast carcinoma as well as increases the survival time of tumor-bearing mice. These results altogether potentiate the anti-cancer efficacy of CuNPANP as a smart therapeutic nanomedicine for treating TNBC in near future after bio-safety evaluation in large animals.
Assuntos
Cobre , Espécies Reativas de Oxigênio , Neoplasias de Mama Triplo Negativas , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Feminino , Camundongos , Cobre/química , Cobre/farmacologia , Cobre/administração & dosagem , Humanos , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Camundongos Endogâmicos BALB C , Nanopartículas Metálicas/uso terapêutico , Nanopartículas Metálicas/química , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
The reaction of Co(OAc)2·6H2O with 2,2'-[{(1E,1'E)-pyridine-2,6-diyl-bis(methaneylylidene)bis(azaneylylidene)}diphenol](LH2) a multisite coordination ligand and Et3N in a 1:2:3 stoichiometric ratio forms a tetranuclear complex Co4(L)2(µ-η1:η1-OAc)2(η2-OAc)2]· 1.5 CH3OH· 1.5 CHCl3 (1). Based on X-ray diffraction investigations, complex 1 comprises a distorted Co4O4 cubane core consisting of two completely deprotonated ligands [L]2- and four acetate ligands. Two distinct types of CoII centers exist in the complex, where the Co(2) center has a distorted octahedral geometry; alternatively, Co(1) has a distorted pentagonal-bipyramidal geometry. Analysis of magnetic data in 1 shows predominant antiferromagnetic coupling (J = -2.1 cm-1), while the magnetic anisotropy is the easy-plane type (D1 = 8.8, D2 = 0.76 cm-1). Furthermore, complex 1 demonstrates an electrochemical oxygen evolution reaction (OER) with an overpotential of 325 mV and Tafel slope of 85 mV dec-1, required to attain a current density of 10 mA cm-2 and moderate stability under alkaline conditions (pH = 14). Electrochemical impedance spectroscopy studies reveal that compound 1 has a charge transfer resistance (Rct) of 2.927 Ω, which is comparatively lower than standard Co3O4 (5.242 Ω), indicating rapid charge transfer kinetics between electrode and electrolyte solution that enhances higher catalytic activity toward OER kinetics.
RESUMO
Dissipative supramolecular assemblies are hallmarks of living systems, contributing to their complex, dynamic structures and emerging functions. Living cells can spatiotemporally control diverse biochemical reactions in membrane compartments and condensates, regulating metabolite levels, signal transduction or remodeling of the cytoskeleton. Herein, we constructed membranous compartments using self-assembly of lipid-like amphiphiles (lipidoid) in aqueous medium. The new double-tailed lipidoid features Cu(II) coordinated with a tetravalent chelator that dictates the binding of two amphiphilic ligands in cis-orientation. Hydrophobic interactions between the lipidoids coupled with intermolecular hydrogen bonding led to a well-defined bilayer vesicle structure. Oil-soluble SNAr reaction is efficiently upregulated in the hydrophobic cavity, acting as a catalytic crucible. The modular system allows easy incorporation of exposed primary amine groups, which augments the catalysis of retro aldol and C-N bond formation reactions. Moreover, a higher-affinity chelator enables consumption of the Cu(II) template leveraging the differential thermodynamic stability, which allows a controllable lifetime of the vesicular assemblies. Concomitant temporal upregulation of the catalytic reactions could be tuned by the metal ion concentration. This work offers new possibilities for metal ion-mediated dynamic supramolecular systems, opening up a massive repertoire of functionally active dynamic "life-like" materials.
RESUMO
A growing number of re-infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in previously immunized individuals has sparked discussions about the potential need for a booster vaccine dosage to counteract declining antibody levels and new strains. The protective immunity produced by vaccinations, and past illnesses relies on immunological memory. CD4 + T cells, CD8 + T cells, B cells, and long-lasting antibody responses are all components of the adaptive immune system that can generate and maintain this immunological memory. Since novel mutant variants have emerged one after the other, the world has been hit by repeated waves. Various vaccine formulations against SARS-CoV-2 have been administered across the globe. Thus, estimating the efficacy of those vaccines against gradually developed mutant stains is the essential parameter regarding the fate of those vaccine formulations and the necessity of booster doses and their frequency. In this review, focus has also been given to how vaccination stacks up against moderate and severe acute infections in terms of the longevity of the immune cells, neutralizing antibody responses, etc. However, hybrid immunity shows a greater accuracy of re-infection of variants of concern (VOCs) of SARS-CoV-2 than infection and immunization. The review conveys knowledge of detailed information about several marketed vaccines and the status of their efficacy against specific mutant strains of SARS-CoV-2. Furthermore, this review discusses the status of immunological memory after infection, mixed infection, and vaccination.