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1.
Nat Methods ; 21(7): 1166-1170, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38877315

RESUMO

The growth of omic data presents evolving challenges in data manipulation, analysis and integration. Addressing these challenges, Bioconductor provides an extensive community-driven biological data analysis platform. Meanwhile, tidy R programming offers a revolutionary data organization and manipulation standard. Here we present the tidyomics software ecosystem, bridging Bioconductor to the tidy R paradigm. This ecosystem aims to streamline omic analysis, ease learning and encourage cross-disciplinary collaborations. We demonstrate the effectiveness of tidyomics by analyzing 7.5 million peripheral blood mononuclear cells from the Human Cell Atlas, spanning six data frameworks and ten analysis tools.


Assuntos
Software , Humanos , Biologia Computacional/métodos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/citologia , Genômica/métodos , Análise de Dados
2.
Proc Natl Acad Sci U S A ; 121(8): e2315190121, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38363865

RESUMO

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion transporter required for epithelial homeostasis in the lung and other organs, with CFTR mutations leading to the autosomal recessive genetic disease CF. Apart from excessive mucus accumulation and dysregulated inflammation in the airways, people with CF (pwCF) exhibit defective innate immune responses and are susceptible to bacterial respiratory pathogens such as Pseudomonas aeruginosa. Here, we investigated the role of CFTR in macrophage antimicrobial responses, including the zinc toxicity response that is used by these innate immune cells against intracellular bacteria. Using both pharmacological approaches, as well as cells derived from pwCF, we show that CFTR is required for uptake and clearance of pathogenic Escherichia coli by CSF-1-derived primary human macrophages. CFTR was also required for E. coli-induced zinc accumulation and zinc vesicle formation in these cells, and E. coli residing in macrophages exhibited reduced zinc stress in the absence of CFTR function. Accordingly, CFTR was essential for reducing the intramacrophage survival of a zinc-sensitive E. coli mutant compared to wild-type E. coli. Ectopic expression of the zinc transporter SLC30A1 or treatment with exogenous zinc was sufficient to restore antimicrobial responses against E. coli in human macrophages. Zinc supplementation also restored bacterial killing in GM-CSF-derived primary human macrophages responding to P. aeruginosa, used as an in vitro macrophage model relevant to CF. Thus, restoration of the zinc toxicity response could be pursued as a therapeutic strategy to restore innate immune function and effective host defense in pwCF.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Macrófagos , Humanos , Antibacterianos/uso terapêutico , Fibrose Cística/microbiologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiologia , Zinco/metabolismo
3.
Trends Biochem Sci ; 47(6): 492-505, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35305898

RESUMO

Post-translational modifications (PTMs) immensely expand the diversity of the proteome. Glycosylation, among the most ubiquitous PTMs, is a dynamic and multifarious modification of proteins and lipids that generates an omnipresent foliage on the cell surface. The resulting protein glycoconjugates can serve important functions in biology. However, their vast complexity complicates the study of their structures, interactions, and functions. There is now a growing appreciation of the need to study glycans and proteins together as complete entities, as the sum of these two components can exhibit unique functions. In this review, we discuss the growing forestry toolbox to characterize the structure, interactions, and biological functions of protein glycoconjugates, as well as the potential payouts of understanding and controlling these enigmatic biomolecules.


Assuntos
Proteoma , Proteômica , Glicoconjugados , Glicosilação , Processamento de Proteína Pós-Traducional , Proteômica/métodos
4.
Cell ; 145(5): 665-77, 2011 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-21620134

RESUMO

Development of malaria parasites within vertebrate erythrocytes requires nutrient uptake at the host cell membrane. The plasmodial surface anion channel (PSAC) mediates this transport and is an antimalarial target, but its molecular basis is unknown. We report a parasite gene family responsible for PSAC activity. We used high-throughput screening for nutrient uptake inhibitors to identify a compound highly specific for channels from the Dd2 line of the human pathogen P. falciparum. Inheritance of this compound's affinity in a Dd2 × HB3 genetic cross maps to a single parasite locus on chromosome 3. DNA transfection and in vitro selections indicate that PSAC-inhibitor interactions are encoded by two clag3 genes previously assumed to function in cytoadherence. These genes are conserved in plasmodia, exhibit expression switching, and encode an integral protein on the host membrane, as predicted by functional studies. This protein increases host cell permeability to diverse solutes.


Assuntos
Eritrócitos/metabolismo , Eritrócitos/parasitologia , Plasmodium falciparum/genética , Proteínas de Protozoários/metabolismo , Sequência de Aminoácidos , Cruzamentos Genéticos , Ensaios de Triagem em Larga Escala , Humanos , Canais Iônicos/metabolismo , Leupeptinas/metabolismo , Dados de Sequência Molecular , Mutação , Permeabilidade , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Alinhamento de Sequência
5.
Nature ; 578(7795): 449-454, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32051587

RESUMO

The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system1,2. Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the origin of these nerves and the mechanism of their inception are unknown1,3. Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy.


Assuntos
Neurônios Adrenérgicos/patologia , Transdiferenciação Celular , Reprogramação Celular , Neoplasias Bucais/patologia , Células Receptoras Sensoriais/patologia , Proteína Supressora de Tumor p53/deficiência , Antagonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/uso terapêutico , Animais , Divisão Celular , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Fibras Nervosas/patologia , Neuritos/patologia , Receptores Adrenérgicos/metabolismo , Estudos Retrospectivos , Microambiente Tumoral , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Emerg Infect Dis ; 30(7): 1467-1471, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38916721

RESUMO

We detected malaria vector Anopheles stephensi mosquitoes in the Al Hudaydah governorate in Yemen by using DNA sequencing. We report 2 cytochrome c oxidase subunit I haplotypes, 1 previously found in Ethiopia, Somalia, Djibouti, and Yemen. These findings provide insight into invasive An. stephensi mosquitoes in Yemen and their connection to East Africa.


Assuntos
Anopheles , Mosquitos Vetores , Animais , Anopheles/genética , Anopheles/parasitologia , Anopheles/classificação , Iêmen , Mosquitos Vetores/genética , Humanos , Complexo IV da Cadeia de Transporte de Elétrons/genética , Haplótipos , Malária/transmissão , Malária/epidemiologia , Filogenia
7.
Anal Chem ; 96(2): 904-909, 2024 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-38158374

RESUMO

Analyzing coeluting impurities with similar masses in synthetic oligonucleotides by liquid chromatography-mass spectrometry (LC-MS) poses challenges due to inadequate separation in either dimension. Herein, we present a direct method employing fully resolved isotopic envelopes, enabled by high resolution mass spectrometry (HRMS), to identify and quantify isobaric impurity ions resulting from the deletion or addition of a uracil (U) or cytosine (C) nucleotide from or to the full-length sequence. These impurities may each encompass multiple sequence variants arising from various deletion or addition sites. The method utilizes a full or targeted MS analysis to measure accurate isotopic distributions that are chemical formula dependent but nucleotide sequence independent. This characteristic enables the quantification of isobaric impurity ions involving sequence variants, a capability typically unavailable in sequence-dependent MS/MS methods. Notably, this approach does not rely on standard curves to determine isobaric impurity compositions in test samples; instead, it utilizes the individual isotopic distributions measured for each impurity standard. Moreover, in cases where specific impurity standards are unavailable, the measured isotopic distributions can be adequately replaced with the theoretical distributions (calculated based on chemical formulas of standards) adjusted using experiment-specific correction factors. In summary, this streamlined approach overcomes the limitations of LC-MS analysis for coeluting isobaric impurity ions, offering a promising solution for the in-depth profiling of complex impurity mixtures in synthetic oligonucleotide therapeutics.


Assuntos
Oligonucleotídeos , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Oligonucleotídeos/química , Espectrometria de Massa com Cromatografia Líquida , Peso Molecular , Contaminação de Medicamentos , Cromatografia Líquida de Alta Pressão/métodos
8.
BMC Biotechnol ; 24(1): 41, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862994

RESUMO

BACKGROUND: Genetic diversity, population structure, agro-morphological traits, and molecular characteristics, are crucial for either preserving genetic resources or developing new cultivars. Due to climate change, water availability for agricultural use is progressively diminishing. This study used 100 molecular markers (25 TRAP, 22 SRAP, 23 ISTR, and 30 SSR). Additionally, 15 morphological characteristics were utilized to evaluate the optimal agronomic traits of 12 different barley genotypes under arid conditions. RESULTS: Substantial variations, ranging from significant to highly significant, were observed in the 15 agromorphological parameters evaluated among the 12 genotypes. The KSU-B101 barley genotype demonstrated superior performance in five specific traits: spike number per plant, 100-grain weight, spike number per square meter, harvest index, and grain yield. These results indicate its potential for achieving high yields in arid regions. The Sahrawy barley genotype exhibited the highest values across five parameters, namely leaf area, spike weight per plant, spike length, spike weight per square meter, and biological yield, making it a promising candidate for animal feed. The KSU-B105 genotype exhibited early maturity and a high grain count per spike, which reflects its early maturity and ability to produce a high number of grains per spike. This suggests its suitability for both animal feed and human food in arid areas. Based on marker data, the molecular study found that the similarity coefficients between the barley genotypes ranged from 0.48 to 0.80, with an average of 0.64. The dendrogram constructed from these data revealed three distinct clusters with a similarity coefficient of 0.80. Notably, the correlation between the dendrogram and its similarity matrix was high (0.903), indicating its accuracy in depicting the genetic relationships. The combined analysis revealed a moderate correlation between the morphological and molecular analysis, suggesting alignment between the two characterization methods. CONCLUSIONS: The morphological and molecular analyses of the 12 barley genotypes in this study effectively revealed the varied genetic characteristics of their agro-performance in arid conditions. KSU-B101, Sahrawy, and KSU-B105 have emerged as promising candidates for different agricultural applications in arid regions. Further research on these genotypes could reveal their full potential for breeding programs.


Assuntos
Genótipo , Hordeum , Hordeum/genética , Variação Genética , Marcadores Genéticos/genética
9.
Biol Proced Online ; 26(1): 16, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831428

RESUMO

BACKGROUND: It is necessary to develop advanced therapies utilizing natural ingredients with anti-inflammatory qualities in order to lessen the negative effects of chemotherapeutics. RESULTS: The bioactive N1-(5-methyl-5H-indolo[2,3-b]quinolin-11-yl)benzene-1,4-diamine hydrochloride (NIQBD) was synthesized. After that, soluble starch nanoparticles (StNPs) was used as a carrier for the synthesized NIQBD with different concentrations (50 mg, 100 mg, and 200 mg). The obtained StNPs loaded with different concentrations of NIQBD were coded as StNPs-1, StNPs-2, and StNPs-3. It was observed that, StNPs-1, StNPs-2, and StNPs-3 exhibited an average size of 246, 300, and 328 nm, respectively. Additionally, they also formed with homogeneity particles as depicted from polydispersity index values (PDI). The PDI values of StNPs-1, StNPs-2, and StNPs-3 are 0.298, 0.177, and 0.262, respectively. In vivo investigation of the potential properties of the different concentrations of StNPs loaded with NIQBD against MTX-induced inflammation in the lung and liver showed a statistically substantial increase in levels of reduced glutathione (GSH) accompanied by a significant decrease in levels of oxidants such as malondialdehyde (MDA), nitric oxide (NO), advanced oxidation protein product (AOPP), matrix metalloproteinase 9/Gelatinase B (MMP-9), and levels of inflammatory mediators including interleukin 1-beta (IL-1ß), nuclear factor kappa-B (NF-κB) in both lung and liver tissues, and a significant decrease in levels of plasma homocysteine (Hcy) compared to the MTX-induced inflammation group. The highly significant results were obtained by treatment with a concentration of 200 mg/mL. Histopathological examination supported these results, where treatment showed minimal inflammatory infiltration and congestion in lung tissue, a mildly congested central vein, and mild activation of Kupffer cells in liver tissues. CONCLUSION: Combining the treatment of MTX with natural antioxidant supplements may help reducing the associated oxidation and inflammation.

10.
J Transl Med ; 22(1): 664, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39014470

RESUMO

BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive and devastating muscle disease, resulting from the absence of dystrophin. This leads to cell membrane instability, susceptibility to contraction-induced muscle damage, subsequent muscle degeneration, and eventually disability and early death of patients. Currently, there is no cure for DMD. Our recent studies identified that lipin1 plays a critical role in maintaining myofiber stability and integrity. However, lipin1 gene expression levels are dramatically reduced in the skeletal muscles of DMD patients and mdx mice. METHODS: To identify whether increased lipin1 expression could prevent dystrophic pathology, we employed unique muscle-specific mdx:lipin1 transgenic (mdx:lipin1Tg/0) mice in which lipin1 was restored in the dystrophic muscle of mdx mice, intramuscular gene delivery, as well as cell culture system. RESULTS: We found that increased lipin1 expression suppressed muscle degeneration and inflammation, reduced fibrosis, strengthened membrane integrity, and resulted in improved muscle contractile and lengthening force, and muscle performance in mdx:lipin1Tg/0 compared to mdx mice. To confirm the role of lipin1 in dystrophic muscle, we then administered AAV1-lipin1 via intramuscular injection in mdx mice. Consistently, lipin1 restoration inhibited myofiber necroptosis and lessened muscle degeneration. Using a cell culture system, we further found that differentiated primary mdx myoblasts had elevated expression levels of necroptotic markers and medium creatine kinase (CK), which could be a result of sarcolemmal damage. Most importantly, increased lipin1 expression levels in differentiated myoblasts from mdx:lipin1Tg/0 mice substantially inhibited the elevation of necroptotic markers and medium CK levels. CONCLUSIONS: Overall, our data suggest that lipin1 is a promising therapeutic target for the treatment of dystrophic muscles.


Assuntos
Camundongos Endogâmicos mdx , Músculo Esquelético , Distrofia Muscular de Duchenne , Fosfatidato Fosfatase , Animais , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/metabolismo , Fosfatidato Fosfatase/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Camundongos Transgênicos , Camundongos , Contração Muscular , Terapia de Alvo Molecular , Camundongos Endogâmicos C57BL , Terapia Genética , Masculino
11.
Hepatology ; 78(1): 179-194, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36632994

RESUMO

BACKGROUND AND AIM: Telehealth interventions may improve access to care, disease-specific, and quality outcomes in chronic liver diseases (CLDs). We aimed to systematically evaluate outcomes of telehealth interventions in CLDs. MATERIALS AND METHODS: We used key terms and searched PubMed/EMBASE from inception to January 10, 2022. Two authors independently screened abstracts. Disagreements were resolved by a third reviewer. We included any type of CLD, including posttransplant patients, and extracted outcomes as defined by authors for each etiology of CLD (sustained virological response in HCV or weight loss in NAFLD). Meta-analysis was not performed because of the heterogeneity of data. Quality assessment was performed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias tool for clinical trials. RESULTS: Of 4250 studies screened, 43 met the inclusion criteria. Of these, 28 reported HCV treatment outcomes. All studies showed no statistically significant differences between sustained virological response rates in TH groups compared with control groups or historic cohorts. Eight studies evaluating liver transplant-related processes and outcomes demonstrated improved rates of transplant evaluation and referrals and decreased short-term readmission rates. Three randomized controlled trials and 1 observational study on NAFLD showed improved weight loss outcomes. One retrospective study showed reduced mortality risk in CLD patients with at least 1 TH encounter. CONCLUSIONS: TH interventions in patients with CLDs consistently show equivalent or improved clinical outcomes compared with traditional encounters. TH in CLDs can bridge the gap in access while maintaining the quality of care for underserved populations.


Assuntos
Hepatite C , Hepatopatia Gordurosa não Alcoólica , Telemedicina , Humanos , Hepatopatia Gordurosa não Alcoólica/terapia , Estudos Retrospectivos , Redução de Peso , Estudos Observacionais como Assunto
12.
Chemistry ; : e202400785, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38958609

RESUMO

Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo-ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl5 served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl5 reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl5; the key regioselectivity-limiting nitrilimine intermediate (8-Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo-electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity-limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl3. DFT calculations, synthetic methodology optimization, X-ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism-inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)-bis-hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)-stereoisomers especially in medicinal chemistry and protein modification.

13.
Nat Chem Biol ; 18(6): 634-642, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35551261

RESUMO

Proteoglycans are heterogeneous macromolecular glycoconjugates that orchestrate many important cellular processes. While much attention has focused on the poly-sulfated glycosaminoglycan chains that decorate proteoglycans, other important elements of their architecture, such as core proteins and membrane localization, have garnered less emphasis. Hence, comprehensive structure-function relationships that consider the replete proteoglycan architecture as glycoconjugates are limited. Here we present an extensive approach to study proteoglycan structure and biology by fabricating defined semisynthetic modular proteoglycans that can be tailored for cell surface display. The expression of proteoglycan core proteins with unnatural amino acids permits bioorthogonal click chemistry with functionalized glycosaminoglycans for methodical dissection of the parameters required for optimal binding and function of various proteoglycan-binding proteins. We demonstrate that these sophisticated materials can recapitulate the functions of native proteoglycan ectodomains in mouse embryonic stem cell differentiation and cancer cell spreading while permitting the analysis of the contributing architectural elements toward function.


Assuntos
Proteoglicanas , Animais , Membrana Celular/metabolismo , Camundongos , Proteoglicanas/análise , Proteoglicanas/metabolismo
14.
Cell Mol Neurobiol ; 44(1): 55, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977507

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory impairment and cognitive dysfunctions. It has been shown that hypoglycemia can adversely affect AD neuropathology. It is well-known that chronic hyperglycemia in type 2 diabetes (T2D) is regarded as a potential risk factor for the development and progression of AD. However, the effect of recurrent hypoglycemia on the pathogenesis of AD was not deeply discussed, and how recurrent hypoglycemia affects AD at cellular and molecular levels was not intensely interpreted by the previous studies. The underlying mechanisms for hypoglycaemia-induced AD are diverse such as endothelial dysfunction, thrombosis, and neuronal injury that causing tau protein hyperphosphorylation and the accumulation of amyloid beta (Aß) in the brain neurons. Of note, the glucagon hormone, which controls blood glucose, can also regulate the cognitive functions. Glucagon increases blood glucose by antagonizing the metabolic effect of insulin. Therefore, glucagon, through attenuation of hypoglycemia, may prevent AD neuropathology. Glucagon/GLP-1 has been shown to promote synaptogenesis, hippocampal synaptic plasticity, and learning and memory, while attenuating amyloid and tau pathologies. Therefore, activation of glucagon receptors in the brain may reduce AD neuropathology. A recent glucagon receptor agonist dasiglucagon which used in the management of hypoglycemia may be effective in preventing hypoglycemia and AD neuropathology. This review aims to discuss the potential role of dasiglucagon in treating hypoglycemia in AD, and how this drug reduce AD neuropathology.


Assuntos
Doença de Alzheimer , Hipoglicemia , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Hipoglicemia/metabolismo , Hipoglicemia/complicações , Animais , Fatores de Risco
15.
World J Urol ; 42(1): 221, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38587648

RESUMO

PURPOSE: Fosfomycin has been used more frequently in managing uncomplicated urinary tract infections (UTIs) due to decreased compliance and increased multidrug-resistant bacteria. The aim of this network meta-analysis was to assess the efficacy of Fosfomycin compared to Nitrofurantoin, Trimethoprim-Sulfamethoxazole (TMP-SMX), and Ciprofloxacin in terms of clinical and microbiological cure alongside with other measurements. MATERIALS AND METHODS: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). We included randomized control trials (RCTs) with uncomplicated UTI patients who received Fosfomycin, Nitrofurantoin, TMP-SMX, or Ciprofloxacin and reported the clinical or microbiological cure. We used Cochrane Risk of Bias Assessment Tool to assess the included studies' quality. R-software was used for all statistical analysis. We ranked all antibiotics using the netrank function which yielded P scores. Frequentist network meta-analysis was used to assess the efficacy of all outcomes. RESULTS: We included 13 RCTs with a total number of 3856 patients that showed Fosfomycin ranked the highest among the other antibiotics with respect to clinical cure (P-score = 0.99) and microbiological cure (P-score = 0.99) while Ciprofloxacin ranked the lowest (P-score = 0.11 and 0.02, respectively). Moreover, Ciprofloxacin yielded the highest relapse rate (P-score = 1), whereas TMP-SMX had the lowest relapse rate (P-score = 0.07). As for the adverse events, Ciprofloxacin demonstrated the highest adverse events as opposed to Fosfomycin (P-score = 0.98 and 0.05, respectively). CONCLUSION: The network meta-analysis demonstrated that Fosfomycin is the most effective antibiotic in treating uncomplicated UTIs with respect to clinical cure, microbiological cure, and adverse events profile.


Assuntos
Fosfomicina , Infecções Urinárias , Humanos , Antibacterianos/uso terapêutico , Fosfomicina/uso terapêutico , Nitrofurantoína , Combinação Trimetoprima e Sulfametoxazol , Metanálise em Rede , Infecções Urinárias/tratamento farmacológico , Ciprofloxacina/uso terapêutico , Recidiva
16.
Diabetes Obes Metab ; 26(8): 3031-3044, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38802993

RESUMO

Depression is a mood disorder that may increase risk for the development of insulin resistance (IR) and type 2 diabetes (T2D), and vice versa. However, the mechanistic pathway linking depression and T2D is not fully elucidated. The aim of this narrative review, therefore, was to discuss the possible link between depression and T2D. The coexistence of T2D and depression is twice as great compared to the occurrence of either condition independently. Hyperglycaemia and dyslipidaemia promote the incidence of depression by enhancing inflammation and reducing brain serotonin (5-hydroxytryptamine [5HT]). Dysregulation of insulin signalling in T2D impairs brain 5HT signalling, leading to the development of depression. Furthermore, depression is associated with the development of hyperglycaemia and poor glycaemic control. Psychological stress and depression promote the development of T2D. In conclusion, T2D could be a potential risk factor for the development of depression through the induction of inflammatory reactions and oxidative stress that affect brain neurotransmission. In addition, chronic stress in depression may induce the development of T2D through dysregulation of the hypothalamic-pituitary-adrenal axis and increase circulating cortisol levels, which triggers IR and T2D.


Assuntos
Depressão , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Depressão/etiologia , Estresse Psicológico/complicações , Estresse Psicológico/fisiopatologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Encéfalo/metabolismo , Estresse Oxidativo/fisiologia , Fatores de Risco , Hiperglicemia/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Sistema Hipófise-Suprarrenal/metabolismo , Transtorno Depressivo/etiologia , Serotonina/metabolismo
17.
Inorg Chem ; 63(8): 3769-3780, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38346334

RESUMO

Lanthanide-based single-ion magnets have attracted much interest due to their great potential for information storage at the level of one molecule. Among various strategies to enhance magnetization blocking in such complexes, the synthesis of axially symmetric compounds is regarded as the most promising. Here, we investigate theoretically the magnetization blocking of several lanthanide ions (Tb3+, Dy3+, Ho3+, Er3+, and Tm3+) encapsulated in highly symmetric zigzag boron nitride nanotubes (BNNTs) of different diameters with ab initio methodology. We found that Tb3+@(7,0)BNNT, Dy3+@(7,0)BNNT, and Tm3+@(5,0)BNNT are suitable SIM candidates, while the other investigated complexes from this series show no signs of magnetization blocking owing to a hard competition between contributions to the crystal field of the lanthanide ion from neighboring and more distant atoms of the nanotube.

18.
Mol Biol Rep ; 51(1): 856, 2024 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-39066893

RESUMO

BACKGROUND: Breast cancer is the most common cancer in the world. Cynaropicrin is a natural sesquiterpene lactone with potential anticancer effects. The present study was conducted to evaluate the effect of cynaropicrin on proliferation and apoptosis in breast cancer cells. METHODS: MDA-MB-231 and MCF-7 cell lines were treated with increasing concentrations of cynaropicrin. The viability of both cell lines was measured using MTT assay. Flowcytometry was used to detect apoptotic cells. The expression levels of apoptosis-related genes were determined using quantitative polymerase chain reaction. The protein expression of apoptosis markers was determined by western blotting. RESULTS: Cynaropicrin significantly diminished the proliferation of MDA-MB-231 and MCF-7 cell lines in a dose-dependent manner. Flowcytometry data uncovered that cynaropicrin augmented early and late apoptosis in MDA-MB-231 cells. Real time-PCR and western blotting results also confirmed the upregulation of pro-apoptotic Bax, caspase-3, -8, and 9 as well as downregulated level of anti-apoptotic marker Bcl-2. Cynaropicrin also remarkably increased the activity of caspase-3, -8, and 9 in MDA-MB-231 cells. However, cynaropicrin neither promoted apoptosis in MCF-7 cells nor altered the expression levels and activity of above mentioned apoptotic markers. CONCLUSION: The present data indicated anti-proliferative properties of cynaropicrin against breast cancer and highlighted apoptosis-inducing effects of this sesquiterpene on triple negative breast cancer (TNBC) cells. These data may suggest cynaropicrin as a potential anti-TNBC agent to tackle therapy resistance in this type of breast cancer.


Assuntos
Apoptose , Proliferação de Células , Lactonas , Sesquiterpenos , Neoplasias de Mama Triplo Negativas , Humanos , Lactonas/farmacologia , Apoptose/efeitos dos fármacos , Sesquiterpenos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Células MCF-7 , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos
19.
J Asthma ; : 1-7, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39231028

RESUMO

OBJECTIVE: Asthma is a chronic respiratory disorder characterized by airway inflammation and narrowing often leading to acute exacerbations that necessitate a visit to the emergency department (ED). While life threatening cases usually require bronchodilator delivery by nebulizers, mild to moderate acute asthma exacerbations can be treated by bronchodilators delivered either by metered dose inhalers (MDI). Numerous studies have attempted to compare between the two modalities and have drawn similar conclusions in that both are comparable in efficacy with minimal differences. What is evident, however, is that physicians remain inclined to favor nebulizers in the majority of acute asthma exacerbations. METHODS: In this questionnaire-based study, a survey was distributed to physicians who treat asthma exacerbations to examine demographics, knowledge, beliefs, and current practice in regard to bronchodilator therapy. RESULTS: The majority (90.8%) of physicians prefer short-acting beta agonists via nebulizer, with 9.2% favoring MDI + spacer. Participants include consultants, residents, and specialists across various emergency disciplines. While 90.1% find MDI + spacer equally effective as nebulizers, advantages cited include cost-effectiveness (49.6%), shorter ED stays (63.4%), quicker administration (67.9%), and ease of use (58.8%). Challenges include availability (66.4%) and ineffectiveness in younger patients (45%). Despite this, 65.6% are willing to switch to MDI for initial asthma management in the ED, while 34.4% are resistant. CONCLUSION: Concerns about availability and effectiveness in younger patients remain barriers. However, a significant number are willing to adopt MDIs with spacers, indicating potential for broader use with better availability and training.

20.
J Asthma ; : 1-7, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38506494

RESUMO

AIM: This study aims to assess the prevalence of asthma triggers and control status among pediatric asthmatic patients in Saudi Arabia. METHODS: From October 2015 to March 2016, an Arabic version of the Asthma Trigger Inventory questionnaire and asthma control test (ACT) were distributed to 200 parents of children diagnosed with asthma at the pulmonary clinic of King Fahad Medical City in Riyadh, Saudi Arabia. Data were collected and analyzed using the Statistical Package for Social Sciences (SPSS) software version 29. Descriptive statistics of the participants were presented in frequencies, percentages, means, and standard deviations for categorical variables. RESULTS: The survey data revealed that the most prevalent asthma triggers among pediatric asthmatic children in Saudi Arabia were Arabic incense (Bakhour) with a mean score of 3.76 (±1.3), followed by being excited 3.70 (±1.5), and stress at home 3.58 (±1.4). Furthermore, the degree of asthma control among children with asthma in Saudi Arabia was 72.0% with a mean score of 17.7 (±4.7) for the ACT, indicating partial degree of asthma. CONCLUSIONS: Arabic incense (Bakhour) and psychological stimuli emerged as significant determinants of asthma triggers in Saudi Arabian children diagnosed with asthma. Further studies are warranted to elucidate the physiological mechanisms underpinning the response to Arabic incense (Bakhour).

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