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2.
Mol Cell ; 61(5): 760-773, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26942679

RESUMO

MicroRNAs predominantly decrease gene expression; however, specific mRNAs are translationally upregulated in quiescent (G0) mammalian cells and immature Xenopus laevis oocytes by an FXR1a-associated microRNA-protein complex (microRNP) that lacks the microRNP repressor, GW182. Their mechanism in these conditions of decreased mTOR signaling, and therefore reduced canonical (cap-and-poly(A)-tail-mediated) translation, remains undiscovered. Our data reveal that mTOR inhibition in human THP1 cells enables microRNA-mediated activation. Activation requires shortened/no poly(A)-tail targets; polyadenylated mRNAs are partially activated upon PAIP2 overexpression, which interferes with poly(A)-bound PABP, precluding PABP-enhanced microRNA-mediated inhibition and canonical translation. Consistently, inhibition of PARN deadenylase prevents activation. P97/DAP5, a homolog of canonical translation factor, eIF4G, which lacks PABP- and cap binding complex-interacting domains, is required for activation, and thereby for the oocyte immature state. P97 interacts with 3' UTR-binding FXR1a-associated microRNPs and with PARN, which binds mRNA 5' caps, forming a specialized complex to translate recruited mRNAs in these altered canonical translation conditions.


Assuntos
Senescência Celular , MicroRNAs/metabolismo , Oócitos/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ribonucleoproteínas/metabolismo , Regiões 3' não Traduzidas , Animais , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Sítios de Ligação , Linhagem Celular , Fator de Iniciação Eucariótico 4G/genética , Fator de Iniciação Eucariótico 4G/metabolismo , Exorribonucleases/genética , Exorribonucleases/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , MicroRNAs/genética , Proteômica/métodos , Capuzes de RNA/genética , Capuzes de RNA/metabolismo , Interferência de RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Ribonucleoproteínas/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Transfecção , Xenopus laevis
3.
Pharmacol Rev ; 73(1): 152-162, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33298513

RESUMO

Cognitive impairment and its severe form dementia are increasingly prevalent in older adults and loom as a public health disaster unless effective interventions are developed. Cognitive impairment is a convergent trait caused by damage from an idiosyncratic mix of four prevalent diseases (Alzheimer disease; vascular brain injury; Lewy body diseases, such as Parkinson disease and dementia with Lewy bodies; and limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy) that is counterbalanced by individually varying resilience, which is comprised of reserve and compensation. Brain regional damage from each of these four prevalent diseases is generated by the net effect of injury and (mal)adaptive response and is accompanied by characteristic lesions. Existing therapeutics enhance resilience, whereas most agents under development target mechanisms of damage with only suppression of vascular brain injury yet to show therapeutic promise. We hope to anticipate future tailored interventions that target mechanisms of damage and thereby avert the oncoming surge of cognitive impairment and dementia in older adults. SIGNIFICANCE STATEMENT: Brain regional damage is generated by the net effect of injury and (mal)adaptive response. The extent to which signs and symptoms of such damage occur is influenced by an underlying resilience comprising reserve and compensation. Finding tailored interventions that target specific mechanisms of damage likely yields the most effective therapies.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença por Corpos de Lewy , Doença de Parkinson , Idoso , Disfunção Cognitiva/tratamento farmacológico , Humanos
4.
Drug Dev Ind Pharm ; : 1-14, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38451066

RESUMO

OBJECTIVES: This study aimed to develop, optimize and evaluate glyceryl monooleate (GMO) based cubosomes as a drug delivery system containing cisplatin for treatment of human lung carcinoma. SIGNIFICANCE: The significance of this research was to successfully incorporate slightly water soluble and potent anticancer drug (cisplatin) into cubosomes, which provide slow and sustained release of drug for longer period of time. METHODS: The delivery system was developed through top-down approach by melting GMO and poloxamer 407 (P407) at 70 °C and then drop-wise addition of warm deionized water (70 °C) containing cisplatin. The formulation then exposed to probe sonicator for about 2 min. A randomized regular two level full factorial design with help of Design Expert was used for optimization of blank cubosomal formulations. Cisplatin loaded cubosomes were then subjected to physico-chemical characterization. RESULTS: The characterization of the formulation revealed that it had a sufficient surface charge of -9.56 ± 1.33 mV, 168.25 ± 5.73 nm particle size, and 60.64 ± 0.11% encapsulation efficiency. The in vitro release of cisplatin from the cubosomes at pH 7.4 was observed to be sustained, with 94.5% of the drug being released in 30 h. In contrast, 99% of cisplatin was released from the drug solution in just 1.5 h. In vitro cytotoxicity assay was conducted on the human lung carcinoma NCI-H226 cell line, the cytotoxicity of cisplatin-loaded cubosomes was relative to that of pure cisplatin solution, while blank (without cisplatin) cubosomes were nontoxic. CONCLUSIONS: The obtained results demonstrated the successful development of cubosomes for sustained delivery of cisplatin.


Cubosomes were prepared, optimized, and evaluated for cisplatin delivery.A randomized regular two level full factorial design was constructed to optimize blank cubosomes.Blank cubosomes consisted of GMO as the lipid and P407 as an emulsifying agent.In vitro release studies demonstrated sustained release of cisplatin from cubosomes at pH 7.4.Cytotoxicity assay on human lung carcinoma cell line NCI-H226 showed similar cytotoxicity between cisplatin-loaded cubosomes and pure cisplatin solution while blank cubosomes exhibited no toxicity.

5.
Alzheimers Dement ; 20(5): 3495-3503, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38602280

RESUMO

INTRODUCTION: We investigated the association between sleep duration and neuropathologic changes 19 to 40 years later in oldest-old (age 90+) participants of The 90+ Study. METHODS: Participants self-reported sleep duration and underwent neuropathologic evaluation. We categorized sleep duration as < 7, 7 to 8 = reference, > 8 hours and dichotomized neuropathologic changes as present/absent. We estimated odds ratio (OR) and 95% confidence intervals (CI) using logistic regression. RESULTS: In 264 participants, mean age at sleep self-report was 69 years, mean age at autopsy was 98 years, and mean interval between sleep self-report and autopsy was 29 years (range: 19-40). Those reporting > 8 hours of sleep had lower likelihood of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) inclusions (OR = 0.18; CI = 0.04-0.82) and amyloid beta deposits (OR = 0.34; 95% CI = 0.12-0.94). DISCUSSION: Long self-reported sleep is associated with lower odds of neurodegenerative neuropathologic changes 19 to 40 years later in the oldest-old, suggesting a potential role of sleep in accumulation of dementia-related neuropathologies. HIGHLIGHTS: Association of self-reported sleep with non-Alzheimer's disease neuropathologic changes has not been explored. Whether sleep duration is related to dementia neuropathologic changes decades later is unclear. Long self-reported sleep is associated with lower odds of Alzheimer's disease neuropathologic change 19 to 40 years later in the oldest-old. Long self-reported sleep is associated with lower odds of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change 19 to 40 years later in the oldest-old.


Assuntos
Encéfalo , Sono , Humanos , Idoso de 80 Anos ou mais , Feminino , Masculino , Encéfalo/patologia , Idoso , Autopsia , Autorrelato , Peptídeos beta-Amiloides/metabolismo , Envelhecimento/patologia , Duração do Sono
6.
Pak J Med Sci ; 40(6): 1073-1076, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38952490

RESUMO

Objective: To know about the trends in the management of neck of femur fractures with arthroplasty in patients ≥ 50 years. Methods: It is a retrospective cross-sectional study with data collection from Hospital Management Information System from 1st January 2020 to 31st July 2023. SPSS version 25 was used for data analysis. Mean & standard deviation was reported for quantitative variable & frequency and proportion were reported for qualitative variables. The cross- tabulations were performed to evaluate the association between the variables. Results: Total number of patients in this study was 305. Mean age was 67.80 ± 10.5 SD. Male to female ratio was 150:155. Co-morbidities were found in 126 patients. The surgical options used were Austin Moore prosthesis (64), Cemented Bipolar (36), Hybrid Total Hip Replacement (7), Non-cemented Total Hip Replacement (86), Cemented Total Hip Replacement (32), Uncemented Bipolar (71). Garden Type-2 fracture was noted in 33 patients, Type-3 in 170 patients and Type-4 in 87 patients. Cemented stem was used in 74 patients while 222 patients had non-cemented stem. Conclusion: One quarter of the patients had cemented stem implanted compared to three quarter of the patients who had non-cemented stem.

7.
J Clin Immunol ; 44(1): 17, 2023 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-38129705

RESUMO

PURPOSE: Inherited deficiencies of CD40 and CD40 ligand (CD40L) reflect the crucial immunological functions of CD40-CD40L interaction/signaling. Although numerous studies have provided a detailed description of CD40L deficiency, reports of CD40 deficiency are scarce. Herein, we describe the characteristics of all reported patients with CD40 deficiency. METHODS: The PubMed, Embase and Web of Science databases were searched for relevant literature published till 7th August 2023. Study deduplication and identification of relevant reports was performed using the online PICO Portal. The data were extracted using a pre-designed data extraction form and the SPSS software was used for analysis. RESULTS: Systematic literature review revealed 40 unique patients with CD40 deficiency. Respiratory tract and gastrointestinal infections were the predominant clinical manifestations (observed in 93% and 57% patients, respectively). Sclerosing cholangitis has been reported in nearly one-third of patients. Cryptosporidium sp. (29%) and Pneumocystis jirovecii (21%) were the most common microbes identified. Very low to undetectable IgG levels and severely reduced/absent switch memory B cells were observed in all patients tested/reported. Elevated IgM levels were observed in 69% patients. Overall, splice-site and missense variants were the most common (36% and 32%, respectively) molecular defects identified. All patients were managed with immunoglobulin replacement therapy and antimicrobial prophylaxis was utilized in a subset. Hematopoietic stem cell transplantation (HSCT) has been performed in 45% patients (curative outcome observed in 73% of these patients). Overall, a fatal outcome was reported in 21% patients. CONCLUSIONS: We provide a comprehensive description of all important aspects of CD40 deficiency. HSCT is a promising curative treatment option for CD40 deficiency.


Assuntos
Criptosporidiose , Cryptosporidium , Síndrome de Imunodeficiência com Hiper-IgM , Síndromes de Imunodeficiência , Linfopenia , Humanos , Ligante de CD40/genética , Síndrome de Imunodeficiência com Hiper-IgM/genética , Síndromes de Imunodeficiência/genética , Antígenos CD40/genética , Imunoglobulina M
8.
J Card Fail ; 29(1): 76-86, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36122817

RESUMO

Cardiac amyloidosis (CA) is caused by extracellular myocardial deposition of amyloid fibrils that are primary derived either from misfolding of transthyretin (ATTR) or light-chain (AL) proteins. CA is associated with atrial fibrillation, potentiated by electromechanical changes as a result of amyloid infiltration in the myocardium. CA also predisposes to thromboembolism and could potentially simultaneously elevate bleeding risk. In this review, we aim to explore and compare the prevalence and pathophysiological mechanisms of atrial fibrillation and thromboembolism in ATTR and AL, examine bleeding risk and factors that promote bleeding, and compare anticoagulation strategies in CA. Finally, we highlight knowledge gaps in the field of thromboembolism in CA to guide future research.


Assuntos
Neuropatias Amiloides Familiares , Amiloidose , Fibrilação Atrial , Insuficiência Cardíaca , Tromboembolia , Humanos , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Insuficiência Cardíaca/complicações , Amiloidose/complicações , Amiloidose/tratamento farmacológico , Amiloidose/epidemiologia , Amiloide , Tromboembolia/epidemiologia , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Anticoagulantes/uso terapêutico , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/epidemiologia
9.
Acta Neuropathol ; 146(3): 415-432, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37382680

RESUMO

Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer's disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR = 3.45, p < 0.001) and aging-related tau astrogliopathy (ARTAG; OR = 2.72, p = 0.008). In contrast, our quantitative approach showed associations between the proportion of HS-A (CA1/subiculum/combined) and LATE-NC (p = 0.001) and arteriolosclerosis (p = 0.005). While traditional binary assessment of HS-A was associated with impaired memory (OR = 2.60, p = 0.007), calculations (OR = 2.16, p = 0.027), and orientation (OR = 3.56, p < 0.001), our quantitative approach revealed additional associations with impairments in language (OR = 1.33, p = 0.018) and visuospatial domains (OR = 1.37, p = 0.006). Our novel quantitative method revealed associations between HS-A and vascular pathologies and impairment in cognitive domains that were not detected using traditional/binary measures.


Assuntos
Envelhecimento , Disfunção Cognitiva , Esclerose Hipocampal , Hipocampo , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Envelhecimento/patologia , Cognição , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Esclerose Hipocampal/patologia , Esclerose Hipocampal/fisiopatologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Modelos Logísticos , Neuropatologia
10.
Alzheimer Dis Assoc Disord ; 37(1): 1-6, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36821174

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. AD neuropathologic change (ADNC) likely begins decades before clinical manifestations. One mechanism implicated in AD is oxidative stress. We explored the potential association of ADNC with antioxidant vitamin supplements taken about 30 years before death. METHODS: The 264 brain-autopsied participants were part of The 90+ Study, a longitudinal study of aging among people aged 90+ years, and originally members of the Leisure World Cohort Study, a population-based health study established in the 1980s. Intake of supplemental vitamins A, C, and E was collected by the Leisure World Cohort Study about 30 years before ADNC assessment. Odds ratios of ADNC (intermediate/high vs. none/low) for vitamin intake were estimated using logistic regression. RESULTS: The adjusted odds ratio (95% CI) of ADNC was 0.52 (0.29-0.92) for vitamin E supplements and 0.51 (0.27-0.93) for vitamin C supplements. Supplemental vitamin E intake was the first variable, after education, to enter the stepwise model. Intake of vitamin A or C did not improve the model fit. CONCLUSIONS: The observed association of ADNC and supplemental vitamin E intake decades earlier suggests a beneficial effect and supports further investigation into a nutritional approach to preventing AD with vitamin supplementation.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Estudos de Coortes , Estudos Longitudinais , Suplementos Nutricionais , Vitaminas , Vitamina A , Vitamina E
11.
Bioorg Chem ; 133: 106404, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36812829

RESUMO

New phthalazone tethered 1,2,3-triazole derivatives 12-21 were synthesized utilizing the Cu(I)-catalyzed click reactions of alkyne-functionalized phthalazone 1 with functionalized azides 2-11. The new phthalazone-1,2,3-triazoles structures 12-21 were confirmed by different spectroscopic tools, like IR; 1H, 13C, 2D HMBC and 2D ROESY NMR; EI MS, and elemental analysis. The antiproliferative efficacy of the molecular hybrids 12-21 against four cancer cell lines was evaluated, including colorectal cancer, hepatoblastoma, prostate cancer, breast adenocarcinoma, and the normal cell line WI38. The antiproliferative assessment of derivatives 12-21 showed potent activity of compounds 16, 18, and 21 compared to the anticancer drug doxorubicin. Compound 16 showed selectivity (SI) towardthe tested cell lines ranging from 3.35 to 8.84 when compared to Dox., that showed SI ranged from 0.75 to 1.61. Derivatives 16, 18 and 21 were assessed towards VEGFR-2 inhibitory activity and result in that derivative 16 showed the potent activity (IC50 = 0.123 µM) in comparison with sorafenib (IC50 = 0.116 µM). Compound 16 caused an interference with the cell cycle distribution of MCF7 and increased the percentage of cells in S phase by 1.37-fold. In silico molecular docking of the effective derivatives 16, 18, and 21 against vascular endothelial growth factor receptor-2 (VEGFR-2) confirmed the formation of stable protein-ligand interactions within the pocket.


Assuntos
Antineoplásicos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacologia , Triazóis/química , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
12.
Appl Opt ; 62(31): 8242-8247, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-38037926

RESUMO

We utilize spatially and temporally tailored laser pulses for polarization enhanced two-photon excited fluorescence contrasts of dyes. The shaped laser pulses are produced by first passing through a temporal pulse shaper and then through a two-dimensional spatial pulse shaper with deformable phase plates. Different spatial beam profiles are presented that demonstrate the potential of the spatial pulse shaper. Particularly, a polarization enhanced fluorescence contrast between two dyes is reported by utilizing specific phase shaping in perpendicular polarization directions. The tailored laser pulses are further modified by the deformable phase plate, and a polarization increased depth-dependent contrast is achieved. This spatial shaping for all polarization directions demonstrates the advantage of deformable phase plate spatial shapers compared to liquid crystals, where only one polarization direction can spatially be modified. The described polarization contrast method allows for three-dimensional scanning of probes and provides perspectives for biophotonic applications.

13.
J Enzyme Inhib Med Chem ; 38(1): 2166036, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36691927

RESUMO

A new series of 2-aminobenzothiazole hybrids linked to thiazolidine-2,4-dione 4a-e, 1,3,4-thiadiazole aryl urea 6a-d, and cyanothiouracil moieties 8a-d was synthesised. The in vitro antitumor effect of the new hybrids was assessed against three cancer cell lines, namely, HCT-116, HEPG-2, and MCF-7 using Sorafenib (SOR) as a standard drug. Among the tested compounds, 4a was the most potent showing IC50 of 5.61, 7.92, and 3.84 µM, respectively. Furthermore, compounds 4e and 8a proved to have strong impact on breast cancer cell line with IC50 of 6.11 and 10.86 µM, respectively. The three compounds showed a good safety profile towards normal WI-38 cells. Flow cytometric analysis of the three compounds in MCF-7 cells revealed that compounds 4a and 4c inhibited cell population in the S phase, whereas 8a inhibited the population in the G1/S phase. The most promising compounds were subjected to a VEGFR-2 inhibitory assay where 4a emerged as the best active inhibitor of VEGFR-2 with IC50 91 nM, compared to 53 nM for SOR. In silico analysis showed that the three new hybrids succeeded to link to the active site like the co-crystallized inhibitor SOR.


Assuntos
Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe/farmacologia , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Proc Natl Acad Sci U S A ; 117(38): 23270-23279, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32661177

RESUMO

Neuronal networks are the standard heuristic model today for describing brain activity associated with animal behavior. Recent studies have revealed an extensive role for a completely distinct layer of networked activities in the brain-the gene regulatory network (GRN)-that orchestrates expression levels of hundreds to thousands of genes in a behavior-related manner. We examine emerging insights into the relationships between these two types of networks and discuss their interplay in spatial as well as temporal dimensions, across multiple scales of organization. We discuss properties expected of behavior-related GRNs by drawing inspiration from the rich literature on GRNs related to animal development, comparing and contrasting these two broad classes of GRNs as they relate to their respective phenotypic manifestations. Developmental GRNs also represent a third layer of network biology, playing out over a third timescale, which is believed to play a crucial mediatory role between neuronal networks and behavioral GRNs. We end with a special emphasis on social behavior, discuss whether unique GRN organization and cis-regulatory architecture underlies this special class of behavior, and review literature that suggests an affirmative answer.


Assuntos
Comportamento , Encéfalo/fisiologia , Redes Reguladoras de Genes , Animais , Encéfalo/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Humanos
15.
Sensors (Basel) ; 23(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36679468

RESUMO

Human antibodies are produced due to the activation of immune system components upon exposure to an external agent or antigen. Human antibody G, or immunoglobin G (IgG), accounts for 75% of total serum antibody content. IgG controls several infections by eradicating disease-causing pathogens from the body through complementary interactions with toxins. Additionally, IgG is an important diagnostic tool for certain pathological conditions, such as autoimmune hepatitis, hepatitis B virus (HBV), chickenpox and MMR (measles, mumps, and rubella), and coronavirus-induced disease 19 (COVID-19). As an important biomarker, IgG has sparked interest in conducting research to produce robust, sensitive, selective, and economical biosensors for its detection. To date, researchers have used different strategies and explored various materials from macro- to nanoscale to be used in IgG biosensing. In this review, emerging biosensors for IgG detection have been reviewed along with their detection limits, especially electrochemical biosensors that, when coupled with nanomaterials, can help to achieve the characteristics of a reliable IgG biosensor. Furthermore, this review can assist scientists in developing strategies for future research not only for IgG biosensors but also for the development of other biosensing systems for diverse targets.


Assuntos
Técnicas Biossensoriais , COVID-19 , Sarampo , Caxumba , Rubéola (Sarampo Alemão) , Humanos , COVID-19/diagnóstico , Imunoglobulina G , Anticorpos Antivirais
16.
Alzheimers Dement ; 19(8): 3417-3425, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36795955

RESUMO

INTRODUCTION: The association between neuropathological changes and dementia among centenarians and nonagenarians remains unclear. METHODS: We examined brain tissue from 100 centenarians and 297 nonagenarians from The 90+ Study, a community-based longitudinal study of aging. We determined the prevalence of 10 neuropathological changes and compared their associations with dementia and cognitive performance between centenarians and nonagenarians. RESULTS: A total of 59% of centenarians and 47% of nonagenarians had at least four neuropathological changes. In centenarians, neuropathological changes were associated with higher odds of dementia and, compared to nonagenarians, the odds were not attenuated. For each additional neuropathological change, the Mini-Mental State Examination score was lower by 2 points for both groups. DISCUSSION: Neuropathological changes continue to be strongly related to dementia in centenarians, highlighting the importance of slowing or preventing the development of multiple neuropathological changes in the aging brain to maintain cognitive health. HIGHLIGHTS: Individual and multiple neuropathological changes are frequent in centenarians. These neuropathological changes are strongly associated with dementia. There is no attenuation of this association with age.


Assuntos
Centenários , Demência , Idoso de 80 Anos ou mais , Humanos , Estudos Longitudinais , Envelhecimento , Encéfalo , Demência/epidemiologia , Demência/diagnóstico
17.
Alzheimers Dement ; 19(7): 3005-3018, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36681388

RESUMO

INTRODUCTION: Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life. METHODS: This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities. RESULTS: Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased. DISCUSSION: Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Comorbidade , Neuropatologia , Biomarcadores
18.
Molecules ; 28(18)2023 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-37764324

RESUMO

The major cause of hyperglycemia can generally be attributed to ß-glucosidase as per its involvement in non-alcoholic fatty liver disease. This clinical condition leads to liver carcinoma (HepG2 cancer). The phthalimides and phthalamic acid classes possess inhibitory potential against glucosidase, forming the basis for designing new phthalimide and phthalamic acid analogs to test their ability as potent inhibitors of ß-glucosidase. The study also covers in silico (molecular docking and MD simulations) and in vitro (ß-glucosidase and HepG2 cancer cell line assays) analyses. The phthalimide and phthalamic acid derivatives were synthesized, followed by spectroscopic characterization. The mechanistic complexities associated with ß-glucosidase inhibition were identified via the docking of the synthesized compounds inside the active site of the protein, and the results were analyzed in terms of the best binding energy and appropriate docking pose. The top-ranked compounds were subjected to extensive MD simulation studies to understand the mode of interaction of the synthesized compounds and binding energies, as well as the contribution of individual residues towards binding affinities. Lower RMSD/RMSF values were observed for 2c and 3c, respectively, in the active site, confirming more stabilized, ligand-bound complexes when compared to the free state. An anisotropic network model was used to unravel the role of loop fluctuation in the context of ligand binding and the dynamics that are distinct to the bound and free states, supported by a 3D surface plot. An in vitro study revealed that 1c (IC50 = 1.26 µM) is far better than standard acarbose (2.15 µM), confirming the potential of this compound against the target protein. Given the appreciable potential of the candidate compounds against ß-glucosidase, the synthesized compounds were further tested for their cytotoxic activity against hepatic carcinoma on HepG2 cancer cell lines. The cytotoxicity profile of the synthesized compounds was performed against HepG2 cancer cell lines. The resultant IC50 value (0.048 µM) for 3c is better than the standard (thalidomide: IC50 0.053 µM). The results promise the hypothesis that the synthesized compounds might become potential drug candidates, given the fact that the ß-glucosidase inhibition of 1c is 40% better than the standard, whereas compound 3c holds more anti-tumor activity (greater than 9%) against the HepG2 cell line than the known drug.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , beta-Glucosidase , Ligantes , Simulação de Acoplamento Molecular , Analgésicos Opioides
19.
Molecules ; 28(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36677801

RESUMO

Nickel-supported hierarchical zeolite catalysts were prepared through a desilication reassembly process under optimized conditions and applied in one-pot menthol synthesis. In this work, the hierarchical zeolite-supported metal bifunctional catalysts were prepared with the help of desilication re-assembly and wetness impregnation techniques and applied in menthol synthesis via citral hydrogenation. The prepared catalysts were characterized using PXRD, BET, FE-TEM, NH3-TPD, H2-TPR, pyridine adsorption, and ICP-OES techniques. As a result, the physicochemical and acidic properties, such as mesopore surface area, metal dispersion, acidity, catalytic activity, and strong Lewis acid sites of pure microporous ZSM-5/USY zeolites, were significantly improved. Consequently, with the occurrence of superior physicochemical and acidic properties, the Ni/HZ-0.5 M catalyst exhibited outstanding catalytic activity (100% conversion, TOF 7.12 h-1) and menthol selectivity (83%, 4 h) with uniform stability at 100 °C, 1.0 MPa hydrogen. Similarly, the cracking rate decreased with the decrease in Bronsted acid sites.

20.
Molecules ; 28(18)2023 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-37764280

RESUMO

Green approaches for nanoparticle synthesis have emerged as biocompatible, economical, and environment-friendly alternatives to counteract the menace of microbial drug resistance. Recently, the utilization of honey as a green source to synthesize Fe2O3-NPs has been introduced, but its antibacterial activity against one of the opportunistic MDR pathogens, Klebsiella pneumoniae, has not been explored. Therefore, this study employed Apis mellifera honey as a reducing and capping agent for the synthesis of iron oxide nanoparticles (Fe2O3-NPs). Subsequent to the characterization of nanoparticles, their antibacterial, antioxidant, and anti-inflammatory properties were appraised. In UV-Vis spectroscopic analysis, the absorption band ascribed to the SPR peak was observed at 350 nm. XRD analysis confirmed the crystalline nature of Fe2O3-NPs, and the crystal size was deduced to be 36.2 nm. Elemental analysis by EDX validated the presence of iron coupled with oxygen in the nanoparticle composition. In ICP-MS, the highest concentration was of iron (87.15 ppm), followed by sodium (1.49 ppm) and other trace elements (<1 ppm). VSM analysis revealed weak magnetic properties of Fe2O3-NPs. Morphological properties of Fe2O3-NPs revealed by SEM demonstrated that their average size range was 100-150 nm with a non-uniform spherical shape. The antibacterial activity of Fe2O3-NPs was ascertained against 30 clinical isolates of Klebsiella pneumoniae, with the largest inhibition zone recorded being 10 mm. The MIC value for Fe2O3-NPs was 30 µg/mL. However, when mingled with three selected antibiotics, Fe2O3-NPs did not affect any antibacterial activity. Momentous antioxidant (IC50 = 22 µg/mL) and anti-inflammatory (IC50 = 70 µg/mL) activities of Fe2O3-NPs were discerned in comparison with the standard at various concentrations. Consequently, honey-mediated Fe2O3-NP synthesis may serve as a substitute for orthodox antimicrobial drugs and may be explored for prospective biomedical applications.


Assuntos
Mel , Abelhas , Animais , Antioxidantes/farmacologia , Estudos Prospectivos , Antibacterianos/farmacologia , Ferro , Klebsiella pneumoniae , Nanopartículas Magnéticas de Óxido de Ferro
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