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OBJECTIVE: We sought to explore the prevalence of type I interferon-neutralizing antibodies in a Chinese cohort and its clinical implications during the Omicron variant wave of SARS-CoV-2. METHODS: Type I interferon (IFN) autoantibodies possessing neutralizing capabilities were identified using luciferase assays. The capacity of the autoantibodies for in vitro interference with antiviral activity of IFN was assessed by using a SARS-CoV-2 replicon system. An analysis of the demographic and clinical profiles of patients exhibiting neutralizing antibodies was also conducted. RESULTS: In this cohort, 11.8% of severe/critical cases exhibited the existence of type I IFN-neutralizing antibodies, specifically targeting IFN-α2, IFN-ω, or both, with an elderly male patient tendency. Notably, these antibodies exerted a pronounced inhibitory effect on the antiviral activity of IFN against SARS-CoV-2 under controlled in vitro conditions. Furthermore, a noteworthy correlation was discerned between the presence of these neutralizing antibodies and critical clinical parameters, including C-reactive protein (CRP) levels, D-dimer levels, and lymphocyte counts. CONCLUSION: The presence of type I IFN-neutralizing antibodies is a pervasive risk factor for severe/critical COVID-19 in the Chinese population.
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COVID-19 , Interferon Tipo I , Idoso , Humanos , Masculino , Autoanticorpos , COVID-19/epidemiologia , SARS-CoV-2 , Prevalência , China/epidemiologia , Anticorpos Neutralizantes , AntiviraisRESUMO
BACKGROUND: Low back pain is the leading cause of productivity loss, imposes a significant economic burden on the patients and society. Oxidative stress is considered a critical factor in the complex pathophysiological process and pathogenic mechanism of low back pain. Adjustment dietary pattern can effectively increase antioxidant biomarkers levels within the body to reduce oxidative stress. The composite dietary antioxidant index (CDAI) serves a reliable scoring system for quantifying the potential dietary antioxidant capacity of daily diets. OBJECTIVE: We aim to investigate the potential association between CDAI and low back pain, in order to enhance the management of low back pain through dietary guidance. METHODS: This study included 17,682 participants from the National Health and Nutrition Examination Survey (NHANES) 1999-2000, 2001-2002, 2003-2004 and 2009-2010. The weighted logistic regression model was used to investigate the association between CDAI and low back pain, while restricted cubic spline (RCS) was employed to examine non-linear trend and cutoffs. RESULTS: After adjusting for all confounders, the results showed that there was no significant association between CDAI and low back pain. However, individuals in the highest quartile of CDAI exhibited an 11.7% less likelihood of experiencing a low back pain than those in the lowest quartile (OR = 0.883; 95% CI [0.787,0.991], P = 0.034), and the trend test was also significant (P for trend < 0.001). RCS indicated a linear relationship between CDAI and low back pain (P for non-linear = 0.876). Gender subgroup analysis showed that this negative association was significant in the female population (OR = 0.983; 95% CI [0.968, 0.998], P = 0.027), and females in the highest quartile of CDAI were 19.7% less likely to suffer low back pain than those in the lowest quartile (OR = 0.803; 95% CI [0.682,0.945], P = 0.008). Additionally, the changes in zinc (OR = 1.009; 95% CI [1.002, 1.016], P = 0.015) and selenium (OR = 0.379; 95% CI [0.164, 0.875], P = 0.023) per milligram were independently associated with low back pain. CONCLUSION: The fully adjusted model showed no significant association between CDAI and low back pain, but it was significant in quartiles. Meanwhile, subgroup analysis by gender revealed a negative association between CDAI and low back pain in the female population. Additionally, the findings of this study also suggested that the antioxidant diets should be studied in a dietary pattern context.
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Antioxidantes , Dor Lombar , Adulto , Feminino , Humanos , Estudos Transversais , Inquéritos Nutricionais , Dor Lombar/epidemiologia , DietaRESUMO
To evaluate the effect of Nirmatrelvir-ritonavir therapy and coronavirus disease 2019 (COVID-19) vaccination on clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron infection, we retrospectively analyzed the clinical data of 762 adult patients with confirmed Omicron BA2.2 variant infection, of them 488 patients received standard therapy and 274 patients received Nirmatrelvir-ritonavir therapy. Subjects were matched by propensity score matching using R language, the baseline factors were balanced by the nearest-neighbor matching method and were compared, together with the factors including progression to severe/critical disease, viral clearance time, length of hospital stay, and virological rebound of SARS-CoV-2 infection. Nirmatrelvir-ritonavir therapy significantly accelerated viral clearance at Days 14 and 28 during hospitalization, but it had no impact on disease progression, length of hospital stay, or infection rebound. In contrast, COVID-19 vaccination before admission was positively correlated with the viral clearance rate and negatively correlated with disease progression in a dose-dependent way. COVID-19 vaccination reduced the probability of infection rebound. Other factors such as the number of comorbidities, pneumonia on-admission, and high D2 levels were positively correlated with disease progression. Our study strongly recommended booster COVID-19 vaccination for the elderly population, particularly patients with comorbidities to prevent critical disease.
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COVID-19 , Adulto , Humanos , Idoso , SARS-CoV-2 , Vacinas contra COVID-19 , Estudos Retrospectivos , Ritonavir , Tratamento Farmacológico da COVID-19 , Vacinação , Progressão da DoençaRESUMO
BACKGROUND: Assessment of lymphovascular invasion (LVI) in breast cancer (BC) primarily relies on preoperative needle biopsy. There is an urgent need to develop a non-invasive assessment method. PURPOSE: To develop an effective model to assess the LVI status in patients with BC using magnetic resonance imaging morphological features (MRI-MF), Radiomics, and deep learning (DL) approaches based on dynamic contrast-enhanced MRI (DCE-MRI). STUDY TYPE: Cross-sectional retrospective cohort study. POPULATION: The study included 206 BC patients, with 136 in the training set [97 LVI(-) and 39 LVI(+) cases; median age: 51.5 years] and 70 in the test set [52 LVI(-) and 18 LVI(+) cases; median age: 48 years]. FIELD STRENGTH/SEQUENCE: 1.5 T/T1-weighted images, fat-suppressed T2-weighted images, diffusion-weighted imaging (DWI), and DCE-MRI. ASSESSMENT: The MRI-MF model was developed with conventional MR features using logistic analyses. The Radiomic feature extraction process involved collecting data from categorized DCE-MRI datasets, specifically the first and second post-contrast images (A1 and A2). Next, a DL model was implemented to determine LVI. Finally, we established a joint diagnosis model by combining the MRI-MF, Radiomics, and DL approaches. STATISTICAL TESTS: Diagnostic performance was compared using receiver operating characteristic curve analysis, confusion matrix, and decision curve analysis. RESULTS: Rim sign and peritumoral edema features were used to develop the MRI-MF model, while six Radiomics signature from the A1 and A2 images were used for the Radiomics model. The joint model (MRI-MF + Radiomics + DL models) achieved the highest accuracy (area under the curve [AUC] = 0.857), being significantly superior to the MRI-MF (AUC = 0.724), Radiomics (AUC = 0.736), or DL (AUC = 0.740) model. Furthermore, it also outperformed the pairwise combination models: Radiomics + MRI-MF (AUC = 0.796), DL + MRI-MF (AUC = 0.796), or DL + Radiomics (AUC = 0.826). DATA CONCLUSION: The joint model incorporating MRI-MF, Radiomics, and DL approaches can effectively determine the LVI status in patients with BC before surgery. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.
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Viridicatin alkaloids as natural products have attracted great interest due to their unique core scaffold. To fully exploit their potential application in DNA-encoded chemical libraries that would facilitate drug discovery, we here describe an efficient on-DNA synthesis of viridicatin alkaloid-like scaffolds from isatins and DNA-tagged aldehydes. Promoted by benzenesulfonyl hydrazide, this reaction provided the corresponding DNA-conjugated viridicatin alkaloid-like products in moderate-to-excellent conversion yields, and DNA compatibility validated by enzymatic ligation and qPCR evaluation exhibited the feasible utility of this methodology in DEL synthesis. Cross substrate scope study, together with subsequent on-DNA chemical diversification, further showed the competence of this approach in focused natural product-like encoded library construction.
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Alcaloides , Hidroxiquinolinas , Bibliotecas de Moléculas Pequenas , DNARESUMO
BACKGROUND: Postoperative bone graft migration (PBGM) is a fairly rare spinal postoperative complication. Its occurrence after endoscopic surgery has rarely been reported in the literature so far. This is a case report of a 52-year-old male occurring PBGM into the thecal sac in the 8th days after an endoscopic lumbar interbody fusion (ELIF), which can make surgeons more minded with such serious rare complication after BGM. CASE PRESENTATION: A 52-year-old male patient, underwent a L4-5 ELIF, presented with an acute radiculopathy on right leg and urinary incontinence in the 8th postoperative day. An emergency lumbar Computed Tomography(CT scan) and Magnetic Resonance Imaging (MRI) demonstrated bone graft migration into the thecal sac at the L4-5 level, and shifting down to the lower level. The revision surgery was performed at once successfully. Finally, the patient got well managed before discharge. CONCLUSION: Supported by this case report, we believe that PBGM into the thecal sac is a rare but horrible complication of ELIF. However, too much volume of bone graft and its posterior placement are more prone to developing this complication. Finally, we are not sure that the outcome presented in this study will be repeated in future cases.
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Endoscopia , Fusão Vertebral , Masculino , Humanos , Pessoa de Meia-Idade , Endoscopia/efeitos adversos , Endoscopia/métodos , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Região Lombossacral , Reoperação , Imageamento por Ressonância Magnética , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Considering the high reoperation rate in degenerative lumbar spondylolisthesis (DLS) patients undergoing lumbar surgeries and controversial results on the risk factors for the reoperation, we performed a systematic review and meta-analysis to explore the reoperation rate and risk factors for the reoperation in DLS patients undergoing lumbar surgeries. METHODS: Literature search was conducted from inception to October 28, 2022 in Pubmed, Embase, Cochrane Library, and Web of Science. Odds ratio (OR) was used as the effect index for the categorical data, and effect size was expressed as 95% confidence interval (CI). Heterogeneity test was performed for each outcome effect size, and subgroup analysis was performed based on study design, patients, surgery types, follow-up time, and quality of studies to explore the source of heterogeneity. Results of all outcomes were examined by sensitivity analysis. Publication bias was assessed using Begg test, and adjusted using trim-and-fill analysis. RESULTS: A total of 39 cohort studies (27 retrospective cohort studies and 12 prospective cohort studies) were finally included in this systematic review and meta-analysis. The overall results showed a 10% (95%CI: 8%-12%) of reoperation rate in DLS patients undergoing lumbar surgeries. In surgery types subgroup, the reoperation rate was 11% (95%CI: 9%-13%) for decompression, 10% (95%CI: 7%-12%) for fusion, and 9% (95%CI: 5%-13%) for decompression and fusion. An increased risk of reoperation was found in patients with obesity (OR = 1.91, 95%CI: 1.04-3.51), diabetes (OR = 2.01, 95%CI: 1.43-2.82), and smoking (OR = 1.51, 95%CI: 1.23-1.84). CONCLUSIONS: We found a 10% of reoperation rate in DLS patients after lumbar surgeries. Obesity, diabetes, and smoking were risk factors for the reoperation.
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Diabetes Mellitus , Fusão Vertebral , Estenose Espinal , Espondilolistese , Humanos , Reoperação/métodos , Espondilolistese/cirurgia , Estudos Retrospectivos , Estudos Prospectivos , Resultado do Tratamento , Estenose Espinal/cirurgia , Descompressão Cirúrgica/métodos , Fusão Vertebral/métodos , Fatores de Risco , Vértebras Lombares/cirurgia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/cirurgia , Obesidade/cirurgiaRESUMO
Sodium-ion batteries (SIBs) are promising alternatives to replace lithium-ion batteries as future energy storage batteries because of their abundant sodium resources, low cost, and high charging efficiency. In order to match the high energy capacity and density, designing an atomically doped carbonous material as the anode is presently one of the important strategies to commercialize SIBs. In this work, we report the preparation of high-performance dual-atom-doped carbon (C) materials using low-cost corn starch and thiourea (CH4N2S) as the precursors. The electronegativity and radii of the doped atoms and C are different, which can vary the embedding properties of sodium ions (Na+) into/on C. As sulfur (S) can effectively expand the layer spacing, it provides more channels for embedding and de-embedding Na+. The synergistic effect of N and S co-doping can remarkably boost the performance of SIBs. The capacity is preserved at 400 mAh g -1 after 200 cycles at 500 mA g-1; more notably, the initial Coulombic efficiency is 81%. Even at a high rate of high current of 10 A g-1, the cell capacity can still reach 170 mAh g-1. More importantly, after 3000 cycles at 1 A g-1, the capacity decay is less than 0.003% per cycle, which demonstrates its excellent electrochemical performance. These results indicate that high-performance carbon materials can be prepared using low-cost corn starch and thiourea.
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With the development of high-performance electrode materials, sodium-ion batteries have been extensively studied and could potentially be applied in various fields to replace the lithium-ion cells, owing to the low cost and natural abundance. As the key anode materials of sodium-ion batteries, hard carbons still face problems, such as poor cycling performance and low initial Coulombic efficiency. Owning to the low synthesis cost and the natural presence of heteroatoms of biomasses, biomasses have positive implications for synthesizing the hard carbons for sodium-ion batteries. This minireview mainly explains the research progress of biomasses used as the precursors to prepare the hard-carbon materials. The storage mechanism of hard carbons, comparisons of the structural properties of hard carbons prepared from different biomasses, and the influence of the preparation conditions on the electrochemical properties of hard carbons are introduced. In addition, the effect of doping atoms is also summarized to provide an in-depth understanding and guidance for the design of high-performance hard carbons for sodium-ion batteries.
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BACKGROUND: Agarwood is a valuable Chinese medicinal herb and spice that is produced from wounded Aquilaria spp., is widely used in Southeast Asia and is highly traded on the market. The lack of highly responsive Aquilaria lines has seriously restricted agarwood yield and the development of its industry. In this article, a comparative transcriptome analysis was carried out between ordinary A. sinensis and Chi-Nan germplasm, which is a kind of A. sinensis tree with high agarwood-producing capacity in response to wounding stress, to elucidate the molecular mechanism underlying wounding stress in different A. sinensis germplasm resources and to help identify and breed high agarwood-producing strains. RESULTS: A total of 2427 and 1153 differentially expressed genes (DEGs) were detected in wounded ordinary A. sinensis and Chi-Nan germplasm compared with the control groups, respectively. KEGG enrichment analysis revealed that genes participating in starch metabolism, secondary metabolism and plant hormone signal transduction might play major roles in the early regulation of wound stress. 86 DEGs related to oxygen metabolism, JA pathway and sesquiterpene biosynthesis were identified. The majority of the expression of these genes was differentially induced between two germplasm resources under wounding stress. 13 candidate genes related to defence and sesquiterpene biosynthesis were obtained by WGCNA. Furthermore, the expression pattern of genes were verified by qRT-PCR. The candidate genes expression levels were higher in Chi-Nan germplasm than that in ordinary A. sinensis during early stage of wounding stress, which may play important roles in regulating high agarwood-producing capacity in Chi-Nan germplasm. CONCLUSIONS: Compared with A. sinensis, Chi-Nan germplasm invoked different biological processes in response to wounding stress. The genes related to defence signals and sesquiterepene biosynthesis pathway were induced to expression differentially between two germplasm resources. A total of 13 candidate genes were identified, which may correlate with high agarwood-producting capacity in Chi-Nan germplasm during the early stage of wounding stress. These genes will contribute to the development of functional molecular markers and the rapid breeding highly of responsive Aquilaria lines.
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Sesquiterpenos , Thymelaeaceae , Perfilação da Expressão Gênica , Oxigênio/metabolismo , Melhoramento Vegetal , Reguladores de Crescimento de Plantas/metabolismo , Sesquiterpenos/metabolismo , Amido/metabolismo , Thymelaeaceae/genética , Thymelaeaceae/metabolismoRESUMO
DNA-encoded chemical libraries (DEL) have attracted substantial attention due to the infinite possibility for hit discovery in both pharmaceutical companies and academia. The encoding method is the initial step of DEL construction and one of the cornerstones of DEL applications. Classified by the DNA format, the existing DEL encoding strategies were categorized into single-stranded DNA-based strategies and double-stranded DNA-based strategies. The two DEL formats have their unique advantages but are usually incompatible with each other. To address this issue, we propose the concept of interconversion between double- and single-stranded DEL based on the "reversible covalent headpiece (RCHP)" design, which combines maximum robustness of synthesis with extraordinary flexibility of applications in distinct setups. Future opportunities in this field are also proposed to advance DEL technology to a comprehensive drug discovery platform.
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DNA de Cadeia Simples , Bibliotecas de Moléculas Pequenas , DNA/genética , Descoberta de Drogas , Biblioteca GênicaRESUMO
PURPOSE: Urinary stone disease (USD) has been associated with an increased risk of chronic kidney disease (CKD) and end-stage renal disease in Western populations. However, the metabolic disorders associated with unilateral and bilateral renal stones and the association of these types of stones with CKD and kidney tubular injury markers, such as urine N-acetyl-ß-D-glucosaminidase (NAG) and alpha-1-microglobulin (α1-MG), have not been fully examined. MATERIALS AND METHODS: We performed a cross-sectional study of 10,281 participants in rural China in 2014. All the subjects underwent renal ultrasound to detect USD; stone formers were divided into groups with unilateral or bilateral renal stones by ultrasound examinations. CKD was defined as a decreased estimated glomerular filtration rate (eGFR, <60 mL/minute/1.73 m2) and/or albuminuria (albumin-to-creatinine ratio ≥30 mg/gm). Increased urine NAG and α1-MG levels were defined as their values above the 75th percentile of the sample distribution. RESULTS: Among all the participants, 4.9% (507) had unilateral renal stones, and 0.7% (75) had bilateral renal stones. The proportion of CKD in the nonstone, unilateral and bilateral renal stone formers was 11.0%, 19.2% and 29.7%, respectively (p for trend <0.001). Individuals with bilateral renal stones had the highest proportion of metabolic components, such as elevated blood pressure and serum glucose. In multivariate analyses after adjustment for multiple confounders, bilateral renal stones were significantly associated with an increased risk of decreased eGFR (OR 3.38; 95% CI 1.05-10.90), albuminuria (OR 3.01; 95% CI 1.76-5.13), CKD (OR 3.18; 95% CI 1.88-5.36), increased urine NAG-to-creatinine ratio (OR 1.95; 95% CI 1.21-3.16) and α1-MG-to-creatinine ratio levels (OR 2.54; 95% CI 1.56-4.12) compared with the lack of stones. CONCLUSIONS: Bilateral renal stones were associated with a higher risk of CKD and higher levels of kidney tubular injury markers. Clinicians should pay attention to metabolic disorders in bilateral renal stone formers.
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Cálculos Renais/complicações , Cálculos Renais/metabolismo , Insuficiência Renal Crônica/etiologia , Idoso , Biomarcadores/urina , Estudos Transversais , Feminino , Humanos , Cálculos Renais/patologia , Cálculos Renais/urina , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/urinaRESUMO
The incorporation of the isoindole core into the DNA-encoded chemical library is highly desirable for the great potential pharmacological characters exampled by molecules like lenalidomide. Herein, we reported a DNA-compatible protocol for the OPA-mediated transformation of amines into drug-like moieties represented by isoindolinone and thio-2-isoindole, respectively. The high conversion and wide substrate-scope property of our protocol render its feasibility in the manipulation of terminal amines on oligonucleotide conjugates, including "cap-and-catch" purification, sequential synthesis during DEL construction, and on-DNA macrocyclization.
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Isoindóis , o-Ftalaldeído , Aminas , DNA , o-Ftalaldeído/químicaRESUMO
Eight versions of the Protocol on Prevention and Control of Coronavirus Disease 2019 (COVID-19) (the Protocol) were issued successively by the Chinese authority to guide the local responses since the first COVID-19 case appeared in Wuhan, China. This study aimed to investigate the evolution of the overall strategy and specific measures in these Protocols, and several recommendations were provided after analysing China's response to the epidemic resurgence. As a result, we found a gradual expanding trend in case surveillance, early screening, and epidemiological investigation, as well as a progressively rigorous tendency in isolation measures and close contact management. With the Protocol's guidance, China had achieved success in several recent fights against domestic COVID-19 resurgences. The city lockdown and multiple city-wide nucleic acid tests adopted were deemed necessary in COVID-19 resurgence's battle. Besides, the large-scale distance centralised quarantine, which is, quarantine in a purpose-built isolation station away from communities where people under quarantine lived, was promoted in rural areas. China's anti-epidemic achievements provide ideas for the global battle against COVID-19.
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COVID-19 , Epidemias , COVID-19/prevenção & controle , China/epidemiologia , Controle de Doenças Transmissíveis , Epidemias/prevenção & controle , Humanos , QuarentenaRESUMO
Inflammation as a host's excessive immune response to stimulation, is involved in the development of numerous diseases. To discover novel anti-inflammatory agents and based on our previous synthetic work on marine natural product Chrysamide B, it and a series of derivatives were synthesized and evaluated for their anti-inflammatory activity on inhibition of LPS-induced NO production. Then the preliminary structure-activity relationships were conducted. Among them, Chrysamide B is the most potent anti-inflammatory agent with low cytotoxicity and strong inhibition on the production of NO (IC50 = 0.010 µM) and the activity of iNOS (IC50 = 0.082 µM) in LPS-stimulated RAW 264.7 cells. Primary studies suggested that the mechanism of action may be that it interfered the formation of active dimeric iNOS but not affected transcription and translation. Furthermore, its good performance of anti-inflammatory effect on LPS-induced multiple inflammatory cytokines production, carrageenan-induced paw edema, and endotoxin-induced septic mice, was observed. We believe that these findings would provide an idea for the further modification and research of these analogs in the future.
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Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Descoberta de Drogas , Inflamação/tratamento farmacológico , Óxido Nítrico/antagonistas & inibidores , Doença Aguda , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Carragenina , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-AtividadeRESUMO
Marine natural products derived from special or extreme environment provide an important source for the development of anti-tumor drugs due to their special skeletons and functional groups. In this study, based on our previous work on the total synthesis and structure revision of the novel marine natural product Chrysamide B, a group of its derivatives were designed, synthesized, and subsequently of which the anti-cancer activity, structure-activity relationships and cellular mechanism were explored for the first time. Compared with Chrysamide B, better anti-cancer performance of some derivatives against five human cancer cell lines (SGC-7901, MGC-803, HepG2, HCT-116, MCF-7) was observed, especially for compound b-9 on MGC-803 and SGC-7901 cells with the IC 50 values of 7.88 ± 0.81 and 10.08 ± 1.08 µM, respectively. Subsequently, cellular mechanism study suggested that compound b-9 treatment could inhibit the cellular proliferation, reduce the migration and invasion ability of cells, and induce mitochondrial-dependent apoptosis in gastric cancer MGC-803 and SGC-7901 cells. Furthermore, the mitochondrial-dependent apoptosis induced by compound b-9 is related with the JAK2/STAT3/Bcl-2 signaling pathway. To conclude, our results offer a new structure for the discovery of anti-tumor lead compounds from marine natural products.
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Amidas/farmacologia , Antineoplásicos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Desenho de Fármacos , Amidas/síntese química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Topoisomerase has been found extremely high level of expression in hepatocellular carcinoma (HCC) and proven to promote the proliferation and survival of HCC. Cancer-associated fibroblasts (CAFs) as a kind of key reactive stromal cell that abundantly present in the microenvironment of HCC, could enhance the metastatic ability and drug resistance of HCC. Therefore, developing new drugs that address the above conundrums would be of the upmost significant in the fight against HCC. Evodiamine, as a multi-target natural product, has been found to exert various biological activities such as anti-cancer and anti-hepatic fibrosis via blocking topoisomerase, NF-κB, TGF-ß/HGF, and Smad2/3. Inspired by these facts, 15 evodiamine derivatives were designed and synthesized for HCC treatment by simultaneously targeting Topo I and CAFs. Most of them displayed preferable anti-HCC activities on three HCC cell lines and low cytotoxicity on one normal hepatic cell. In particular, compound 8 showed the best inhibitory effect on HCC cell lines and a good inhibition on Topo I in vitro. Meanwhile, it also induced obvious G2/M arrest and apoptosis, and significantly decreased the migration and invasion capacity of HCC cells. In addition, compound 8 down-regulated the expression of type I collagen in the activated HSC-T6 cells, and induced the apoptosis of activated HSC-T6 cells. In vivo studies demonstrated that compound 8 markedly decreased the volume and weight of tumor (TGI = 40.53%). In vitro and in vivo studies showed that its effects were superior to those of evodiamine. This preliminary attempt may provide a promising strategy for developing anti-HCC lead compounds taking effect through simultaneous inhibition on Topo I and CAFs.
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Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Desenho de Fármacos , Neoplasias Hepáticas/tratamento farmacológico , Quinazolinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
BACKGROUND: Pemphigus is a group of rare and severe autoimmune blistering disease mediated by pathogenic autoantibodies against desmogleins. Plasmapheresis can directly remove autoantibodies from circulation, which has been applied to the treatment of pemphigus as an adjuvant therapy. But the results of the researches are controversial. This study aims to evaluate the efficacy and safety of double filtration plasmapheresis (DFPP) combined with immunosuppressive treatment for patients with severe pemphigus in our single center. METHODS: We retrospectively analyzed 17 patients with severe pemphigus who were unresponsive to high-dose corticosteroid and received DFPP treatment between January 2010 and January 2020. The information on demographic characteristics, clinical and laboratory data, treatment regimens, and clinical outcomes were collected. RESULTS: All the patients were diagnosed as severe pemphigus and had a period of at least 1 week of high-dose prednisone (1-1.5 mg/kg/day), but they were unresponsive to corticosteroid and immunosuppressants treatment. They received DFPP treatment as an adjuvant therapy. After DFPP treatment, the titers of desmogleins antibodies significantly decreased (P < .001), Nikolsky's sign became negative and no new blisters appeared. The dosage of corticosteroid could begin to taper down rapidly in 9 ± 4 days. On discharge, the dosage of prednisone decreased significantly (51 ± 3 mg/day, P < .001). No major adverse events happened that could lead to the termination of DFPP treatment. CONCLUSION: Double filtration plasmapheresis combined with immunosuppressive treatment is an effective and safe therapeutic regimen for severe pemphigus. DFPP can also contribute to the dosage reduction of steroid to avoid more drug-related side effect.
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Imunossupressores/uso terapêutico , Pênfigo/terapia , Plasmaferese/métodos , Corticosteroides/efeitos adversos , Adulto , Autoanticorpos/sangue , Desmogleína 1/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pênfigo/imunologia , Plasmaferese/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: This study assessed the reliability and validity of the modified Unified Classification System for femur fractures after hip arthroplasty. METHODS: Four hundred and two cases were evaluated by 6 observers, 3 experts and 3 trainee surgeons. Each observer read the radiographs on 2 separate occasions and classified each case as to its type. Reliability was assessed by looking at the intraobserver and interobserver agreement using the Kappa statistic. Validity was assessed within the B group by looking at the agreement between the radiographic classification and the intraoperative findings. Interobserver and intraobserver agreement and validity were analyzed, using weighted kappa statistics. RESULTS: The mean k value for interobserver agreement was found to be 0.882 (0.833-0.929) for consultants (almost perfect agreement) and 0.776 (0.706-0.836) for the trainees (substantial agreement). Intraobserver k values ranged from 0.701 to 0.972, showing substantial to almost perfect agreement. Validity analysis of 299 type B cases revealed 89.854% agreement with a mean k value of 0.849 (0.770-0.946) (almost perfect agreement). CONCLUSIONS: This study has shown that the modified Unified Classification System is reliable and valid. We believe it is useful to improve the judgment of the implant stability, and establish the therapeutic strategy for periprosthetic femoral fracture.
Assuntos
Artroplastia de Quadril , Fraturas do Fêmur , Fraturas Periprotéticas , Artroplastia de Quadril/efeitos adversos , Fraturas do Fêmur/diagnóstico por imagem , Fraturas do Fêmur/etiologia , Fraturas do Fêmur/cirurgia , Fêmur/cirurgia , Humanos , Variações Dependentes do Observador , Fraturas Periprotéticas/diagnóstico por imagem , Fraturas Periprotéticas/etiologia , Fraturas Periprotéticas/cirurgia , Reprodutibilidade dos TestesRESUMO
A series of 1,3-benzothiazinone derivatives were designed and synthesized for pharmacological assessments. Among the synthesized 19 compounds, some compounds showed high activities on inhibiting LPS-induced nitrite oxide and TNF-α production, down-regulating COX-2 and increasing IL-10 production in RAW264.7 cells. All the compounds had no obvious cytotoxicity in in vitro assay. LD50 value of compound 25 was greater than 2000 mg/kg, which was safer than meloxicam. Compound 25 significantly inhibited phosphorylation of NF-κB and STAT3 in LPS-induced RAW264.7 cells. Inhibition of synthesized compounds on COX activity was weaker than meloxicam. Compound 25 displayed lower gastrointestinal toxicity than meloxicam. Besides, compound 25 decreased the swelling in carrageenan-induced paw edema models of inflammation and reduced PGE2 level significantly. In summary, 1,3-benzothiazinone derivatives are unique scaffolds with anti-inflammatory activity and low toxicity.