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BACKGROUND: Recent clinical trials have evaluated the efficacy of vonoprazan-amoxicillin (VA) dual therapy as the first-line treatment for Helicobacter pylori infection in different regions with inconsistent results reported. In this systematic review and meta-analysis, we aimed to evaluate the efficacy of VA dual therapy compared to the currently recommended therapy for eradicating H. pylori. MATERIALS AND METHODS: A comprehensive search of the PubMed, Cochrane, and Embase databases was performed using the following search terms: ("Helicobacter" OR "H. pylori" OR "Hp") AND ("vonoprazan" OR "potassium-competitive acid blocker" OR "P-CAB") AND ("amoxicillin" OR "penicillin") AND ("dual"). The primary outcome was to evaluate the eradication rate according to intention-to-treat and per-protocol analysis. The secondary outcomes were adverse events and compliance. RESULTS: A total of 15 studies involving 4, 568 patients were included. The pooled eradication rate of VA dual therapy was 85.0% and 90.0% by intention-to-treat and per-protocol analysis, respectively. The adverse events rate and compliance of VA dual therapy were 17.5% and 96%, respectively. The efficacy of VA dual therapy was superior to proton pump inhibitors-based triple therapy (82.0% vs. 71.4%, p < 0.01) but lower than vonoprazan-containing quadruple therapy (83.1% vs. 93.3%, p = 0.02). 7-day VA dual therapy showed lower eradication rates than 10-day (χ2 = 24.09, p < 0.01) and 14-day VA dual therapy (χ2 = 11.87, p < 0.01). The adverse events rate of VA dual therapy was lower than vonoprazan triple therapy (24.6% vs. 30.9%, p = 0.01) and bismuth-containing quadruple therapy (20.5% vs. 47.9%, p < 0.01). No significant difference of compliance was observed between VA dual therapy and each subgroup. CONCLUSION: VA dual therapy, a novel regimen, showed high efficacy as the first-line treatment for H. pylori eradication, which should be optimized before application in different regions.
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Infecções por Helicobacter , Helicobacter pylori , Humanos , Amoxicilina , Antibacterianos/uso terapêutico , Quimioterapia Combinada , Infecções por Helicobacter/tratamento farmacológico , Inibidores da Bomba de Prótons , Resultado do TratamentoRESUMO
A novel multi-functional fluorescence probe HMIC based on hydrazide Schiff base has been successfully synthesized and characterized. It can distinguish Al3+/Zn2+/Cd2+ in ethanol, in which fluorescence emission with different colors (blue for Al3+, orange for Zn2+, and green for Cd2+) were presented. The limits of detection of HMIC towards three ions were calculated from the titration curve as 7.70 × 10- 9 M, 4.64 × 10- 9 M, and 1.35 × 10- 8 M, respectively. The structures of HMIC and its complexes were investigated using UV-Vis spectra, Job's plot, infrared spectra, mass spectrometry, 1H-NMR and DFT calculations. Practical application studies have also demonstrated that HMIC can be applied to real samples with a low impact of potential interferents. Cytotoxicity and cellular imaging assays have shown that HMIC has good cellular permeability and potential antitumor effects. Interestingly, HMIC can image Al3+, Zn2+ and Cd2+ in the cells with different fluorescence signals.
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Gut microbiota dysbiosis is an essential factor contributing to non-alcoholic fatty liver disease (NAFLD), in which the gut-liver axis plays a crucial role. Peroxisome proliferator-activated receptor δ (PPARδ) is considered a new direction for the research on NAFLD due to its positive regulation of glucose and lipid metabolism. Our experiment aimed to investigate the effect of PPARδ gene deletion on gut microbiota and NAFLD through the gut-liver axis. PPARδ-/- mice and wild-type mice were randomly divided into high-fat diet(HFD) groups and normal diet groups. In each group, six mice were sacrificed at weeks 4, 8, and 12. Metabolic indicators and inflammation indicators were measured, and the degree of liver steatosis and the ileum mucosa integrity were evaluated. Additionally, fecal samples were subjected to 16S rDNA gene sequencing and analysis of gut microbiota. Deletion of the PPARδ gene exhibited exacerbated effects on HFD-induced NAFLD and displayed more severe liver inflammation and intestinal mucosal barrier injuries. The HFD reduced the abundance of short-chain fatty acid (SCFA)-producing bacteria and increased the abundance of intestinal endotoxin-rich bacteria in mice. Deletion of the PPARδ gene exacerbated this trend, resulting in decreased abundances of norank_f__Eubacterium_coprostanoligenes_group and Alloprevotella and increased abundances of Acidibacter, unclassified_f__Comamonadaceae, unclassified_c__Alphaproteobacteria, unclassified_f__Beijerinckiaceae, unclassified_f__Caulobacteraceae, unclassified_c__Bacteroidia and Bosea. Spearman's correlation analysis found Lachnoclostridium, unclassified_f__Rhizobiaceae, Allobaculum, Acinetobacter, Romboutsia, norank_f__Muribaculaceae and Dubosiella showed some correlations with metabolic indicators, inflammation indicators, NAS and occludin. Deletion of the PPARδ gene exacerbated HFD-induced gut microbiota dysbiosis and affected NAFLD through the gut-liver axis.
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Hepatopatia Gordurosa não Alcoólica , PPAR delta , Animais , Camundongos , Dieta Hiperlipídica/efeitos adversos , Disbiose/metabolismo , Inflamação/genética , Inflamação/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , PPAR delta/genética , PPAR delta/metabolismoRESUMO
BACKGROUND: Midkine is a multi-functional molecule participating in a various key pathological process. We aimed to evaluate the change of midkine in sepsis and its association with angiotensin-converting enzyme (ACE) system, as well as the mechanism by which midkine induced in sepsis and lung injury. METHODS: The peripheral blood sample of septic patients on admission was obtained and measured for midkine, ACE and angiotensin II. Cecal ligation and puncture (CLP) mouse model was used, and adeno-associated virus (AAV) was stilled trans-trachea for regional targeting midkine expression, comparing the severity of lung injury. Furthermore, we studied the in vitro mechanism of midkine activates ACE system by using inhibitors targeting candidate receptors of midkine, and its effects on the vascular endothelial cells. RESULTS: Plasma midkine was significantly elevated in sepsis, and was closely associated with ACE system. Both circulating and lung midkine was increased in CLP mouse, and was related to severe lung injury. Regional interfering midkine expression in lung tissue by AAV could alleviate acute lung injury in CLP model. In vitro study elucidated that Notch 2 participated in the activation of ACE system and angiotensin II release, induced by midkine and triggered vascular endothelial injury by angiotensin II induced reactive oxygen species production. CONCLUSIONS: Midkine inhibition ameliorates sepsis induced lung injury, which might via ACE/Ang II pathway and the participation of Notch 2 in the stimulation of ACE. Trial registration Clinicaltrials.gov NCT02605681. Registered 12 November 2015.
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Lesão Pulmonar Aguda , Sepse , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Células Endoteliais , Humanos , Pulmão , Camundongos , Midkina , Sepse/complicações , Sepse/tratamento farmacológicoRESUMO
A new schiff base cobalt(III) complex [N,N'-bis(2'-hydroxyphenylacetone)-o-ethanediamine] cobalt(III) (M3) has been synthesized and characterized by single X-ray crystallography. The cytotoxicity of complex M3 was evaluated against HeLa, LoVo, A549, A549/cis cancer cell lines, and the normal cell lines LO2 by MTT assays. The IC50 is in the range of 6.27-22.68 µM, which is somewhat lower than cisplatin on the basis of platinum molar concentration. Furthermore, anticancer mechanistic studies showed that the complex M3 inhibited cell proliferation by blocking DNA synthesis and then acted on nuclear division of HeLa cells over time. Moreover, western blot analysis indicated M3 dramatically decreased the target protein c-Myc and KLF5 expression levels, and activated many signaling pathways including ER stress, apoptosis, cell cycle and DNA damage in HeLa. M3 did not affect proteasomal activity.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cobalto/farmacologia , Complexos de Coordenação/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cobalto/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Bases de Schiff/química , Bases de Schiff/farmacologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND: We aim to synthesize the up-to-date studies to investigate the diagnostic value of serum soluble triggering expressed receptor on myeloid cells 1 (sTREM-1) in suspected sepsis. RESULTS: A total of 19 studies with 2418 patients were finally enrolled in the meta-analysis. The pooled sensitivity was 0.82 (95% CI 0.73 to 0.89), specificity 0.81 (95% CI 0.75 to 0.86), positive likelihood ratio 4.3 (95% CI 3.02 to 6.12), negative likelihood ratio 0.22 (95% CI 0.24 to 0.35), diagnostic odds ratio 20 (95% CI 9 to 41) and AuROC 0.88 (95% CI 0.85 to 0.91). The meta-regression analysis revealed that the sample size, reference standard description, prevalence of sepsis in the trials and consecution of patient recruitment might be the source of heterogeneity. CONCLUSIONS: The serum sTREM-1 had a moderate ability in diagnosis in suspected sepsis based on the current studies. However, more large-scale studies were needed to further evaluate the diagnostic accuracy of sTREM-1.
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Biomarcadores/sangue , Células Mieloides/metabolismo , Sepse/diagnóstico , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Diagnóstico Diferencial , Humanos , Células Mieloides/patologia , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Midkine has been reported to play a crucial role in inflammatory, hypoxia, and tissue injury processes. We aimed to investigate plasma midkine in septic patients and its association with 28-day mortality and organ function. METHODS: Septic patients admitted to the Department of Critical Care Medicine, Zhongda Hospital, a tertiary hospital, from November 2017 to March 2018 were enrolled in the study. The baseline characteristics of the septic patients were recorded at admission. A peripheral blood sample was obtained at admission, and plasma midkine levels were evaluated with an immunoassay. All patients were followed up with for 28 days, with all-cause mortality being recorded. RESULTS: A total of 26 septic patients were enrolled, which included 18 survivors and 8 nonsurvivors at day 28. Plasma midkine levels were significantly elevated in the nonsurvivor group compared with the survivors (ng/L, 763.6 [404.7-1305], 268.5 [147.8-511.4]; P = .0387]. Plasma midkine levels were elevated in septic patients with moderate/severe acute respiratory distress syndrome (ARDS) compared with patients with non/mild ARDS (ng/L, 522.3 [336.6-960.1] vs 243.8 [110.3-478.9]; P = .0135) and in those with acute kidney injury compared with those without (ng/L, 489.8 [259.2-1058] vs 427.9 [129.6-510.3]; P = .0973). Changes in plasma midkine levels were also associated with extravascular lung water index (P = .063) and pulmonary vascular permeability index (P = .049). CONCLUSIONS: Plasma midkine was associated with 28-day mortality, as well as pulmonary and kidney injury, in septic patients.
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Injúria Renal Aguda , Síndrome do Desconforto Respiratório , Sepse , Humanos , Midkina , Plasma , PrognósticoRESUMO
A new dual functional turn-on chemosensor, 2,6-diformyl-4-methylphenol-di(isoquinolinyl-1-hydrazone) (HL), has been developed, which could highly selectively discriminate Mg2+ and Zn2+ in different solvent systems. The chemosensor HL exhibits rapid visual turn-on fluorescence enhancing recognition toward Mg2+/Zn2+, which is not interfered by other cations, especially for respective congeners Ca2+/Cd2+. The remarkable fluorescence enhancement (71-fold or 11-fold) was observed after adding Mg2+ in acetonitrile or Zn2+ in DMF-H2O solvent systems. Additionally such a solvent medium-controlled platform could achieve the quantitative determination of Mg2+ and Zn2+ quantitation with low detection limits of 2.97 × 10-8 M and 3.07 × 10-7 M, respectively. Furthermore, the turn-on fluorescence sensing mechanism is also investigated by 1H NMR, FT-IR and ESI-MS spectroscopy. Density functional theory (DFT) calculations derive optimized geometries of HL and its complexes. Notably, non-toxic HL also can be successfully applied as a visual probe for the practical determination of Mg2+/Zn2+ in MCF-7 cells, Zebrafish larvae, syrup and water samples, which might provide extensive application in biology and medicine fields.
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Corantes Fluorescentes/química , Hidrazonas/química , Isoquinolinas/química , Magnésio/análise , Zinco/análise , Animais , Teoria da Densidade Funcional , Água Potável/análise , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Hidrazonas/síntese química , Hidrazonas/toxicidade , Isoquinolinas/síntese química , Isoquinolinas/toxicidade , Lagos/análise , Limite de Detecção , Células MCF-7 , Modelos Químicos , Solventes/química , Espectrometria de Fluorescência/métodos , Peixe-ZebraRESUMO
OBJECTIVE: To evaluate the effectiveness of noninvasive ventilation in patients with acute hypoxemic nonhypercapnic respiratory failure unrelated to exacerbation of chronic obstructive pulmonary disease and cardiogenic pulmonary edema. DATA SOURCES: PubMed, EMBASE, Cochrane library, Web of Science, and bibliographies of articles were retrieved inception until June 2016. STUDY SELECTION: Randomized controlled trials comparing application of noninvasive ventilation with standard oxygen therapy in adults with acute hypoxemic nonhypercapnic respiratory failure were included. Chronic obstructive pulmonary disease exacerbation and cardiogenic pulmonary edema patients were excluded. The primary outcome was intubation rate; ICU mortality and hospital mortality were secondary outcomes. DATA EXTRACTION: Demographic variables, noninvasive ventilation application, and outcomes were retrieved. Internal validity was assessed using the risk of bias tool. The strength of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation methodology. DATA SYNTHESIS: Eleven studies (1,480 patients) met the inclusion criteria and were analyzed by using a random effects model. Compared with standard oxygen therapy, the pooled effect showed that noninvasive ventilation significantly reduced intubation rate with a summary risk ratio of 0.59 (95% CI, 0.44-0.79; p = 0.0004). Furthermore, hospital mortality was also significantly reduced (risk ratio, 0.46; 95% CI, 0.24-0.87; p = 0.02). Subgroup meta-analysis showed that the application of bilevel positive support ventilation (bilevel positive airway pressure) was associated with a reduction in ICU mortality (p = 0.007). Helmet noninvasive ventilation could reduce hospital mortality (p = 0.0004), whereas face/nasal mask noninvasive ventilation could not. CONCLUSIONS: Noninvasive ventilation decreased endotracheal intubation rates and hospital mortality in acute hypoxemia nonhypercapnic respiratory failure excluding chronic obstructive pulmonary disease exacerbation and cardiogenic pulmonary edema patients. There is no sufficient scientific evidence to recommend bilevel positive airway pressure or helmet due to the limited number of trials available. Large rigorous randomized trials are needed to answer these questions definitely.
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Ventilação não Invasiva/métodos , Insuficiência Respiratória/terapia , Doença Aguda , Adulto , Idoso , Feminino , Mortalidade Hospitalar , Humanos , Intubação Intratraqueal/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Whether early goal-directed therapy (EGDT) improves outcome in severe sepsis and septic shock remains unclear. We performed a meta-analysis of existing clinical trials to examine whether EGDT improved outcome in the resuscitation of adult sepsis patients compared with control care. METHODS: We searched for eligible studies using MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials, and Web of Science databases. Studies were eligible if they compared the effects of EGDT versus control care on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Data including mortality, sample size of the patients with severe sepsis and septic shock, and resuscitation end points were extracted. Data were analyzed using methods recommended by the Cochrane Collaboration Review Manager 4.2 software. Random errors were evaluated by trial sequential analysis (TSA). RESULTS: Nine studies compared EGDT with control care, and 5202 severe sepsis and septic shock patients were included. A nonsignificant trend toward reduction in the longest all-cause mortality was observed in the EGDT group compared with control care (relative risk, 0.89; 99% confidence interval, 0.74-1.07; P = 0.10). However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients (relative risk, 0.72; 99% confidence interval, 0.57-0.90; P = 0.0002). TSA indicated lack of firm evidence for a beneficial effect. CONCLUSIONS: In this meta-analysis, a nonsignificant trend toward reduction in the longest all-cause mortality in patients resuscitated with EGDT was noted. However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients. TSA indicated a lack of firm evidence for the results. More powered, randomized controlled trials are needed to determine the effects.
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Planejamento de Assistência ao Paciente , Assistência Centrada no Paciente , Sepse/terapia , Choque Séptico/terapia , Causas de Morte , Distribuição de Qui-Quadrado , Mortalidade Hospitalar , Humanos , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Sepse/diagnóstico , Sepse/mortalidade , Índice de Gravidade de Doença , Choque Séptico/diagnóstico , Choque Séptico/mortalidade , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: The effect of mean arterial pressure titration to a higher level on microcirculation in septic shock patients with previous hypertension remains unknown. Our goal is to assess the effect of mean arterial pressure titration to a higher level on microcirculation in hypertensive septic shock patients. METHODS: This is a single-center, open-label study. Hypertensive patients with septic shock for less than 24 hours after adequate fluid resuscitation and requiring norepinephrine to maintain a mean arterial pressure of 65 mmHg were enrolled. Mean arterial pressure was then titrated by norepinephrine from 65 mmHg to the normal level of the patient. In addition to hemodynamic variables, sublingual microcirculation was evaluated by sidestream dark field imaging. RESULTS: Nineteen patients were enrolled in the study. Increasing mean arterial pressure from 65 mmHg to normal levels was associated with increased central venous pressure (from 11 ± 4 to 13 ± 4 mmHg, P = 0.002), cardiac output (from 5.4 ± 1.4 to 6.4 ± 2.1 l/minute, P = 0.001), and central venous oxygen saturation (from 81 ± 7 to 83 ± 7%, P = 0.001). There were significant increases in small perfused vessel density (from 10.96 ± 2.98 to 11.99 ± 2.55 vessels/mm(2), P = 0.009), proportion of small perfused vessels (from 85 ± 18 to 92 ± 14%, P = 0.002), and small microvascular flow index (from 2.45 ± 0.61 to 2.80 ± 0.68, P = 0.009) when compared with a mean arterial pressure of 65 mmHg. CONCLUSIONS: Increasing mean arterial pressure from 65 mmHg to normal levels is associated with improved microcirculation in hypertensive septic shock patients. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01443494; registered 28 September 2011.
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Pressão Arterial/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Microcirculação/efeitos dos fármacos , Choque Séptico/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Hidratação , Hemodinâmica/efeitos dos fármacos , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Soalho Bucal/irrigação sanguínea , Norepinefrina/administração & dosagem , Norepinefrina/farmacologia , Estudos Prospectivos , Respiração Artificial/métodos , Choque Séptico/fisiopatologia , Vasoconstritores/administração & dosagem , Vasoconstritores/farmacologiaRESUMO
INTRODUCTION: The aim of this study was to examine whether albumin reduced mortality when employed for the resuscitation of adult patients with severe sepsis and septic shock compared with crystalloid by meta-analysis. METHODS: We searched for and gathered data from MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. Studies were eligible if they compared the effects of albumin versus crystalloid therapy on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Disagreements were resolved by discussion with other two reviewers until a consensus was achieved. Data including mortality, sample size of the patients with severe sepsis, sample size of the patients with septic shock and resuscitation endpoints were extracted. Data were analyzed by the methods recommended by the Cochrane Collaboration Review Manager 4.2 software. RESULTS: A total of 5,534 records were identified through the initial search. Five studies compared albumin with crystalloid. In total, 3,658 severe sepsis and 2,180 septic shock patients were included in the meta-analysis. The heterogeneity was determined to be non-significant (P = 0.86, I(2) = 0%). Compared with crystalloid, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin (odds ratio (OR) 0.88; 95% CI, 0.76 to 1.01; P = 0.08). However, the use of albumin for resuscitation significantly decreased 90-day mortality in septic shock patients (OR 0.81; 95% CI, 0.67 to 0.97; P = 0.03). Compared with saline, the use of albumin for resuscitation slightly improved outcome in severe sepsis patients (OR 0.81; 95% CI, 0.64 to 1.08; P = 0.09). CONCLUSIONS: In this meta-analysis, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin compared with crystalloid and saline. Moreover, the 90-day mortality of patients with septic shock decreased significantly.
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Albuminas/administração & dosagem , Soluções Isotônicas/administração & dosagem , Choque Séptico/mortalidade , Choque Séptico/terapia , Adulto , Soluções Cristaloides , Humanos , Mortalidade/tendências , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/mortalidade , Ressuscitação/métodos , Sepse/mortalidade , Sepse/terapiaRESUMO
Exploring novel chemotherapeutic agents is a great challenge in cancer medicine. To that end, 2-substituted benzimidazole copper(II) complex, [Cu(BMA)Cl2]·(CH3OH) (1) [BMA = N,N'-bis(benzimidazol-2-yl-methyl)amine], was synthesized and its cytotoxicity was characterized. The interaction between complex 1 and calf thymus DNA was detected by spectroscopy methods. The binding constant (K b = 1.24 × 10(4 )M(-1)) and the apparent binding constant (K app = 6.67 × 10(6 )M(-1)) of 1 indicated its moderate DNA affinity. Complex 1 induced single strand breaks of pUC19 plasmid DNA in the presence of H2O2 through an oxidative pathway. Cytotoxicity studies proved that complex 1 could inhibit the proliferation of human cervical carcinoma cell line HeLa in both time- and dose-dependent manners. The results of nuclei staining by Hoechst 33342 and alkaline single-cell gel electrophoresis proved that complex 1 caused cellular DNA damage in HeLa cells. Furthermore, treatment of HeLa cells with 1 resulted in S-phase arrest, loss of mitochondrial potential, and up-regulation of caspase-3 and -9 in HeLa cells, suggesting that complex 1 was capable of inducing apoptosis in cancer cells through the intrinsic mitochondrial pathway.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzimidazóis/química , Cobre/química , Dano ao DNA , DNA/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Bovinos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HeLa , Humanos , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade , Fatores de Tempo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
Twenty-one compounds were isolated from the rhizomes of Iris germanica by various chromatographic techniques such as silica gel, ODS and Sephadex LH-20 chromatography. Their structures were established on basis of physical properties, MS and NMR spectroscopic data Their structures were identified as ombuin (1), 5, 3, 3'-trihydroxy-7, 4'-dimethoxyflavanone (2), naringenin (3), cirsiliol-4'-glucoside (4), 3beta, 4'-dihydroxy-7,3'-dimethoxyflavonone-5-O-beta-D-glucopyranoside (5), genistein (6), irilin D (7), muningin (8), 5, 7, 4'-trihydroxy-6, 3', 5'-trimethoxyisoflavone (9), tectorigenin (10), irigenin (11), tectoridin (12), iridin (13), mangiferin (14), irisxanthone (15), pyroglutamic acid (16), 2, 4', 6-trihydroxy-4-methoxybenzophenone-2-O-beta-D-glucoside (17), apocynin (18), androsin (19), beta-sitosterol (20), and daucosterol (21). Among them, compounds 1-9, 16, 17 were obtained from this plant for the first time, compounds 8 and 9 were separated from Iris species for the first time, compounds 1, 4, and 17 were obtained from the family for the first time.
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Medicamentos de Ervas Chinesas/química , Gênero Iris/química , Rizoma/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Estrutura Molecular , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A novel technique is introduced to predict the printer model used to produce a given document. Samples containing only a few letters printed under varying conditions (i.e., different printing modes, letter types, fonts) were collected to establish a dataset of 41 inkjet printer models from common manufacturers, such as HP, Canon, and Epson. Morphological features were analyzed by extraction of image features using several algorithms in a series of microscopic images and a Wilcoxon test was used to measure the significance of variations between printed samples. Significant differences between various printing conditions might post potential challenge to questioned document examination. Discriminant analysis and the k-nearest neighbor (KNN) algorithm were also employed for source printer prediction under varying printing condition on 30% images with the rest images as training dataset. The results of a validation experiment demonstrated that while quadratic discriminant analysis (QDA) achieved an accuracy of 96.3%, a combination of KNN and QDA reached 98.6%. As such, this technique could aid in the forensic examination of printed documents.
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Printer source prediction is an important task when examining questioned documents. While some research has provided methods to predict the source printer of documents, with the advent of compatible consumables, printer prediction could become more complex and difficult. Predicting the source printer after replacing cartridges and identifying the source of printer cartridges are unresolved issues that are rarely addressed in current research. Herein, we introduce a novel technique to predict the manufacturer, model, and cartridges of laser printers (i.e., compatible, and original cartridges) used to produce a given document. Document samples produced using eight laser printers and 247 cartridges were collected to establish a dataset. Common manufacturers included HP, Canon, Lenovo, and Epson. After obtaining white-light images and three-dimensional profile images of printed characters, a morphological analysis was conducted by questioned document examiners (QDEs) using microscopy. Microscopic image features across a series of images were also extracted and analyzed using algorithms. Then, six high-dimensional reduction algorithms were used to obtain between- and within-printer variations as well as between- and within-cartridge variations. Finally, we conducted principal component analysis (PCA) and discriminant analysis. For 40â¯% of the samples, mixed discrimination analysis (MDA) and fixed discrimination analysis (FDA) were employed to predict the manufacturer, model and cartridge of laser printers used to produce the questioned printed document; the remaining 60â¯% samples comprised the training dataset. In the prediction of manufacturer, model and cartridge, our method achieved mean accuracies of 95.5â¯%, 97.5â¯%, and 90.2â¯%, respectively. Hence, this technique could reasonably aid in predicting the manufacturer, model, and cartridge of a laser printer, even if different cartridges are loaded into printers.
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Platinum(II) drugs as a first-line anticancer reagent are limited by side effects and drug resistance. Stimuli-responsive nanosystems hold promise for precise spatiotemporal manipulation of drug delivery, with the aim to promote bioavailability and minimize side effects. Herein, a multitargeting octahedral platinum(IV) prodrug with octadecyl aliphatic chain and histone deacetylase inhibitor (phenylbutyric acid, PHB) at axial positions to improve the therapeutic effect of cisplatin was loaded on the upconversion nanoparticles (UCNPs) through hydrophobic interaction. Followed attachment of DSPE-PEG2000 and arginine-glycine-aspartic (RGD) peptide endowed the nanovehicles with high biocompatibility and tumor specificity. The fabricated nanoparticles (UCNP/Pt(IV)-RGD) can be triggered by upconversion luminescence (UCL) irradiation and glutathione (GSH) reduction to controllably release Pt(II) species and PHB, inducing profound cytotoxicity. Both in vitro and in vivo experiments demonstrated that UCNP/Pt(IV)-RGD exhibited remarkable antitumor efficiency, high tumor-targeting specificity, and real-time UCL imaging capacity, presenting an intelligent platinum(IV) prodrug-loaded nanovehicle for UCL-guided dual-stimuli-responsive combination therapy.
Assuntos
Antineoplásicos , Glutationa , Nanopartículas , Oligopeptídeos , Pró-Fármacos , Animais , Humanos , Camundongos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/química , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Glutationa/química , Glutationa/metabolismo , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/diagnóstico por imagem , Oligopeptídeos/química , Platina/química , Platina/farmacologia , Platina/uso terapêutico , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , ProibitinasRESUMO
The development of acute respiratory distress syndrome (ARDS) in sepsis is associated with substantial morbidity and mortality. However, the molecular pathogenesis underlying sepsis-induced ARDS remains elusive. Neutrophil heterogeneity and dysfunction contribute to uncontrolled inflammation in patients with ARDS. A specific subset of neutrophils undergoing reverse transendothelial migration (rTEM), which is characterized by an activated phenotype, is implicated in the systemic dissemination of inflammation. Using single-cell RNA sequencing (scRNA-seq), it identified functionally activated neutrophils exhibiting the rTEM phenotype in the lung of a sepsis mouse model using cecal ligation and puncture. The prevalence of neutrophils with the rTEM phenotype is elevated in the blood of patients with sepsis-associated ARDS and is positively correlated with disease severity. Mechanically, scRNA-seq and proteomic analys revealed that inflamed endothelial cell (EC) released extracellular vesicles (EVs) enriched in karyopherin subunit beta-1 (KPNB1), promoting abluminal-to-luminal neutrophil rTEM. Additionally, EC-derived EVs are elevated and positively correlated with the proportion of rTEM neutrophils in clinical sepsis. Collectively, EC-derived EV is identified as a critical regulator of neutrophil rTEM, providing insights into the contribution of rTEM neutrophils to sepsis-associated lung injury.
RESUMO
OBJECTIVE: To explore the effects of blood, crystalloid and colloid on mesenteric microcirculation in rabbits of acute hemorrhagic shock. METHODS: Hemorrhagic shock was induced in 28 anesthetized mechanically ventilated rabbits by withdrawing blood to a mean arterial blood pressure (MAP) of 40 mm Hg and maintained for 30 min. The animals were randomized into blank control group, whole blood resuscitation group, Ringer's solution resuscitation (RR) group and volume resuscitation (VR) group (n = 7 each). The data of vital signs, systemic hemodynamic parameters, arterial blood gas analysis and mesenteric microcirculation were collected at baseline, hemorrhagic shock (HS-0), resuscitation 0 min (Res-0) and resuscitation 30 min (Res-30). And side-stream dark field imaging (SDF) was employed to acquire the images of mesenteric microcirculation. RESULTS: No significant difference existed in the basic status between 4 groups. MAP decreased to around 40 mm Hg in all groups. MAP increased significantly after active fluid resuscitation (P < 0.05). In addition to blank control group, total vascular density (TVD), perfused vessel density (PVD), proportion of perfused vessels (PPV) and microvascular flow index (MFI) significantly increased after active fluid resuscitation in the other three groups. TVD and PVD were significantly lower at Res-0 in VR than in RR (P < 0.05). CONCLUSION: After acute hemorrhagic shock, fluid resuscitation with whole blood and Ringer's solution improves systemic hemodynamics. And the combined regimen of whole blood and Ringer's solution is better at restoring mesenteric microcirculation.
Assuntos
Hidratação/métodos , Mesentério/irrigação sanguínea , Microcirculação , Choque Hemorrágico/terapia , Animais , Modelos Animais de Doenças , Soluções Isotônicas , Coelhos , Ressuscitação/métodos , Solução de RingerRESUMO
Cancer treatment requires the participation of multiple targets/pathways, and single approach is hard to effectively curb the proliferation and metastasis of carcinoma cells. In this work, we conjugated FDA-approved riluzole and platinum(II) drugs into a series of unreported riluzole-Pt(IV) compounds, which were designed to simultaneously target DNA, the solute carrier family 7 member 11 (SLC7A11, xCT), and the human ether a go-go related gene 1 (hERG1), to exert synergistic anticancer effect. Among them, c,c,t-[PtCl2(NH3)2(OH)(glutarylriluzole)] (compound 2) displayed excellent antiproliferative activity with IC50 value of 300-times lower than that of cisplatin in HCT-116, and optimal selectivity index between carcinoma and human normal liver cells (LO2). Mechanism studies indicated that compound 2 released riluzole and active Pt(II) species after entering cells to exhibit a prodrug behavior against cancer, which obviously increased DNA-damage and cell apoptosis, as well as suppressed metastasis in HCT-116. Compound 2 persisted in the xCT-target of riluzole and blocked the biosynthesis of glutathione (GSH) to trigger oxidative stress, which could boost the killing to cancer cells and reduce Pt-drug resistance. Meanwhile, compound 2 significantly inhibited invasion and metastasis of HCT-116 cells by targeting hERG1 to interrupt the phosphorylation of phosphatidylinositide 3-kinases/proteinserine-threonine kinase (PI3K/Akt), and reverse epithelial-mesenchymal transformation (EMT). Based on our results, the riluzole-Pt(IV) prodrugs studied in this work could be regarded as a new class of very promising candidates for cancer treatment compared to traditional platinum drugs.