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1.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(4): 598-603, 2022 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-35527497

RESUMO

OBJECTIVE: To investigate the inhibitory effect of AZD2014, a dual mTORC1/2 inhibitor, against acute graft rejection in a rat model of allogeneic liver transplantation. METHODS: Liver transplantation from Lewis rat to recipient BN rat (a donor-recipient combination that was prone to induce acute graft rejection) was performed using Kamada's two-cuff technique. The recipient BN rats were randomized into 2 groups for treatment with daily intraperitoneal injection of AZD2014 (5 mg/kg, n=4) or vehicle (2.5 mL/kg, n=4) for 14 consecutive days, starting from the first day after the transplantation. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) levels of the rats were measured 3 days before and at 1, 3, 5, 7, 10, and 14 days after the transplantation, and the survival time of the rats within 14 days were recorded. Immunohistochemical staining was used to examine the expressions of CD3 and Foxp3 in the liver graft, and acute graft rejection was assessed using HE staining based on the Banff schema. RESULTS: Three rats in the control group died within 14 days after the surgery, while no death occurred in the AZD2014 group, demonstrating a significantly longer survival time of the rats in AZD2014 group (χ2=4.213, P=0.04). Serum ALT, AST and TBIL levels in the control group increased progressively after the surgery and were all significantly higher than those in AZD2014 group at the same time point (P < 0.05). Pathological examination revealed significantly worse liver graft rejection in the control group than in AZD2014 group based on assessment of the rejection index (P < 0.01); the rats in the control group showed more serious T lymphocyte infiltration and significantly fewer Treg cells in the liver graft than those in AZD2014 group (P < 0.01). CONCLUSIONS: AZD2014 can effectively inhibit acute graft rejection in rats with allogeneic liver transplantation.


Assuntos
Rejeição de Enxerto , Transplante de Fígado , Animais , Benzamidas , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Fígado/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Morfolinas , Pirimidinas , Ratos , Ratos Endogâmicos Lew
3.
PLoS One ; 17(4): e0266476, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35413091

RESUMO

The ataxia telangiectasia and rad3-related-checkpoint kinase 1 (ATR-CHK1) pathway is involved in DNA damage responses in many cancer cells. ATR inhibitors have been used in clinical trials in combination with radiation or chemotherapeutics; however, their effects against bladder cancer remain unclear. Here, the efficacy of combining gemcitabine with the novel ATR inhibitor AZD6738 was investigated in vitro in three bladder cancer cell lines (J82, T24, and UM-UC-3 cells). The effects of gemcitabine and AZD6738 on cell viability, clonogenicity, cell cycle, and apoptosis were examined. The combined use of gemcitabine and AZD6738 inhibited the viability and colony formation of bladder cancer cells compared to either treatment alone. Gemcitabine (5 nM) and AZD6738 (1 µM) inhibited cell cycle progression, causing cell accumulation in the S phase. Moreover, combined treatment enhanced cleaved poly[ADP-ribose]-polymerase expression alongside the number of annexin V-positive cells, indicating apoptosis induction. Mechanistic investigations showed that AZD6738 treatment inhibited the repair of gemcitabine-induced double-strand breaks by interfering with CHK1. Combining AZD6738 with gemcitabine could therefore be useful for bladder cancer therapy.


Assuntos
Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica , Proteínas Mutadas de Ataxia Telangiectasia , Quinase 1 do Ponto de Checagem , Desoxicitidina , Neoplasias da Bexiga Urinária , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Humanos , Indóis/farmacologia , Morfolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Sulfóxidos/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
4.
Int J Mol Sci ; 23(8)2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35457111

RESUMO

The aberrant activation of the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) pathway is common in pancreatic ductal adenocarcinomas (PDAC). The application of inhibitors against PI3K and AKT has been considered as a therapeutic option. We investigated PDAC cell lines exposed to increasing concentrations of MK-2206 (an AKT1/2/3 inhibitor) and Buparlisib (a pan-PI3K inhibitor). Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated. Further, whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were performed to analyze the recurrent aberrations and expression profiles of the inhibitor target genes and the genes frequently mutated in PDAC (Kirsten rat sarcoma virus (KRAS), Tumor protein p53 (TP53)). MK-2206 and Buparlisib demonstrated pronounced cytotoxic effects and limited cell-line-specific effects in cell death induction. WES revealed two sequence variants within the direct target genes (PIK3CA c.1143C > G in Colo357 and PIK3CD c.2480C > G in Capan-1), but a direct link to the Buparlisib response was not observed. RNA-seq demonstrated that the expression level of the inhibitor target genes did not affect the efficacy of the corresponding inhibitors. Moreover, increased resistance to MK-2206 was observed in the analyzed cell lines carrying a KRAS variant. Further, increased resistance to both inhibitors was observed in SU.86.86 carrying two TP53 missense variants. Additionally, the presence of the PIK3CA c.1143C > G in KRAS-variant-carrying cell lines was observed to correlate with increased sensitivity to Buparlisib. In conclusion, the present study reveals the distinct antitumor effects of PI3K/AKT pathway inhibitors against PDAC cell lines. Aberrations in specific target genes, as well as KRAS and TP53, individually or together, affect the efficacy of the two PI3K/AKT pathway inhibitors.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Aminopiridinas , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Compostos Heterocíclicos com 3 Anéis , Humanos , Morfolinas , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais
5.
Am J Manag Care ; 28(3): e88-e95, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35404552

RESUMO

OBJECTIVES: To determine whether baloxavir use is associated with lower health care resource utilization (HCRU) and costs for secondary influenza complications post treatment compared with oseltamivir. STUDY DESIGN: Retrospective cohort study. METHODS: Patients filling a prescription for baloxavir or oseltamivir within 48 hours following an influenza-related outpatient visit were identified in the 2018-2019 influenza season from the US Truven MarketScan Research Databases and propensity matched 1:2 (baloxavir:oseltamivir). Outcomes were assessed 15 and 30 days after antiviral treatment and included all-cause, all respiratory-related, and select respiratory-related (influenza, asthma, chronic obstructive pulmonary disease, or infection) HCRU and costs. RESULTS: The study included 5080 baloxavir-treated and 10,160 matched oseltamivir-treated patients. All-cause emergency department (ED) visits and inpatient hospitalizations were lower in baloxavir-treated patients, with a statistically significant difference in the percentage hospitalized at 30 days (0.3% vs 0.5%; P = .04). ED visits for all or select respiratory-related conditions were significantly reduced with baloxavir (P < .01 for all comparisons). Mean per-patient cost savings at day 30 for all-cause, all respiratory-related, and select respiratory-related conditions were $79, $50, and $51, respectively, despite slightly higher prescription costs for baloxavir. In high-risk patients (baloxavir: n = 1958; oseltamivir: n = 3949), the incidence of ED visits was significantly lower for all respiratory-related and select respiratory-related conditions (P < .01); cost savings with baloxavir in the high-risk cohort were substantially greater than in the overall cohort. CONCLUSIONS: Treatment of patients with influenza with single-dose baloxavir was generally associated with lower HCRU and costs post treatment compared with oseltamivir, particularly in high-risk patients.


Assuntos
Influenza Humana , Oseltamivir , Antivirais/uso terapêutico , Dibenzotiepinas , Humanos , Influenza Humana/tratamento farmacológico , Morfolinas/uso terapêutico , Oseltamivir/uso terapêutico , Piridonas/uso terapêutico , Estudos Retrospectivos , Triazinas/uso terapêutico
6.
Sci Rep ; 12(1): 4173, 2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-35264603

RESUMO

To improve the potency of Heptamethine cyanines (Hcyanines) in cancer research, we designed and synthesized two novel Hcyanines based theranostic probes, IR794-Morph and IR794-Morph-Mpip, to enhance cancer cell internalization and targeting. In acidic conditions that resemble to tumour environment, both IR794 derivatives exhibited broad NIR absorption band (704‒794 nm) and fluorescence emission (798‒828 nm) that is suitable for deep seated tumour imaging. Moreover, in vitro study revealed that IR794-Morph-Mpip exhibited better cancer targetability towards various cancer cell lines under physiological and slightly acidic conditions compared to normal cells. IR794-Morph-Mpip was fast internalized into the cancer cells within the first 5 min and mostly localized in lysosomes and mitochondria. In addition, the internalized signal was brighter when the cells were in the hypoxic environment. Furthermore, cellular uptake mechanism of both IR794 dyes, investigated via flow cytometry, revealed that endocytosis through OATPs receptors and clathrin-mediated endocytosis were the main routes. Moreover, IR794-Morph-Mpip, displayed anti-cancer activity towards all tested cancer cell types with IC50 below 7 µM (at 6 h incubation), which is approximately three times lower than that of the normal cells. Therefore, increasing protonated cites in tumour environment of Hcyanines together with incorporating morpholine in the molecule can enhance structure-inherent targeting of these dyes.


Assuntos
Neoplasias , Quinolinas , Fluorescência , Corantes Fluorescentes/química , Humanos , Morfolinas/farmacologia
7.
Biochem Biophys Res Commun ; 602: 8-14, 2022 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-35247703

RESUMO

Apoptosis inhibition often leads to resistance to chemotherapeutics in bladder cancer (BC), resulting in poor prognosis of patients. Accumulating evidence suggests that induction of necroptosis, another type of programmed cell death, can be applied as an alternative strategy to kill apoptosis-insensitive BC cells. In this study, we showed that a novel Smac mimetic, ASTX660, also known as Tolinapant, can induce necroptosis in BC cells when apoptosis is inhibited. This is achieved by turning tumour necrosis factor (TNF)-α into a cytotoxic signal; ASTX660 then acts synergistically with TNF-α to induce necroptosis in BC cells. Mechanistic investigation showed that ASTX660 promoted the formation of the necrosome complex. Genetic or pharmacological inhibition of RIP1, RIP3, or MLKL, which are components of necrosome complex, provided protection against cell death induced by ASTX660 alone or ASTX660/TNF-α upon caspase inhibition. In addition, TNF-α/TNFR1 signalling and IRF1 are essential for the necroptosis induced by ASTX660 after the caspases are blocked. Our study highlights that ASTX660 can overcome the limitation of apoptosis induction via triggering necroptosis in BC cells. Therefore, our findings may provide some important clues for the design of a novel treatment strategy for BC.


Assuntos
Fator de Necrose Tumoral alfa , Neoplasias da Bexiga Urinária , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Feminino , Humanos , Masculino , Morfolinas , Necroptose , Necrose/induzido quimicamente , Piperazinas , Pirróis , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico
8.
J Healthc Eng ; 2022: 3053277, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35340223

RESUMO

In order to investigate the efficacy of mosapril citrate combined with ShenQu Xiaoshi oral liquid in the treatment of children with functional dyspepsia and the effect on serum cytokines, 136 children with functional dyspepsia admitted from May 2017 to September 2020 were divided into 2 groups randomly, 68 cases in each group. The western medicine group was treated with mosapril citrate tablets, and the combined group was treated with Shenqu xiaoshi oral liquid on the basis of the western medicine group. The efficacy of patients was evaluated 14 days after treatment, and the safety, symptom score, and serum cytokines of the two groups were compared. The results showed that, after 14 days of treatment, the scores of abdominal distension and abdominal pain (ADAP), lack of food (LOF), nausea and vomiting (NAV), irregular stool (IS), and mental fatigue (MF) in the combined group were all lower than those in the western group (P < 0.05). There was no statistical significance in the incidence of diarrhea, abnormal liver and kidney, and allergic rash between the two groups (p > 0.05). In conclusion, mosapride citrate tablets combined with Shenqu Xiaoshi oral liquid can achieve good therapeutic effects in children with functional dyspepsia, reduce symptom scores, improve serum cytokine levels, and have high drug safety, which is worthy of promotion and application.


Assuntos
Desinfetantes , Dispepsia , Benzamidas , Criança , Citratos/uso terapêutico , Citocinas/uso terapêutico , Desinfetantes/uso terapêutico , Dispepsia/diagnóstico , Dispepsia/tratamento farmacológico , Humanos , Morfolinas , Comprimidos/uso terapêutico , Resultado do Tratamento
10.
Antimicrob Agents Chemother ; 66(4): e0000922, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35262375

RESUMO

Baloxavir is an anti-influenza endonuclease inhibitor that targets the polymerase acidic (PA) protein of influenza A and B viruses. Our knowledge regarding the pleiotropic effects of baloxavir resistance-associated substitutions is limited. We generated recombinant A/California/04/09 (H1N1)-, A/Hong Kong/218849/2006 (H3N2)-, and B/Victoria/504/2000-like viruses that contained PA substitutions identified in baloxavir clinical trials and surveillance that could potentially be associated with baloxavir resistance. We characterized their susceptibility to baloxavir, impact on polymerase activity, viral growth, and ability to induce interferon (IFN) and IFN-stimulated genes expression in vitro. Four PA substitutions, H1N1 I38L/T, E199D, and B G199R, significantly reduced the sensitivity of the recombinant viruses to baloxavir (14.1-fold). We confirmed our findings by using the luciferase-based ribonucleoprotein minigenome assay and by using virus yield reduction assay in Calu-3 and normal human bronchial epithelial (NHBE) cells. We observed that I38L and E199D resulted in decreased viral replication of the H1N1 wild-type virus (1.4-fold) but the H1N1 I38T and B G199R substitutions did not significantly alter replication capacity in Calu-3 cells. In addition, H1N1 variants with PA I38L/T and E199D induced significantly higher levels of IFNB1 gene expression compared to the wild-type virus (4.2-fold). In contrast, the B variant, G199R, triggered the lowest levels of IFN genes in Calu-3 cells (1.6-fold). Because baloxavir is a novel anti-influenza therapeutic agent, identifying and characterizing substitutions associated with reduced sensitivity to baloxavir, as well as the impact of these substitutions on viral fitness, is paramount to the strategic implementation of this novel countermeasure.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Substituição de Aminoácidos , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas , Farmacorresistência Viral/genética , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/tratamento farmacológico , Interferons/uso terapêutico , Morfolinas , Piridonas/farmacologia , Piridonas/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêutico
11.
Neurosci Lett ; 778: 136585, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35318075

RESUMO

Ethanol-induced conditioned taste aversion (CTA) is greater in late adolescence or young adulthood than in early adolescence. The role of the sigma receptor system in this age-related difference has not been extensively explored, particularly in female rats. This study assessed the effects of the activation of sigma-1 receptors (S1-R), via the selective S1-R agonist PRE-084, on ethanol-induced CTA at early or at terminal adolescence/emerging adulthood (28 or 56 days-old at the beginning of the procedures, respectively) in female Wistar rats. The modulation of binge-like ethanol intake by PRE-084 was assessed at terminal adolescence. S1-R activation at the acquisition of ethanol-induced CTA attenuated such learning at terminal but not at early adolescence. PRE-084 did not significantly affect ethanol binge drinking in the terminal adolescents. These results highlight the role of S1-R in ethanol-induced CTA and suggest that differential functionality of this transmitter system may underlie age-specific sensitivities to the aversive effects of ethanol.


Assuntos
Etanol , Paladar , Consumo de Bebidas Alcoólicas , Animais , Aprendizagem da Esquiva , Etanol/farmacologia , Feminino , Morfolinas , Ratos , Ratos Wistar , Receptores sigma
12.
PLoS One ; 17(3): e0265879, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35333888

RESUMO

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, severely debilitating, and fatal neuromuscular disease characterized by progressive muscle degeneration. Like in many orphan diseases, randomized controlled trials are uncommon in DMD, resulting in the need to indirectly compare treatment effects, for example by pooling individual patient-level data from multiple sources. However, to derive reliable estimates, it is necessary to ensure that the samples considered are comparable with respect to factors significantly affecting the clinical progression of the disease. To help inform such analyses, the objective of this study was to review and synthesise published evidence of prognostic indicators of disease progression in DMD. We searched MEDLINE (via Ovid), Embase (via Ovid) and the Cochrane Library (via Wiley) for records published from inception up until April 23 2021, reporting evidence of prognostic indicators of disease progression in DMD. Risk of bias was established with the grading system of the Centre for Evidence-Based Medicine (CEBM). RESULTS: Our search included 135 studies involving 25,610 patients from 18 countries across six continents (Africa, Asia, Australia, Europe, North America and South America). We identified a total of 23 prognostic indicators of disease progression in DMD, namely age at diagnosis, age at onset of symptoms, ataluren treatment, ATL1102, BMI, cardiac medication, DMD genetic modifiers, DMD mutation type, drisapersen, edasalonexent, eteplirsen, glucocorticoid exposure, height, idebenone, lower limb surgery, orthoses, oxandrolone, spinal surgery, TAS-205, vamorolone, vitlolarsen, ventilation support, and weight. Of these, cardiac medication, DMD genetic modifiers, DMD mutation type, and glucocorticoid exposure were designated core prognostic indicators, each supported by a high level of evidence and significantly affecting a wide range of clinical outcomes. CONCLUSION: This study provides a current summary of prognostic indicators of disease progression in DMD, which will help inform the design of comparative analyses and future data collection initiatives in this patient population.


Assuntos
Distrofia Muscular de Duchenne , Progressão da Doença , Glucocorticoides/uso terapêutico , Humanos , Morfolinas , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Piperidinas , Prognóstico , Pirróis
13.
Antiviral Res ; 200: 105281, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35292289

RESUMO

Global analysis of the susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs) and the polymerase acidic (PA) inhibitor (PAI) baloxavir was conducted by five World Health Organization Collaborating Centres for Reference and Research on Influenza during two periods (May 2018-May 2019 and May 2019-May 2020). Combined phenotypic and NA sequence-based analysis revealed that the global frequency of viruses displaying reduced or highly reduced inhibition (RI or HRI) or potential to show RI/HRI by NAIs remained low, 0.5% (165/35045) and 0.6% (159/26010) for the 2018-2019 and 2019-2020 periods, respectively. The most common amino acid substitution was NA-H275Y (N1 numbering) conferring HRI by oseltamivir and peramivir in A(H1N1)pdm09 viruses. Combined phenotypic and PA sequence-based analysis showed that the global frequency of viruses showing reduced susceptibility to baloxavir or carrying substitutions associated with reduced susceptibility was low, 0.5% (72/15906) and 0.1% (18/15692) for the 2018-2019 and 2019-2020 periods, respectively. Most (n = 61) of these viruses had I38→T/F/M/S/L/V PA amino acid substitutions. In Japan, where baloxavir use was highest, the rate was 4.5% (41/919) in the 2018-2019 period and most of the viruses (n = 32) had PA-I38T. Zoonotic viruses isolated from humans (n = 32) in different countries did not contain substitutions in NA associated with NAI RI/HRI phenotypes. One A(H5N6) virus had a dual substitution PA-I38V + PA-E199G, which may reduce susceptibility to baloxavir. Therefore, NAIs and baloxavir remain appropriate choices for the treatment of influenza virus infections, but close monitoring of antiviral susceptibility is warranted.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Substituição de Aminoácidos , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas , Farmacorresistência Viral/genética , Endonucleases/genética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza B , Morfolinas , Neuraminidase/genética , Neuraminidase/uso terapêutico , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Piridonas , Triazinas
14.
Front Immunol ; 13: 834988, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35309299

RESUMO

Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease. Platelets are important mediators and sensors of inflammation and are directly affected by cardiovascular stressors. In this report, we found that platelets from severely ill, hospitalized COVID-19 patients exhibited higher basal levels of activation measured by P-selectin surface expression and had poor functional reserve upon in vitro stimulation. To investigate this question in more detail, we developed an assay to assess the capacity of plasma from COVID-19 patients to activate platelets from healthy donors. Platelet activation was a common feature of plasma from COVID-19 patients and correlated with key measures of clinical outcome including kidney and liver injury, and APACHEIII scores. Further, we identified ferritin as a pivotal clinical marker associated with platelet hyperactivation. The COVID-19 plasma-mediated effect on control platelets was highest for patients that subsequently developed inpatient thrombotic events. Proteomic analysis of plasma from COVID-19 patients identified key mediators of inflammation and cardiovascular disease that positively correlated with in vitro platelet activation. Mechanistically, blocking the signaling of the FcγRIIa-Syk and C5a-C5aR pathways on platelets, using antibody-mediated neutralization, IgG depletion or the Syk inhibitor fostamatinib, reversed this hyperactivity driven by COVID-19 plasma and prevented platelet aggregation in endothelial microfluidic chamber conditions. These data identified these potentially actionable pathways as central for platelet activation and/or vascular complications and clinical outcomes in COVID-19 patients. In conclusion, we reveal a key role of platelet-mediated immunothrombosis in COVID-19 and identify distinct, clinically relevant, targetable signaling pathways that mediate this effect.


Assuntos
Plaquetas/imunologia , COVID-19/imunologia , Complemento C5a/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Receptores de IgG/metabolismo , SARS-CoV-2/fisiologia , Tromboembolia/imunologia , Adulto , Aminopiridinas/farmacologia , Células Cultivadas , Feminino , Hospitalização , Humanos , Masculino , Morfolinas/farmacologia , Ativação Plaquetária , Pirimidinas/farmacologia , Índice de Gravidade de Doença , Transdução de Sinais , Quinase Syk/antagonistas & inibidores
15.
N Engl J Med ; 386(11): 1034-1045, 2022 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-35294813

RESUMO

BACKGROUND: Iberdomide, a cereblon modulator promoting degradation of the transcription factors Ikaros and Aiolos, which affect leukocyte development and autoimmunity, is being evaluated for the treatment of systemic lupus erythematosus (SLE). METHODS: In this phase 2 trial, we randomly assigned patients in a 2:2:1:2 ratio to receive oral iberdomide (at a dose of 0.45, 0.30, or 0.15 mg) or placebo once daily for 24 weeks, in addition to standard medications. The primary end point at week 24 was a response on the SLE Responder Index (SRI-4), which was defined as a reduction of at least 4 points in the Systemic Lupus Erythematosus Disease Activity Index 2000 score (a 24-item weighted score of lupus activity that ranges from 0 to 105, with higher scores indicating greater disease activity), no new disease activity as measured on the British Isles Lupus Assessment Group 2004 index, and no increase of 0.3 points or more in the Physician's Global Assessment score (on a visual-analogue scale ranging from 0 [no disease activity] to 3 [maximal disease]). RESULTS: A total of 288 patients received the assigned intervention: 81 received iberdomide at a dose of 0.45 mg, 82 received iberdomide at a dose of 0.30 mg, 42 received iberdomide at a dose of 0.15 mg, and 83 received placebo. At week 24, the percentages of patients with an SRI-4 response were 54% in the iberdomide 0.45-mg group, 40% in the iberdomide 0.30-mg group, 48% in the iberdomide 0.15-mg group, and 35% in the placebo group (adjusted difference between the iberdomide 0.45-mg group and the placebo group, 19.4 percentage points; 95% confidence interval, 4.1 to 33.4; P = 0.01), with no significant differences between the groups that received the lower doses of iberdomide and the group that received placebo. Iberdomide-associated adverse events included urinary tract and upper respiratory tract infections and neutropenia. CONCLUSIONS: In this 24-week, phase 2 trial involving patients with SLE, iberdomide at a dose of 0.45 mg resulted in a higher percentage of patients with an SRI-4 response than did placebo. Data from larger, longer trials are needed to determine the efficacy and safety of iberdomide in SLE. (Funded by Bristol Myers Squibb; ClinicalTrials.gov number, NCT03161483; EudraCT number, 2016-004574-17.).


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/agonistas , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Morfolinas/uso terapêutico , Ftalimidas/uso terapêutico , Piperidonas/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Fator de Transcrição Ikaros/metabolismo , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/farmacologia , Ftalimidas/administração & dosagem , Ftalimidas/farmacologia , Piperidonas/administração & dosagem , Piperidonas/farmacologia , Índice de Gravidade de Doença , Ubiquitina-Proteína Ligases/metabolismo
16.
Eur J Med Chem ; 233: 114251, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35278855

RESUMO

By following up on the design vector of optimizing amine-based HIV-1 protease inhibitors, we have designed and biologically evaluated a novel class of inhibitors with the free nitrogen or sulphone in morpholine cores as P2 ligands in combination with diverse substituted phenylsulfonamide P2' ligands. As it turns out, a majority of these inhibitors exhibit prominent enzymatic inhibitory activity in low nanomolar ranges with relatively low cytotoxicity. Particularly, inhibitor 1e containing a morpholine carboxamide P2 ligand and a 4-hydroxyphenylsulfonamide P2' ligand illustrates a robust enzyme inhibitory IC50 value of 90 pM. Furthermore, 1e demonstrates impressive in vivo antiviral activity with EC50 value of 89 nM and a degree of inhibitory potency against the DRV-resistant variant. More importantly, 1e exhibits remarkable activity with EC50 values of 13.59 nM and 8.23 nM against subtype C HIV-1 strains ZM246 and Indie, respectively. Furthermore, the in silico studies provide molecular insights into binding features of inhibitors with HIV-1 protease, and furnish a valuable forecast on further process.


Assuntos
Inibidores da Protease de HIV , HIV-1 , Cristalografia por Raios X , Desenho de Fármacos , Protease de HIV/metabolismo , Ligantes , Morfolinas , Relação Estrutura-Atividade
17.
Dis Markers ; 2022: 5196682, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35308137

RESUMO

Methods: Wound-healing assay and Transwell assay were utilized to evaluate the effect of ginsenoside Rb1 on the migration of BMSCs. RT-PCR and Western blotting were performed to evaluate the expression of stromal-derived factor 1 (SDF-1), C-X-C chemokine receptor type 4 (CXCR4), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (PKB; AKT). Results: Ginsenoside Rb1 significantly enhanced the migration of BMSCs through the activation of SDF-1, CXCR4, p-PI3K/PI3K, and p-Akt/Akt relative expression. Furthermore, this stimulus was blocked by the pretreatment with AMD3100 and LY294002. Conclusions: Ginsenoside Rb1 facilitated the migration of BMSCs through the activation of the SDF-1/CXCR4 axis and PI3K/Akt pathway.


Assuntos
Ginsenosídeos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CXCR4/metabolismo , Transdução de Sinais , Animais , Osso e Ossos/metabolismo , Movimento Celular/efeitos dos fármacos , Cromonas/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/antagonistas & inibidores , Panax , Células Estromais/metabolismo
18.
Eur J Pharmacol ; 922: 174875, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35314158

RESUMO

Although paclitaxel (PTX) is potent chemotherapeutic agent commonly used in variety of cancers, in colorectal carcinoma its usage is excluded because of low effectivity. Up to now, some experimental attempts were utilized to improve sensitivity of colorectal carcinoma to PTX. We used a slow sulfide donor GYY4137 to increase sensitivity of colorectal carcinoma cells to PTX. As a model of colorectal carcinoma, we utilized three different cell lines - HCT116, SW620 and DLD1. We compared IC50 for PTX and PTX/GYY4137, cell cycle, apoptosis, ATP levels and changes in intracellular pH. We observed significant decrease in IC50 levels in PTX/GYY4137 groups compared to PTX in all three cell lines. PTX arrested cell cycle in G2/M phase. Differences in S phase were observed in HCT116 and DLD1 cells treated with 20 nM PTX/GYY4137, but not in SW620 cell. GYY4137 increased early, but not late phase of apoptosis. This increase was not detected in non-cancer EAHy926 cells. Upregulation of IP3R1 suggested involvement of these receptors in PTX and/or GYY4137 induced apoptosis. We also observed partial ATP depletion and intracellular acidification in PTX treated groups. In PTX/GYY4137 groups of all three cell lines no ATP depletion was detectable and intracellular acidification was lower than in PTX treated groups. Slight differences in all measured parameters were determined among HCT116, SW620 and DLD1 cells, which is probably due to physiological variations in these cells. Taking together, sensitivity of PTX to colorectal carcinoma cell lines could be increased by slow sulfide donor GYY4137, probably through potentiation of apoptosis.


Assuntos
Neoplasias Colorretais , Sulfeto de Hidrogênio , Trifosfato de Adenosina/farmacologia , Apoptose , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Humanos , Sulfeto de Hidrogênio/metabolismo , Morfolinas , Compostos Organotiofosforados , Paclitaxel/farmacologia , Sulfetos/farmacologia , Sulfetos/uso terapêutico
19.
Antiviral Res ; 201: 105310, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35358601

RESUMO

Data on the clinical effectiveness of the novel anti-influenza drug baloxavir marboxil (baloxavir) in children remain limited. We conducted an observational study to compare the duration of fever and symptoms between baloxavir- and oseltamivir-treated children infected with influenza A and B. In total, 159 outpatients with influenza A(H1N1)pdm09 or B/Victoria-lineage infections, aged <19 years, during the 2019-2020 influenza season in Japan were enrolled and assessed the duration of fever and symptoms using the Kaplan-Meier method and a multivariate Cox proportional hazard regression model. Polymerase acidic (PA) variants were examined before and after baloxavir treatment. In the multivariable analysis, the duration of fever and symptoms was unaltered between the A(H1N1)pdm09 (n = 116) and B/Victoria-lineage (n = 43) groups. Conversely, the fever duration was marginally longer in the oseltamivir-treated group (n = 59) than in the baloxavir group (n = 100) (hazard ratio (HR) = 0.67, p = 0.05); however, the duration of symptoms was unaltered between the two groups (HR = 0.74, p = 0.11). No patient presented PA reduced susceptibility marker(s) before baloxavir treatment in the analyzed groups. The PA/E23K variant was detected in one case (1.5%, 1/66) of A(H1N1)pdm09 after baloxavir treatment. One case (2.0%, 1/50) of A(H1N1)pdm09 with an N295S substitution in neuraminidase was detected following oseltamivir treatment. These results suggested that the duration of fever was likely to be shorter with baloxavir than with oseltamivir, but the difference between influenza A (H1N1)pdm09 and B/Victoria-lineage was unclear. It is important to continue evaluating the clinical effectiveness of baloxavir and monitoring its drug susceptibility to the influenza virus.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Antivirais/uso terapêutico , Criança , Dibenzotiepinas , Febre/tratamento farmacológico , Humanos , Japão , Morfolinas , Nucleotidiltransferases , Oseltamivir/uso terapêutico , Piridonas/uso terapêutico , Estações do Ano , Triazinas/uso terapêutico
20.
Mol Pharmacol ; 101(5): 371-380, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35236771

RESUMO

The synthetic cannabinoid WIN55,212-2 (WIN) is widely used as a pharmacological tool to study the biologic activity of cannabinoid receptors. In contrast to many other cannabinoid agonists, however, WIN also causes broad effects outside of neurons, such as reducing inflammatory responses, causing cell cycle arrest, and reducing general protein expression. How exactly WIN causes these broad effects is not known. Here we show that WIN partially disrupts the Golgi apparatus at nanomolar concentrations and fully disperses the Golgi apparatus in neuronal and non-neuronal cells at micromolar concentrations. WIN55,212-3, the enantiomer of WIN; JWH-018, a related alkylindole; or 2-arachidonoylglycerol, an endocannabinoid, did not cause Golgi disruption, suggesting that the effect was specific to the chirality of WIN. WIN treatment also perturbed the microtubule network. Importantly, WIN disrupted the Golgi in primary cortical neurons derived from mice where cannabinoid receptor-1 (CB1) was genetically knocked out, indicating that the effects were independent of CB1 signaling. The Golgi dispersion could not be explained by WIN's action on peroxisome proliferator-activated receptors. Our results show that WIN can disrupt the Golgi apparatus independent of CB1 in cultured cells. These effects could contribute to the unique physiologic effects that WIN exhibits in neuronal behavior, as well as its role as an antiproliferative and anti-inflammatory agent. SIGNIFICANCE STATEMENT: The synthetic cannabinoid WIN55,212-2 (WIN), widely used to investigate the cannabinoid system, also shows unique broader effects at cellular and organismal levels compared to endogenous cannabinoids. Our study shows that WIN can disrupt the Golgi apparatus and the microtubule network in multiple cell types, independent of cannabinoid receptors. These results could explain how WIN reduces surface levels of proteins and contributes to the unique physiological effects observed with WIN.


Assuntos
Benzoxazinas , Canabinoides , Animais , Benzoxazinas/farmacologia , Canabinoides/farmacologia , Complexo de Golgi , Camundongos , Morfolinas/farmacologia , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Receptores de Canabinoides
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