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1.
Circ Res ; 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34515499

RESUMO

Rationale: Timely inhibition of inflammation and initiation of resolution are important to repair injured tissues. Mammalian STE20-like protein kinase 1/2 (MST1/2) acts as a regulator of macrophage-associated immune responses to bacterial infections. However, the role of MST1/2 in regulating macrophage phenotype and function in myocardial infarction (MI) remains unclear. Objective: To determine the function and underlying mechanism of macrophage MST1/2 in cardiac repair post-MI. Methods and Results: Using LysMCre-mediated Mst1/2-deficient mice, we found that MST1 deficiency exacerbated cardiac dysfunction after MI. Single-cell RNA sequencing assay indicated that the effect was attributed to a shift of macrophage subtypes from those expressing Cxcl2 and Cd163 toward Ccl2 and Ccl4 expression. Mass spectrometry identified leukotriene B4 (LTB4) as the lipid mediator that was upregulated in the absence of MST1. We found that MST1 phosphorylated 5-lipoxygenase (5-LOX) at its T218 residue, disrupting the interaction between 5-LOX and 5-LOX-activating protein, resulting in a reduction of LTB4 production. In contrast, a 5-LOXT218A variant showed no response to MST1. Moreover, treatment of peritoneal macrophages with LTB4 or medium conditioned by Mst1-deficient macrophages resulted in high Ccl2 and Ccl4 expression and low Cxcl2 and Cd163 expression, except when the cells were co-treated with the LTB4 receptor 1 (BLT1) antagonist CP105696. Furthermore, CP105696 ameliorated cardiac dysfunction in LysMCre-mediated Mst1/2-deficient mice and enhanced cardiac repair in wild-type mice treated with XMU-MP-1 after MI. Conclusions: Taken together, our results demonstrate that inhibition of MST1/2 impaired post-MI repair through activating macrophage 5-LOX-LTB4-BLT1 axis.

2.
Mater Sci Eng C Mater Biol Appl ; 128: 112326, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474877

RESUMO

Bone defects remain a challenging problem for doctors and patients in clinical practice. Processed pyritum is a traditional Chinese medicine that is often used to clinically treat bone fractures. It contains mainly Fe, Zn, Cu, Mn, and other elements. In this study, we added the extract of processed pyritum to ß-tricalcium phosphate and produced a porous composite TPP (TCP/processed pyritum) scaffold using digital light processing (DLP) 3D printing technology. Scanning electron microscopy (SEM) analysis revealed that TPP scaffolds contained interconnected pore structures. When compared with TCP scaffolds (1.35 ± 0.15 MPa), TPP scaffolds (5.50 ± 0.24 MPa) have stronger mechanical strength and can effectively induce osteoblast proliferation, differentiation, and mineralization in vitro. Meanwhile, the in vivo study showed that the TPP scaffold had better osteogenic capacity than the TCP scaffold. Furthermore, the TPP scaffold had good biosafety after implantation. In summary, the TPP scaffold is a promising biomaterial for the clinical treatment of bone defects.


Assuntos
Fosfatos de Cálcio , Tecidos Suporte , Humanos , Porosidade , Impressão Tridimensional
3.
Diabetes Care ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475032

RESUMO

OBJECTIVE: Early menopause may be associated with higher cardiovascular disease (CVD) risk. Type 2 diabetes mellitus (T2DM), coupled with early menopause, may result in even greater CVD risk in women. We examined CVD risk in women with early compared with normal-age menopause, with and without T2DM overall, and by race/ethnicity. RESEARCH DESIGN AND METHODS: We pooled data from the Atherosclerosis Risk in Communities study, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. We included women with data on menopausal status, menopausal age, and T2DM, excluding pre- or perimenopausal women and those with prevalent CVD. Outcomes included incident coronary heart disease (CHD), stroke, heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD) (CHD or stroke). We estimated the risk associated with early (<45 years) compared with normal-age menopause using Cox proportional hazards models. Covariates included age, race/ethnicity, education, BMI, blood pressure, cholesterol, smoking, alcohol consumption, antihypertensive medication, lipid-lowering medication, hormone therapy use, and pregnancy history. RESULTS: We included 9,374 postmenopausal women for a median follow-up of 15 years. We observed 1,068 CHD, 659 stroke, 1,412 HF, and 1,567 ASCVD events. T2DM significantly modified the effect of early menopause on CVD risk. Adjusted hazard ratios for early menopause and the outcomes were greater in women with T2DM versus those without (CHD 1.15 [95% CI 1.00, 1.33] vs. 1.09 [1.03, 1.15]; stroke 1.21 [1.04, 1.40] vs. 1.10 [1.04, 1.16]; ASCVD 1.29 [1.09, 1.51] vs. 1.10 [1.04, 1.17]; HF 1.18 [1.00, 1.39] vs. 1.09 [1.03, 1.16]). The modifying effect of T2DM on the association between early menopause and ASCVD was only statistically significant in Black compared with White women. CONCLUSIONS: Early menopause was associated with an increased risk for CVD in postmenopausal women. T2DM may further augment the risk, particularly in Black women.

4.
J Virol ; : JVI0135621, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34549983

RESUMO

A-1(L) is a freshwater cyanophage with a contractile tail that specifically infects Anabaena sp. PCC 7120, one of the model strains for molecular studies of cyanobacteria. Although isolated for half a century, its structure remains unknown, which limits our understanding on the interplay between A-1(L) and its host. Here we report the 3.35 Å cryo-EM structure of A-1(L) capsid, representing the first near-atomic resolution structure of a phage capsid with a T number of 9. The major capsid gp4 proteins assemble into 91 capsomers, including 80 hexons: 20 at the center of the facet and 60 at the facet edge, in addition to 11 identical pentons. These capsomers further assemble into the icosahedral capsid, via gradually increasing curvatures. Different from the previously reported capsids of known-structure, A-1(L) adopts a non-covalent chainmail structure of capsid stabilized by two kinds of mortise-and-tenon inter-capsomer interactions: a three-layered interface at the pseudo three-fold axis combined with the complementarity in shape and electrostatic potential around the two-fold axis. This unique capsomer construction enables A-1(L) to possess a rigid capsid, which is solely composed of the major capsid proteins with an HK97 fold. IMPORTANCE Cyanobacteria are the most abundant photosynthetic bacteria, contributing significantly to the biomass production, O2 generation, and CO2 consumption on our planet. Their community structure and homeostasis in natural aquatic ecosystems are largely regulated by the corresponding cyanophages. In this study, we solved the structure of cyanophage A-1(L) capsid at near-atomic resolution and revealed a unique capsid construction. This capsid structure provides the molecular details for better understanding the assembly of A-1(L), and a structural platform for future investigation and application of A-1(L) in combination with its host Anabaena sp. PCC 7120. As the first isolated freshwater cyanophage that infects the genetically tractable model cyanobacterium, A-1(L) should become an ideal template for the genetic engineering and synthetic biology studies.

5.
Medicine (Baltimore) ; 100(35): e27014, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477130

RESUMO

BACKGROUND: This study aimed to assess the efficacy and safety of minimally invasive percutaneous nephrolithotomy (MPCNL) versus standard percutaneous nephrolithotomy in patients with renal and upper ureteric stones. METHODS: We conducted a pooled analysis on randomized controlled trials (RCTs). The eligible RCTs were selected from the following databases: MEDLINE, Embase, Web of Science, and the Cochrane Library. The reference lists of retrieved studies were also investigated. RESULTS: Our analysis included 10 RCTs with 1612 patients. Pooled data from 10 RCTs revealed the following: stone-free rate (odds ratio = 1.46, 95% confidence interval (CI) [1.12,1.88], P = .004), operative time (mean difference [MD]  = 4.10, 95% CI [-1.37,9.56], P = .14), length of hospital stay (MD = -15.31, 95% CI [-29.43,-1.19], P = .03), hemoglobin decrease (MD = -0.86, 95% CI [-1.19,-0.53], P < .00001), postoperative fever (MD = 0.83, 95% CI [0.49,1.40], P = .49), and urine leakage (MD = 0.59, 95% CI [0.25,1.37], P = .22). Besides, we performed sub-group analysis based on vacuum suction effect and multiple kidney stones. For vacuum suction effect, it revealed the following: stone-free rate in vacuum suction group (P = .007) and in non-vacuum suction group (P = .19). Operative time in vacuum suction group (P = .89), non-vacuum suction group (P = .16). Postoperative fever in vacuum suction group (P = .49), non-vacuum suction group (P = .85). CONCLUSION: This pooled analysis indicated that MPCNL was a safe and effective method for treating renal stones compared with standard percutaneous nephrolithotomy. Besides, the vacuum suction effect in MPCNL played a more important role. When it comes to multiple or staghorn stones, the longer operative time in MPCNL could not be ignored.


Assuntos
Cálculos Renais/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos/normas , Nefrolitotomia Percutânea/normas , Humanos , Tempo de Internação , Procedimentos Cirúrgicos Minimamente Invasivos/estatística & dados numéricos , Nefrolitotomia Percutânea/estatística & dados numéricos , Razão de Chances , Complicações Pós-Operatórias/epidemiologia , Resultado do Tratamento
6.
Environ Sci Technol ; 55(17): 11916-11924, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34424674

RESUMO

The mechanism of self-flocculation remains unclear, partially impeding its efficiency enhancement and commercial application of microalgae-based municipal wastewater (MW) bioremediation technology. This study revealed the contributions of exoproteins [PN, proteins in extracellular polymeric substances (EPS)] to the separation of indigenous microalgae from treated MW. Compared to the low light intensity group, the high light intensity (HL) group produced Chlorella sp. with 4.3-fold higher self-flocculation efficiencies (SE). This was attributed to the enriched biological functions and positional rearrangement of increased PN within 2.9-fold higher EPS. Specifically, a total of 75 PN was over-expressed in the HL group among the 129 PN identified through label-free proteomics. The algal cell-adhesion molecules (Algal-CAMs) and metal-ion-binding PN were demonstrated as two dominant contributors promoting cell adhesion and bridging, through function prediction based on the contained domains. The modeled 3D structure showed that Algal-CAMs presented less hydrophilic α-helix abundance and were distributed in the outermost position of the EPS matrix, further facilitating microalgal separation. Moreover, the 10.1% lower hydrophily degree value, negative interfacial free energy (-19.5 mJ/m2), and 6.8-fold lower energy barrier between cells also supported the observed higher SE. This finding is expected to further fill the knowledge gap of the role of PN in microalgal self-flocculation and promote the development of biomass recovery from the microalgae-wastewater system.


Assuntos
Chlorella , Microalgas , Biomassa , Floculação , Águas Residuárias
7.
Rev Sci Instrum ; 92(6): 063522, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34243503

RESUMO

A fast response Doppler spectroscopy system with high throughput and high resolution is under development for studying the drifting velocity, rotation velocity, and ion temperature on the HUST field-reversed configuration (HFRC) device. The system has been designed to observe the spectral line of oxygen V (O V) ion emission at 278.1 nm (1s22s3p → 1s22s3s) over the lifetime (∼0.5 ms) of the FRC plasma. A high throughput Czerny-Turner monochromator with 3600 g/mm grating and 670 mm focal length is applied to achieve high spectral resolution; a 32-channel multi-anode photomultiplier tube (PMT) detector is utilized to achieve the high-speed response of up to 1 MHz; a 1D magnification optics combined with a cylindrical lens assembly and a fiber optic expansion is developed to magnify the spectral dispersion fitting the PMT channel interval. Through the ray-tracing analysis, the system's final spectral resolution is evaluated to be ∼0.03 nm. Taking into account the system sensitivity and O V line emissivity in HFRC plasma, the system is expected to be workable with the temporal response of 1 µs.

8.
Expert Opin Drug Deliv ; 18(10): 1473-1500, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34253129

RESUMO

Introduction: The treatment of tumors is one of the most difficult problems in the medical field at present. Patients often use a comprehensive therapy that combines surgery, radiotherapy, and chemotherapy. Photodynamic therapy (PDT) has prominent potential for eradicating various cancers. Chlorin-based photosensitizers (PSs), as one of the most utilized photosensitizers, have many advantages over conventional photosensitizers; however, a successful chlorin-based PDT needs multi-functional nano-carriers for selective photosensitizer delivery. The number of researches about nanoparticles designed for improved chlorin-based PSs is increasing in the current era. In this article, we give a brief review focused on the recent research progress in design of chlorin-based nanoparticles for the treatment of malignant tumors with photodynamic therapy.Areas covered: This review focuses on the current nanoparticle platforms for PDT, and describes different strategies to achieve controllable PDT by chlorin-nano-delivery systems. The challenges and prospects of PDT in clinical applications are also discussed.Expert opinions: The requirement for PDT to eradicate cancers has increased exponentially in recent years. The major clinically used photosensitizers are hydrophobic. The main obstacles in effective delivery of PSs are associated with this intrinsic nature. The design of nano-delivery systems to load PSs is pivotal for PSs' widespread use.

9.
BMC Geriatr ; 21(1): 361, 2021 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-34120598

RESUMO

BACKGROUND: With the increase in life expectancy, a large number of patients with osteoporosis (OP) are undergoing spine surgery, which may adversely affect the surgical success rate. The prevalence of OP varies in different regions, and no data are available that represent the prevalence of OP among Chinese patients over 50 years of age who are undergoing spine surgery. It was the first multicenter study to assess OP in these patients. Aiming to obtain comprehensive data, this study combined bone mineral density (BMD) measurements and visual radiography assessment (VRA) to analyze the prevalence of OP in patients aged > 50 years who underwent spine surgery. METHODS: Data from 1,856 patients aged over 50 years undergoing spine surgery who resided in northern, central, and southern China were reviewed between 2018 and 2019. Based on the perioperative BMD and X-ray data, we calculated the prevalence of OP in this special population according to sex, age, and spine degenerative disease. RESULTS: A total of 1,245 patients (678 females and 567 males) were included in the study. The prevalence of OP diagnosed by BMD was 52.8 % in females and 18.7 % in males. When we combined with BMD and VRA, the prevalence of OP increased from 52.8 to 65.9 % in females and from 18.7 to 40.6 % in males. Although OP was more severe in females than in males, a significant difference in the rate of vertebral fracture (VF) was not observed between females and males with a normal BMD and osteopenia (females vs. males: aged 50-59 years, P = 0.977; 60-69 years, P = 0.302; >70 years, P = 0.172). Similarly, no significant difference in the vertebral fracture rate was observed within different age groups of patients with a normal BMD and osteopenia (females: P = 0.210; males, P = 0.895). The incidence of OP in patients with degenerative scoliosis was higher than that in the remaining patients (females: 63.6 % vs. 42.4 %, P = 0.018; males: 38.9 % vs. 13.8 %, P = 0.004). CONCLUSIONS: A high prevalence of OP was identified in patients aged > 50 years undergoing spine surgery, especially in patients whose primary diagnosis was degenerative scoliosis. BMD and VRA evaluations should be included in the clinical routine for these patients prior to surgery.


Assuntos
Osteoporose , Fraturas da Coluna Vertebral , Absorciometria de Fóton , Densidade Óssea , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico por imagem , Osteoporose/epidemiologia , Prevalência
10.
J Control Release ; 335: 637-649, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34087249

RESUMO

Targeting a single molecule or a single pathway and poor drug delivery to the brain hamper the therapy of Alzheimer's disease (AD) based on abnormal metabolism of amyloid-ß (Aß). To solve these problems, we designed and synthesized a multi - strategy peptide (MOP), an ingenious apolipoprotein E mimetic peptide, which could reduce Aß deposition via inhibiting Aß aggregation and at the same time accelerate Aß clearance. Meanwhile, MOP could be self-assembled into different nanostructure, thus we constructed a multifunctional delivery system (APND-3) based on MOP self-assembled nanorods (aspect ratios of 3) that was a favorable morphology to enhance the permeation across the blood brain barrier (BBB) to address the poor delivery to brain issues. Besides, the drug delivery system introduces polydopamine (PDA) and COG1410 ligand as a shell to keep the favorable morphology of core and enhance the BBB targeting efficiency. As a result, the delivery system significantly enhances the delivery of MOP to the brain, thus reducing Aß deposition, mitigating the memory deficits, and ameliorating neurologic damage in AD model mice. Our findings suggest that our drug and carrier integrated multifunctional delivery system has the potential for AD treatment.


Assuntos
Doença de Alzheimer , Nanotubos , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Biomimética , Barreira Hematoencefálica/metabolismo , Camundongos
11.
Transl Vis Sci Technol ; 10(7): 7, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34100925

RESUMO

Purpose: To explore whether subtle changes in visual quality can be detected using different measures of visual function against the quick contrast sensitivity function test (quick CSF). Methods: Sixty participants, aged 17 to 34 years, were enrolled. Participants' vision was degraded by 0.25 D undercorrection (0.25 D), 60% neutral density filter brightness reduction (60% ND), and 0.8 Bangerter foil optical diffusion (0.8BAN). Visual function tests including visual acuity and contrast sensitivity (CSV-1000E and quick CSF) were measured with participant's best-corrected vision and under simulated visual degradation conditions. Test sensitivities in detecting differences were compared. Results: Statistically significant visual acuity degradation was observed in the 0.8BAN condition only (Pcorrected < 0.001). With CSV-1000E and outliers removed, significant CS degradation was observed in all spatial frequencies, area under log CSF (AULCSF) in the 0.8BAN condition (Pcorrected < 0.001 for all), medium and high spatial frequencies and AULCSF in the 60%ND condition (Pcorrected,6cpd = 0.002, Pcorrected,12cpd = 0.005, Pcorrected,18cpd = 0.001, Pcorrected,AULCSF < 0.001) and the 0.25 D condition (Pcorrected,6cpd = 0.011, Pcorrected,12cpd = 0.013, Pcorrected,18cpd = 0.015, Pcorrected,AULCSF < 0.001). With the quick CSF, significant CS degradation was observed in all simulated visual conditions in all spatial frequencies, cutoff frequency and AULCSF (Pcorrected < 0.001 for all). Test-retest reliability of the quick CSF method was high; coefficient of repeatability ranged from 0.14 to 0.18 logCS. Conclusions: Compared with visual acuity and chart-based CS tests, the quick CSF method provided more reliable and sensitive measures to detect small visual changes. Translational Relevance: The quick CSF method can provide sensitive and reliable measures to monitor disease progression and assess treatment outcomes.


Assuntos
Sensibilidades de Contraste , Testes Visuais , Humanos , Reprodutibilidade dos Testes , Visão Ocular , Acuidade Visual
12.
World Neurosurg ; 152: e589-e596, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34129986

RESUMO

BACKGROUND: Pedicle screw fixation (PSF) has been considered the preferred surgery for the treatment of severe osteoporotic vertebral compression fracture (sOVCF), and sOVCF was traditionally regarded as a relative contraindication to minimally invasive percutaneous kyphoplasty (PKP). Debate has continued regarding the selection of the best surgical method for sOVCF. In the present study, we compared the efficacy and safety between PKP and PSF. METHODS: PKP was performed in 376 patients in group 1 and PSF in 121 patients in group 2. The visual analog scale (VAS), Oswestry disability index (ODI), local kyphotic angle, fractured vertebral body height, and complications were evaluated. RESULTS: In the immediate postoperative analysis, the mean VAS score for group 1 was 2.4, significantly lower than the VAS score of 4.7 for group 2. The mean ODI score was 44.4% for group 1, lower than the ODI score of 57.1% for group 2. In addition, group 1 had had a significantly better ODI score at 1 year of follow-up. The local kyphotic angle and fractured vertebral body height had recovered better in group 2. In group 1, 113 patients had experienced cement leakage, and 29 patients had undergone PKP for adjacent new vertebral fractures. In group 2, 2 patients had developed wound infections, 4 had developed pneumonia, 2 had developed urinary tract infection, 3 had experienced asymptomatic screw loosening, and 7 had undergone PKP to treat new vertebral fractures and 1 had undergone removal of internal fixation because of back pain. CONCLUSIONS: The results of the clinical and radiological evaluations showed that PKP is comparable to PSF for the treatment of sOVCF with kyphosis, with PKP having the advantages of minimal invasion, quick postoperative pain relief, and functional recovery.

13.
J Neurosurg Spine ; : 1-8, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087791

RESUMO

OBJECTIVE: The aim of this study was to compare a traditional cervical cage with a zero-profile (ZP) fixation device in patients who underwent three-level anterior cervical decompression and fusion (ACDF) in terms of patient-reported outcomes (visual analog scale [VAS], Japanese Orthopaedic Association [JOA], and Neck Disability Index [NDI] scores), radiographic findings (sagittal alignment 2 years after surgery and likelihood of fusion), and complications. METHODS: This study was a retrospective case series. Between January 2012 and December 2016, 58 patients with cervical spondylotic myelopathy (CSM) who required three-level ACDF procedures, as identified by spinal surgeons, were treated with three-level ACDF and an anterior cage-plate construct (ACPC) (n = 38) or a three-level stand-alone ZP device (n = 20). On the basis of patient choice, patients were divided into two groups (ACPC group and ZP group). All patients completed a minimum of 2 years of follow-up. Patient-reported outcome scores included VAS, JOA, and NDI scores. The radiographic findings included sagittal alignment and likelihood of fusion 2 years after surgery. Data related to patient-reported outcomes and sagittal alignment were collected preoperatively, postoperatively, and at the final follow-up. Intraoperative and postoperative complications were also documented and analyzed. RESULTS: The clinical outcomes, including VAS, JOA, and NDI scores, showed improvement in both groups, and no significant difference was observed between the two groups. Sagittal alignment and height of the fused segments were restored in all patients. However, the authors found no differences between the ZP and ACPC groups, and the groups exhibited similar fusion rates. The authors found no differences in complications, including dysphagia, adjacent-segment degeneration, and postoperative hematoma, between the groups. CONCLUSIONS: Use of ZP implants yielded satisfactory long-term clinical and radiological outcomes that were similar to those of the standard ACPC. Additionally, the rates of complications between the groups were not significantly different. Although the best surgical option for multilevel CSM remains controversial, the results of this work suggest that ACDF with the ZP device is feasible, safe, and effective, even for multilevel CSM.

14.
Theranostics ; 11(13): 6592-6606, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995678

RESUMO

Purpose: Clinical success of cancer therapy is severely limited by drug resistance, attributed in large part to the loss of function of tumor suppressor genes (TSGs). Developing effective strategies to treat those tumors is challenging, but urgently needed in clinic. Experimental Design: MYOCD is a clinically relevant TSG in lung cancer patients. Our in vitro and in vivo data confirm its tumor suppressive function. Further analysis reveals that MYOCD potently inhibits stemness of lung cancer stem cells. Mechanistically, MYOCD localizes to TGFBR2 promoter region and thereby recruits PRMT5/MEP50 complex to epigenetically silence its transcription. Conclusions: NSCLC cells deficient of MYOCD are particularly sensitive to TGFBR kinase inhibitor (TGFBRi). TGFBRi and stemness inhibitor synergize with existing drugs to treat MYOCD deficient lung cancers. Our current work shows that loss of function of MYOCD creates Achilles' heels in lung cancer cells, which might be exploited in clinic.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Nucleares/deficiência , Receptor do Fator de Crescimento Transformador beta Tipo II/antagonistas & inibidores , Transativadores/deficiência , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Código das Histonas , Humanos , Neoplasias Pulmonares/genética , Metilação , Camundongos Transgênicos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Regiões Promotoras Genéticas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Processamento de Proteína Pós-Traducional , Proteína-Arginina N-Metiltransferases/fisiologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Transdução de Sinais , Transativadores/biossíntese , Transativadores/genética , Transativadores/fisiologia , Carga Tumoral
15.
Biomaterials ; 274: 120855, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33975276

RESUMO

Drug-loaded hydrogels can improve blood supply and inhibit extracellular matrix degradation after myocardial infarction. However, due to the continual dynamic motion of cardiac tissue, the hydrogel structure cannot be reconstructed in time, causing accelerated degradation and drug burst release. Here, a novel, superior, self-healing elastin-mimic peptide hydrogel (EMH) was fabricated for the local delivery of salvianolic acid B (SaB). The self-healing ability of EMH is enhanced by SaB-loaded polydopamine nanoparticles (SaB-PDA). In vitro, the pre-hydrogel (SaB-PDA/pre-EMH) is endowed with excellent biocompatibility and a low viscosity, making it suitable for intramyocardial injection. Once injected into the myocardial infarction (MI) region, SaB-PDA/pre-EMH can form SaB-PDA/EMH with great mechanical strength under the action of upregulated transglutaminase (TGase) in heart tissue post-MI. The superior self-healing ability of SaB-PDA/EMH allows for an increase in retention time in the beating ventricular wall. Therefore, with long-term release of SaB, SaB-PDA/EMH can inhibit ventricular remodeling and promote angiogenesis for MI treatment.


Assuntos
Hidrogéis , Infarto do Miocárdio , Benzofuranos , Humanos , Infarto do Miocárdio/tratamento farmacológico , Peptídeos , Remodelação Ventricular
16.
J Med Chem ; 64(11): 7371-7389, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34029463

RESUMO

The previous virtual screening of ten million compounds yielded two novel nonlipopeptide-like chemotypes as TLR2 agonists. Herein, we present the chemical optimization of our initial hit, 1-phenyl-3-(thiophen-2-yl)urea, which resulted in the identification of SMU-C80 (EC50 = 31.02 ± 1.01 nM) as a TLR2-specific agonist with a 370-fold improvement in bioactivity. Mechanistic studies revealed that SMU-C80, through TLR1/2, recruits the adaptor protein MyD88 and triggers the NF-κB pathway to release cytokines such as TNF-α and IL-1ß from human, but not murine, cells. To the best of our knowledge, it is the first species-specific TLR1/2 agonist reported until now. Moreover, SMU-C80 increased the percentage of T, B, and NK cells ex vivo and activated the immune cells, which suppressed cancer cell growth in vitro. In summary, we obtained a highly efficient and specific human TLR1/2 agonist that acts through the MyD88 and NF-κB pathway, facilitating cytokine release and the simultaneous activation of immune cells that in turn affects the apoptosis of cancer cells.


Assuntos
Desenho de Fármacos , Tioureia/análogos & derivados , Receptor 1 Toll-Like/agonistas , Receptor 2 Toll-Like/agonistas , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Imunoterapia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Neoplasias/terapia , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Tioureia/metabolismo , Tioureia/uso terapêutico , Receptor 1 Toll-Like/metabolismo , Receptor 2 Toll-Like/metabolismo
17.
JMIR Med Inform ; 9(5): e24721, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33973862

RESUMO

BACKGROUND: Though shock wave lithotripsy (SWL) has developed to be one of the most common treatment approaches for nephrolithiasis in recent decades, its treatment planning is often a trial-and-error process based on physicians' subjective judgement. Physicians' inexperience with this modality can lead to low-quality treatment and unnecessary risks to patients. OBJECTIVE: To improve the quality and consistency of shock wave lithotripsy treatment, we aimed to develop a deep learning model for generating the next treatment step by previous steps and preoperative patient characteristics and to produce personalized SWL treatment plans in a step-by-step protocol based on the deep learning model. METHODS: We developed a deep learning model to generate the optimal power level, shock rate, and number of shocks in the next step, given previous treatment steps encoded by long short-term memory neural networks and preoperative patient characteristics. We constructed a next-step data set (N=8583) from top practices of renal SWL treatments recorded in the International Stone Registry. Then, we trained the deep learning model and baseline models (linear regression, logistic regression, random forest, and support vector machine) with 90% of the samples and validated them with the remaining samples. RESULTS: The deep learning models for generating the next treatment steps outperformed the baseline models (accuracy = 98.8%, F1 = 98.0% for power levels; accuracy = 98.1%, F1 = 96.0% for shock rates; root mean squared error = 207, mean absolute error = 121 for numbers of shocks). The hypothesis testing showed no significant difference between steps generated by our model and the top practices (P=.480 for power levels; P=.782 for shock rates; P=.727 for numbers of shocks). CONCLUSIONS: The high performance of our deep learning approach shows its treatment planning capability on par with top physicians. To the best of our knowledge, our framework is the first effort to implement automated planning of SWL treatment via deep learning. It is a promising technique in assisting treatment planning and physician training at low cost.

18.
Cardiovasc Eng Technol ; 12(4): 398-406, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33844137

RESUMO

PURPOSE: Size of the embolic microspheres is of critical importance in the transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) to achieve the optimal embolization therapy. In this regard, to optimize the size distribution of the embolic microspheres and enhance the embolization efficacy, the aggregate gradation theory is used to formulate the microspheres. METHODS: Finite element analysis (FEA) and in vitro experiments confirmed a better embolic efficacy for the poly(vinyl alcohol) (PVA) microspheres formulated according to the aggregate gradation theory. RESULTS: The average volume flow of the graded group was 1.31 × 10-4 mL/s in vitro experiment, which was lowest among all the groups suggesting the graded group had the optimal embolic effect. The graded group has the largest pressure gradient of 314.22 Pa/µm in FEA among all the groups, which can be attributed to the highest packing density of the graded group compared with other groups. CONCLUSIONS: The graded embolic microspheres have a larger drag coefficient compared with the narrow size distribution groups both in vitro experiment and FEA. These findings can be used to formulate the embolic agents with optimal size distributions and are significant for the improvement of clinical embolization therapy.

19.
Protein Sci ; 30(8): 1566-1576, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33928692

RESUMO

Carboxysome is an icosahedral self-assembled microcompartment that sequesters RuBisCO and carbonic anhydrases within a selectively permeable protein shell. The scaffolding proteins, CcmM, and CcmN were proposed to act as adaptors that crosslink the enzymatic core to shell facets. However, the details of interaction pattern remain unknown. Here we obtained a stable heterotrimeric complex of CcmM γ-carbonic anhydrase domain (termed CcmMNT ) and CcmN, with a 1:2 stoichiometry, which interacts with the shell proteins CcmO and CcmL in vitro. The 2.9 Å crystal structure of this heterotrimer revealed an asymmetric bundle composed of one CcmMNT and two CcmN subunits, all of which adopt a triangular left-handed ß-helical barrel structure. The central CcmN subunit packs against CcmMNT and another CcmN subunit via a wall-to-edge or wall-to-wall pattern, respectively. Together with previous findings, we propose CcmMNT -CcmN functions as an adaptor to facilitate the recruitment of shell proteins and the assembly of intact ß-carboxysome.

20.
Drug Dev Ind Pharm ; 47(6): 857-866, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33650446

RESUMO

OBJECTIVE: This study was aimed at improving the water solubility and oral bioavailability of Chl by self-microemulsifying drug delivery system (Chl-SMEDDS). METHODS: Compatibility experiments, pseudo-ternary phase diagram and central composite design were used to optimize the formulation. The selected systems were further evaluated for physical characteristics, including particle size, zeta potential, and appearance. The stability, in vitro dispersion test, and in vivo intestinal perfusion experiments were used to evaluate the SMEDDS. RESULTS: The optimal composition of Chl-SMEDDS included: Labrafil M 1944 CS (35%), kolliphor RH 40 (46%), Transcutol HP (19%) and 60 mg/g Chl. The appearance of water emulsified Chl-SMEDDS was green and transparent. The particle size, ζ-potential, and transmission electron microscopy studies showed that spherical globules of Chl-SMEDDS with a size of about 22.82 ± 1.29 nm and a negative surface charge of -24.21 ± 3.45 mV were obtained. Chl-SMEDDS could remain stable at 25 °C and 4 °C for at least 6 months. The dispersion test showed that Chl-SMEDDS dispersed spontaneously to form microemulsion after disintegration of capsule shell and 90% drug dispersed in just 30 min in pH 1.2 HCl without any drug precipitation during the test period. In vivo intestinal perfusion experiment revealed that the main absorption site for Chl-SMEDDS was duodenum. CONCLUSIONS: This study indicates that SMEDDS formulation could be an effective strategy for the oral administration of Chl.


Assuntos
Clorofila , Sistemas de Liberação de Medicamentos , Administração Oral , Animais , Disponibilidade Biológica , Emulsões , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , Tensoativos
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