Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 357
Filtrar
1.
Front Mol Neurosci ; 15: 930526, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36187347

RESUMO

Ischemic and hemorrhagic stroke (including intracerebral hemorrhage, intraventricular hemorrhage, and subarachnoid hemorrhage) is the dominating cause of disability and death worldwide. Neuroinflammation, blood-brain barrier (BBB) disruption, neuronal death are the main pathological progress, which eventually causes brain injury. Increasing evidence indicated that lipocalin 2 (LCN2), a 25k-Da acute phase protein from the lipocalin superfamily, significantly increased immediately after the stroke and played a vital role in these events. Meanwhile, there exists a close relationship between LCN2 levels and the worse clinical outcome of patients with stroke. Further research revealed that LCN2 elimination is associated with reduced immune infiltrates, infarct volume, brain edema, BBB leakage, neuronal death, and neurological deficits. However, some studies revealed that LCN2 might also act as a beneficial factor in ischemic stroke. Nevertheless, the specific mechanism of LCN2 and its primary receptors (24p3R and megalin) involving in brain injury remains unclear. Therefore, it is necessary to investigate the mechanism of LCN2 induced brain damage after stroke. This review focuses on the role of LCN2 and its receptors in brain injury and aiming to find out possible therapeutic targets to reduce brain damage following stroke.

2.
Front Pharmacol ; 13: 932934, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105197

RESUMO

Tenofovir (TFV) ester prodrugs, a class of nucleotide analogs (NAs), are the first-line clinical anti-hepatitis B virus (HBV) drugs with potent antiviral efficacy, low resistance rate and high safety. In this work, three marketed TFV ester drugs, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF) and tenofovir amibufenamide fumarate (TMF), were used as probes to investigate the relationships among prodrug structures, pharmacokinetic characteristics, metabolic activations, pharmacological responses and to reveal the key factors of TFV ester prodrug design. The results indicated that TMF and TAF exhibited significantly stronger inhibition of HBV DNA replication than did TDF in HBV-positive HepG2.2.15 cells. The anti-HBV activity of TMF was slightly stronger than TAF after 9 days of treatment (EC50 7.29 ± 0.71 nM vs. 12.17 ± 0.56 nM). Similar results were observed in the HBV decline period post drug administration to the HBV transgenic mouse model, although these three TFV prodrugs finally achieved the same anti-HBV effect after 42 days treatments. Furthermore, TFV ester prodrugs showed a correcting effect on disordered host hepatic biochemical metabolism, including TCA cycle, glycolysis, pentose phosphate pathway, purine/pyrimidine metabolism, amino acid metabolism, ketone body metabolism and phospholipid metabolism. The callback effects of the three TFV ester prodrugs were ranked as TMF > TAF > TDF. These advantages of TMF were believed to be attributed to its greater bioavailability in preclinical animals (SD rats, C57BL/6 mice and beagle dogs) and better target loading, especially in terms of the higher hepatic level of the pharmacologically active metabolite TFV-DP, which was tightly related to anti-HBV efficacy. Further analysis indicated that stability in intestinal fluid determined the actual amount of TFV prodrug at the absorption site, and hepatic/intestinal stability determined the maintenance amount of prodrug in circulation, both of which influenced the oral bioavailability of TFV prodrugs. In conclusion, our research revealed that improved pharmacokinetics of TFV ester prodrugs (especially intestinal stability) strengthened the inhibition of HBV replication and the rebalance of hepatocellular metabolism, which provides new insights and a basis for the design, modification and evaluation of new TFV prodrugs in the future.

3.
Front Plant Sci ; 13: 983600, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36147225

RESUMO

Drought greatly affects the growth and development of garden plants and affects their ornamental value. WRKY transcription factors make up one of the largest transcription factor families in plants and they play an important role in the plant response to drought stress. However, the function of the WRKY gene in response to drought stress in Iris germanica, which is commonly used in landscaping, has not been studied. In this study, we isolated two WRKY transcription factor genes from Iris germanica, IgWRKY50 and IgWRKY32, which belong to Group II and Group III of the WRKY family, respectively. IgWRKY50 and IgWRKY32 could be induced by PEG-6000, high temperature and ABA in Iris germanica. IgWRKY50 and IgWRKY32 could quickly respond to drought and they peaked at 3 h after PEG-6000 treatment (19.93- and 23.32-fold). The fusion proteins IgWRKY50-GFP and IgWRKY32-GFP were located in the nucleus of mesophyll protoplasts of Arabidopsis. The overexpression of the IgWRKY50 and IgWRKY32 genes improved the osmotic tolerance of transgenic Arabidopsis, mainly exhibited by the transgenic plants having a higher germination rate and a longer total root length on 1/2 MS medium containing mannitol. Under PEG-6000 stress, the transgenic plants had higher stomatal closure than the wild type (WT). Under natural drought stress, the water loss rate of the isolated leaves of transgenic Arabidopsis was lower than that of WT, the contents of proline (Pro) and soluble protein (SP) and the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) in the transgenic plants were higher, but the content of malondialdehyde (MDA) was lower. Furthermore, the expression of several stress-related genes (RD29A, DREB2A, PP2CA, and ABA2) was significantly increased in IgWRKY50- and IgWRKY32- overexpressing transgenic Arabidposis plants after drought treatment. These results suggest that IgWRKY50 and IgWRKY32, as two positive regulators, enhance the drought resistance of transgenic Arabidopsis by mediating the ABA signal transduction pathway. IgWRKY50 and IgWRKY32 can be used as candidate genes for molecular breeding of drought resistance in Iris.

4.
Lasers Med Sci ; 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36066778

RESUMO

Low-level laser therapy (LLLT) also known as photobiomodulation is a treatment to change cellular biological activity. The exact effects of LLLT remain unclear due to the different irradiation protocols. The purpose of this study was to investigate the effects of LLLT by three different irradiation methods on the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro. BMSCs were inoculated in 24-well plates and then irradiated or not (control) with a laser using three different irradiation methods. The irradiation methods were spot irradiation, covering irradiation, and scanning irradiation according to different spot areas (0.07 cm2 or 1.96 cm2) and irradiation areas (0.35 cm2 or 1.96 cm2), respectively. The laser was applied three times at energy densities of 4 J/cm2. The cell proliferation by CCK-8. ALP activity assay, alizarin red, and quantitative real-time polymerase chain reaction (RT-PCR) were performed to assess osteogenic differentiation and mineralization. Increases in cell proliferation was obvious following irradiation, especially for covering irradiation. The ALP activity was significantly increased in irradiated groups compared with non-irradiated control. The level of mineralization was obviously improved following irradiation, particularly for covering irradiation. RT-PCR detected significantly higher expression of ALP, OPN, OCN, and RUNX-2 in the group covering than in the others, and control is the lowest. The presented results indicate that the biostimulative effects of LLLT on BMSCs was influenced by t he irradiation method, and the covering irradiation is more favorable method to promote the proliferation and osteogenic differentiation of BMSCs.

5.
Adv Sci (Weinh) ; : e2203652, 2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36180388

RESUMO

In nature, biological compartments such as cells rely on dynamically controlled permeability for matter exchange and complex cellular activities. Likewise, the ability to engineer compartment permeability is crucial for in vitro systems to gain sustainability, robustness, and complexity. However, rendering in vitro compartments such a capability is challenging. Here, a facile strategy is presented to build permeability-configurable compartments, and marked advantages of such compartmentalization are shown in reconstituting sustained synthetic biology systems in vitro. Through microfluidics, the strategy produces micrometer-sized layered microgels whose shell layer serves as a sieving structure for biomolecules and particles. In this configuration, the transport of DNAs, proteins, and bacteriophages across the compartments can be controlled an guided by a physical model. Through permeability engineering, a compartmentalized cell-free protein synthesis system sustains multicycle protein production; ≈100 000 compartments are repeatedly used in a five-cycle synthesis, featuring a yield of 2.2 mg mL-1 . Further, the engineered bacteria-enclosing compartments possess near-perfect phage resistance and enhanced environmental fitness. In a complex river silt environment, compartmentalized whole-cell biosensors show maintained activity throughout the 32 h pollutant monitoring. It is anticipated that permeability-engineered compartmentalization should pave the way for practical synthetic biology applications such as green bioproduction, environmental sensing, and bacteria-based therapeutics.

6.
JASA Express Lett ; 2(3): 035202, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-36154628

RESUMO

Previous studies suggest that listeners may use segmental coarticulation cues to facilitate spoken word recognition. Based on existing production studies which showed a pre-low raising effect in Cantonese tonal coarticulation, this study used a word identification task to investigate whether the tonal coarticulatory cue, carried by high-level and rising tones, was used when native listeners recognized pre-low and pre-high disyllabic words. The finding indicated that the listeners may rely on F0 of the rising tone to resolve lexical competition when hearing pre-high words. However, it did not provide evidence supporting the use of pre-low raising cue in spoken word recognition.


Assuntos
Sinais (Psicologia) , Percepção da Fala , Cafeína , Audição
7.
Artigo em Inglês | MEDLINE | ID: mdl-35962841

RESUMO

PURPOSE: To develop a simple and effective method for evaluating the femoral tunnel position using the apex of the deep cartilage (ADC) as the landmark. METHODS: A total of 52 patients who underwent arthroscopic ACL reconstruction were recruited between June and September 2021. The femoral tunnel was placed on the central point of the anteromedial footprint with an accessory anteromedial and a high anterolateral portal. Then, the length from the ADC to the shallow cartilage margin (L1) and to the center of the femoral tunnel (l1), as well as the center to the low cartilage margin (H1, intraoperative height), was measured under arthroscopy and on postoperative CT scans (L2, l2 and H2). Moreover, intraoperative and postoperative cartilage ratios were equivalent to l1/L1 and l2/L2, respectively. Linear regression, Pearson correlation and Bland-Altman analysis were performed to evaluate the consistency between these two measurements of cartilage ratio (l/L) and height (H). RESULTS: The mean age at the time of surgery was 28.7 years; 42 patients were male, and 17 patients were hurt in the left knee among 52 patients. The intraoperative cartilage ratio was 0.37 ± 0.04, and the height was 8.1 ± 1.1 mm with almost perfect inter-observer reproducibility. After the surgery, the cartilage ratio and height were measured as 0.39 ± 0.04 and 8.2 ± 1.3 mm on 3D-CT, respectively, with almost perfect intra- and inter-observer reproducibility. Significant positive correlations and linear regression were detected in the cartilage ratio (r = 0.844, p < 0.001), and height (r = 0.926, p < 0.001) intraoperatively and postoperatively. The Bland-Altman plot also showed excellent consistency between arthroscopy and 3D-CT. CONCLUSIONS: The ADC is a good landmark in the assessment of femoral tunnel position, with excellent consistency between intraoperative arthroscopic measurements and postoperative 3D-CT. CLINICALTRIALS: gov Identifier: NCT04937517. LEVEL OF EVIDENCE: Level III.

8.
EClinicalMedicine ; 52: 101616, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36016695

RESUMO

Background: The elbow joint is sensitive to trauma from accidents, sports injuries, and surgical trauma. Some patients develop ossification or contracture of the medial collateral ligament (MCL) after elbow trauma. A less invasive reconstruction of the MCL can be performed after resection of diseased MCL. The biomechanical characteristics of this technique have been demonstrated and validated. However, its clinical effectiveness and safety require further confirmation in clinical practice. Methods: This open-label, non-randomised, prospective, multicentre trial included consecutive patients with elbow stiffness from five orthopaedic centres in China. Patients willing to participate in the study, with elbow stiffness caused by traumatic injury, who had reached skeletal maturity, and who had a range of motion of <100° were eligible for inclusion. Patients with immunological or metabolic causes of elbow stiffness, burns, or central nervous system injuries were excluded. In addition, patients who did not require MCL release and reconstruction after intraoperative release of other structures were also excluded. All patients underwent resection of the diseased MCL part in an open arthrolysis. Medial stability of the elbow was reconstructed using a less invasive MCL reconstruction technique that uses fascia and tendon patches. In this study, the primary outcomes, including stability, Mayo Elbow Performance Score (MEPS), Amadio score, were used to comprehensively evaluate this technique. Outcomes were assessed at 6 weeks, 6 months, and 1 year postoperatively and annually thereafter. This study reports the results of one arm of the trial that has been registered with the Chinese Clinical Trial Registry (chictr.org.cn), ChiCTR-INC-16010019. Findings: Between January 1, 2017 and March 1, 2020, 104 eligible patients were enrolled. The mean follow-up time was 43·47 (95% CI, 41·45 - 45·49) months. Among all 104 patients, 100 (96%) patients who underwent MCL reconstruction retained medial stability at the last follow-up. All outcomes from the last follow-up were used for comparison with the preoperative outcomes. No differences in preoperative and postoperative stability scores were observed (P = 0·7820). Extension, flexion, pronation, and supination of the injured elbow improved significantly (P < 0·0001, P < 0·0001, P < 0·0001, P < 0·0001). The mean range of motion (ROM) and forearm rotational range of motion (FRR) increased by 71·25° (152%) (P < 0·0001) and 30·83° (25%) (P < 0·0001), respectively. Additionally, the Mayo Elbow Performance Score (MEPS) and muscle strength had increased after evaluation at follow-ups (P < 0·0001, P < 0·0001). Drastic pain relief and nerve symptom reduction were observed, as evaluated using VAS scores and Amadio scores, respectively (P < 0·0001, P < 0·0001). Seventeen (16%) patients experienced a recurrence of elbow stiffness of varying severity, but only two patients had poor or fair results. Several common and non-severe complications, including infection in one (1%) patient, new nerve symptoms in seven (7%) patients, new pain in one (1%) patient, fracture in one (1%) patient, and valgus instability in four (4%) patients, were observed and properly treated in this study. Interpretation: The less invasive MCL reconstruction technique using fascia and tendon patches is an effective method for restoring medial stability in patients with elbow stiffness after complete arthrolysis with certain safety. The technique shows prospects for elbow MCL reconstruction in clinical practice. Funding: The study was supported by the National Key Research and Development Program of China (No. 2021YFC2400805), National Natural Science Foundation of China (No. 81830076), Young Elite Scientist Sponsorship Program by Cast (No. YESS20200153), Shanghai Sailing Program (No. 20YF1436000), Shanghai Municipal Science and Technology Commission Foundation (No.19ZR1439200), Municipal Hospital Newly-developing Cutting-edge Technologies Joint Research Program of Shanghai Shenkang Hospital Development Centre (No. SHDC12018130).

9.
Bioengineering (Basel) ; 9(8)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-36004884

RESUMO

Bronchiectasis is defined as a permanent dilation of the bronchi that can cause pulmonary ventilation dysfunction. CT examination is an important means of diagnosing bronchiectasis. It can also be used in severity scoring. Current studies on bronchiectasis have focused on high-resolution CT (HRCT), ignoring the more common low-dose CT (LDCT). Methodologically, existing studies have not adopted an authoritative standard to classify the severity of bronchiectasis. In effect, the accuracy of detection and classification needs to be improved for practical application. In this paper, the ACER image enhancement method, RDU-Net lung lobe segmentation method and HDC Mask R-CNN model were proposed to detect and classify bronchiectasis. Moreover, a Python-based system was developed: after inputing an LDCT image of a patient's lung, it can automatically perform a series of processing, then call on the trained deep learning model for detection and classification, and automatically obtain the patient's bronchiectasis final score according to the Reiff and BRICS scoring criteria. In this paper, the mapping relationship between original lung CT image data and bronchiectasis scoring system was established. The accuracy of the method proposed in this paper was 91.4%; the IOU, sensitivity and specificity were 88.8%, 88.6% and 85.4%, respectively; and the recognition speed of one picture was about 1 s. Compared to a human doctor, the system can process large amounts of data simultaneously, quickly and efficiently, with the same judgment accuracy as a human doctor. Doctors only need to judge the uncertain cases, which significantly reduces the burden of doctors and provides a useful reference for doctors to diagnose the disease.

10.
Surg Endosc ; 2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36002683

RESUMO

BACKGROUND: It is important to identify gallbladder polyps (GPs) with malignant potential and avoid unnecessary cholecystectomy by constructing prediction model. The aim of the study is to develop a Bayesian network (BN) prediction model for GPs with malignant potential in a long diameter of 8-15 mm based on preoperative ultrasound. METHODS: The independent risk factors for GPs with malignant potential were screened by χ2 test and Logistic regression model. Prediction model was established and validated using data from 1296 patients with GPs who underwent cholecystectomy from January 2015 to December 2019 at 11 tertiary hospitals in China. A BN model was established based on the independent risk variables. RESULTS: Independent risk factors for GPs with malignant potential included age, number of polyps, polyp size (long diameter), polyp size (short diameter), and fundus. The BN prediction model identified relationships between polyp size (long diameter) and three other variables [polyp size (short diameter), fundus and number of polyps]. Each variable was assigned scores under different status and the probabilities of GPs with malignant potential were classified as [0-0.2), [0.2-0.5), [0.5-0.8) and [0.8-1] according to the total points of [- 337, - 234], [- 197, - 145], [- 123, - 108], and [- 62,500], respectively. The AUC was 77.38% and 75.13%, and the model accuracy was 75.58% and 80.47% for the BN model in the training set and testing set, respectively. CONCLUSION: A BN prediction model was accurate and practical for predicting GPs with malignant potential patients in a long diameter of 8-15 mm undergoing cholecystectomy based on preoperative ultrasound.

11.
Infect Genet Evol ; 104: 105352, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35998870

RESUMO

To date, many studies have been conducted to investigate associations between variants and tuberculosis risk; however, the results have been inconclusive. Here, we systematically provide a summary of the understanding of the genetic architecture of tuberculosis susceptibility. We searched PubMed, Embase and Web of Science to identify genetic association studies of tuberculosis published through October 31, 2021. We conducted meta-analyses for the genetic association with tuberculosis risk. We graded levels of cumulative epidemiological evidence of significant associations with risk of tuberculosis and false-positive report probability tests. We performed functional annotations for these variants using data from the Encyclopedia of DNA Elements (ENCODE) Project and other databases. We identified 703 eligible articles comprising 298,074 cases and 879,593 controls through screening a total of 24,398 citations. Meta-analyses were conducted for 614 genetic variants in 469 genes or loci. We found 39 variants that were nominally significantly associated with tuberculosis risk. Cumulative epidemiological evidence for a significant association was graded strong for 9 variants in or near 9 genes. Among them, 5 variants were associated with tuberculosis risk in at least three main ethnicity (African, Asian and White) which together explained approximately 9.59% of the familial relative risk of tuberculosis. Data from ENCODE and other databases suggested that 8 of these 9 genetic variants with strong evidence might fall within putative functional regions. Our study summarizes the current literature on the genetic architecture of tuberculosis susceptibility and provides useful data for designing future studies to investigate the genetic association with tuberculosis risk.


Assuntos
Predisposição Genética para Doença , Tuberculose , Estudos de Associação Genética , Humanos , Risco , Tuberculose/epidemiologia , Tuberculose/genética
12.
Acta Pharm Sin B ; 12(4): 1825-1839, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35847509

RESUMO

Vascular abnormality is a hallmark of most solid tumors and facilitates immune evasion. Targeting the abnormal metabolism of tumor endothelial cells (TECs) may provide an opportunity to improve the outcome of immunotherapy. Here, in comparison to vascular endothelial cells from adjacent peritumoral tissues in patients with colorectal cancer (CRC), TECs presented enhanced glycolysis with higher glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Then an unbiased screening identified that osimertinib could modify the GAPDH and thus inhibit its activity in TECs. Low-dose osimertinib treatment caused tumor regression with vascular normalization and increased infiltration of immune effector cells in tumor, which was due to the reduced secretion of lactate from TECs by osimertinib through the inhibition of GAPDH. Moreover, osimertinib and anti-PD-1 blockade synergistically retarded tumor growth. This study provides a potential strategy to enhance immunotherapy by targeting the abnormal metabolism of TECs.

13.
Cell Commun Signal ; 20(1): 107, 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35850889

RESUMO

BACKGROUND: Type 2 diabetes mellitus is a global health problem. It often leads to a decline in the differentiation capacity of myoblasts and progressive loss of muscle mass, which in turn results in deterioration of skeletal muscle function. However, effective therapies against skeletal muscle diseases are unavailable. METHODS: Skeletal muscle mass and differentiation ability were determined in db/+ and db/db mice. Transcriptomics and metabolomics approaches were used to explore the genetic mechanism regulating myoblast differentiation in C2C12 myoblasts. RESULTS: In this study, the relatively uncharacterized solute carrier family gene Slc2a6 was found significantly up-regulated during myogenic differentiation and down-regulated during diabetes-induced muscle atrophy. Moreover, RNAi of Slc2a6 impaired the differentiation and myotube formation of C2C12 myoblasts. Both metabolomics and RNA-seq analyses showed that the significantly differentially expressed genes (e.g., LDHB) and metabolites (e.g., Lactate) during the myogenic differentiation of C2C12 myoblasts post-Slc2a6-RNAi were enriched in the glycolysis pathway. Furthermore, we show that Slc2a6 regulates the myogenic differentiation of C2C12 myoblasts partly through the glycolysis pathway by targeting LDHB, which affects lactic acid accumulation. CONCLUSION: Our study broadens the understanding of myogenic differentiation and offers the Slc2a6-LDHB axis as a potential therapeutic target for the treatment of diabetes-associated muscle atrophy. Video abstract.


Assuntos
Diabetes Mellitus Tipo 2 , Animais , Diferenciação Celular , Diabetes Mellitus Tipo 2/metabolismo , Camundongos , Desenvolvimento Muscular/genética , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/metabolismo , Mioblastos/metabolismo
14.
Front Med (Lausanne) ; 9: 892593, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35783605

RESUMO

Background: Alterations of epigenetic modification patterns are potential markers of cancer. The current study characterized six histone modifications in osteosarcoma and identified epigenetically dysregulated long non-coding RNAs (epi-lncRNAs). Methods: Multi-omics data were obtained from osteosarcoma cell line SJSA1 and a normal cell line. Differentially expressed lncRNAs (DElncRNAs) between osteosarcoma and normal skeletal muscle were analyzed using Limma. MACS2 was applied to identify the "peaks" modified by each histone in the cell. Promoters or enhancers of DElncRNA were overlapped with differential histone-modified regions (DHMR) to screen epi-lncRNAs. Univariate and multivariate Cox regression analysis were performed to detect the genes closely related to the prognosis of osteosarcoma and to construct risk models. Results: A total of 17 symbolic epi-lncRNA in osteosarcoma were screened, and 13 of them were differentially expressed between osteosarcoma and normal samples. Eight epi-lncRNAs were retained by Univariate Cox regression analysis. Four of these epi-lncRNAs were used to construct an epi-lncRNA signature. The risk score of each osteosarcoma sample in the high- or low-risk group was estimated according to the epi-lncRNA signature. The overall survival (OS) of the low-risk group was significantly better than that of the high-risk group. The area under the receiver operating characteristic (ROC) curve of the model was 0.79 and 0.82 for 1-, 3-, and 5-year OS, respectively. Conclusion: Our results revealed the histone modification pattern in osteosarcoma and developed 4-epi-lncRNA signature to predict the prognosis of osteosarcoma, laying a foundation for the identification of highly specific epigenetic biomarkers for osteosarcoma.

15.
Biomater Sci ; 10(15): 4356-4366, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35786722

RESUMO

Hepatitis B represents a major global public health burden, which is caused by the hepatitis B virus (HBV) with a high infection rate. Although several anti-HBV drugs have been developed for clinical treatment of hepatitis B, the current therapeutic strategies still suffer from undeniable adverse effects, insufficient efficacy after systemic administration and chronic inflammation. Here, we develop a carrier-free metal-organic hybrid nanoassembly that is co-loaded with tenofovir (TFV), an anti-viral agent and phosphorylated glycyrrhetinic acid (GAP), an anti-inflammatory compound (TFV/GAP/NA) to enhance the anti-HBV effect and alleviate the inflammatory response for hepatitis B treatment. The nanoassembly is easily prepared through the ionic interactions between the anionic phosphonate/phosphate groups from TFV/GAP and the zirconium cation, which has a stable nanostructure and a high drug-loading capacity. The nanoassembly prolongs the circulation time with reduced drug leakage in the blood and elevates drug accumulation in the liver after intravascular administration. After internalization mediated by the GAP ligand-GA receptor interaction, TFV/GAP/NA disassembles by the phosphatase-triggered degradation of the phosphate ester bonds in GAP and releases TFV, GAP and GA within the HBV-positive hepatocytes. The released TFV interferes with the HBV polymerase to inhibit the viral DNA replication, while the released GAP and GA suppress the pro-inflammatory protein expression. In mouse models, treatment with TFV/GAP/NA inhibits HBV production and alleviates inflammation-mediated liver injury.


Assuntos
Antivirais , Hepatite B , Adenina/farmacologia , Animais , Antivirais/farmacologia , Replicação do DNA , DNA Viral/farmacologia , DNA Viral/uso terapêutico , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/metabolismo , Inflamação/tratamento farmacológico , Camundongos , Organofosfatos , Fosfatos , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Replicação Viral
16.
Sci Total Environ ; 842: 156659, 2022 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-35709994

RESUMO

As the strata sedimentary process proceeds, considerable amounts of nitrogen (N) is buried in sediments, which controls the sources and fate of N in the "groundwater-sediment" system. However, there is little concern regarding N burial characteristics in continuous sediment profiles from surface layer to deep aquifer thus far. In this study, lithology, grain size, geochronology, exchangeable N contents and geochemical proxies of sediments were analyzed to reveal the controlling mechanisms of N burial characteristics in Quaternary sediments and to interpret the enrichment of N in groundwater of central Yangtze River Basin. The results demonstrated a similar distribution trend for buried N in two sedimentary cores, which were high in the surface layer and decreased to stable in the deep aquifer. Excessive exchangeable N (EX-N) contents in sediments were mainly attributed to geologic origin. The N burial characteristics were controlled by the evolution of depositional environment: sedimentary facies determined the concentrations of total organic nitrogen (TON), further affecting the mineralization capacity of sediments; while paleoclimate regulated the intensity of the N transformation processes, ultimately influencing the actual concentrations of EX-N in sediments. In addition, due to the fast accumulation of alluvial deposits after Last Glacial Maximum and rapid development of Jianghan Lake Groups during Holocene, abundant organic matter (with high TON contents) was buried in sediments, which were still able to produce more ammonium or nitrate, and further posing continuous threats to groundwater quality. This study provided a new interpretation for the formation of high-ammonium aquifer in terms of depositional evolution.


Assuntos
Compostos de Amônio , Água Subterrânea , Poluentes Químicos da Água , China , Monitoramento Ambiental , Sedimentos Geológicos/química , Água Subterrânea/química , Nitrogênio/análise , Rios , Poluentes Químicos da Água/análise
17.
Front Bioeng Biotechnol ; 10: 900905, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35721851

RESUMO

Aims: In revision total hip arthroplasty (THA), large acetabular bone defects pose challenges for surgeons. Recently, wide application of trabecular tantalum, which has outstanding biocompatibility and mechanical properties, and the development of three-dimensional (3D) printing have led to the introduction of new schemes for acetabular reconstruction. However, few studies have focused on the treatment of bone defects with customized 3D-printed titanium augments combined with tantalum trabecular cup. Thus, we aimed to evaluate the effect of this therapy in patients who underwent revision THAs. Patients and Methods: We included 23 patients with Paprosky type III acetabular bone defects who underwent revision THA between January 2013 and June 2019. The preoperative hip rotation center and functional score were compared with those at 2-7 years (average 4.7 years) postoperatively to evaluate the midterm prognosis of our treatment choice. Results: Postoperatively, the rotation centres of all hips were comparable with those of the contralateral hips. Hip function improved with average Harris Hip Score improved from 33.5 (22.7-40.2) to 86.1 (73.5-95.6) and average Oxford Hip Score improved from 8.3 (0-14) to 38.8 (35-48) during follow-up. One dislocation, which occurred due to extreme hip flexion within 6 weeks, was treated with closed reduction, and no recurrent dislocation occurred. No nerve injury, infection, aseptic loosening, or osteolysis were observed and no re-revision was performed in any patient. Conclusion: Satisfactory midterm outcomes were obtained with 3D-printed titanium augment combined with tantalum cup for the treatment of acetabular defects in revision THA. Changes in the Harris Hip Score and Oxford Hip Score suggested a significant improvement in hip function.

18.
Front Pharmacol ; 13: 804377, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35694247

RESUMO

Aim: The 20(S)-ginsenoside Rh2 (Rh2) is being developed as a new antitumor drug. However, to date, little is known about the kinetics of its deglycosylation metabolite (protopanoxadiol) (PPD) following Rh2 administration. The aim of this work was to 1) simultaneously characterise the pharmacokinetics of Rh2 and PPD following intravenous and oral Rh2 administration, 2) develop and validate a mechanism-based pharmacokinetic model to describe the deglycosylation kinetics and 3) predict the percentage of Rh2 entering the systemic circulation in PPD form. Methods: Plasma samples were collected from rats after the I.V. or P.O. administration of Rh2. The plasma Rh2 and PPD concentrations were determined using HPLC-MS. The transformation from Rh2 to PPD, its absorption, and elimination were integrated into the mechanism based pharmacokinetic model to describe the pharmacokinetics of Rh2 and PPD simultaneously at 10 mg/kg. The concentration data collected following a 20 mg/kg dose of Rh2 was used for model validation. Results: Following Rh2 administration, PPD exhibited high exposure and atypical double peaks. The model described the abnormal kinetics well and was further validated using external data. A total of 11% of the administered Rh2 was predicted to be transformed into PPD and enter the systemic circulation after I.V. administration, and a total of 20% of Rh2 was predicted to be absorbed into the systemic circulation in PPD form after P.O. administration of Rh2. Conclusion: The developed model provides a useful tool to quantitatively study the deglycosylation kinetics of Rh2 and thus, provides a valuable resource for future pharmacokinetic studies of glycosides with similar deglycosylation metabolism.

19.
Front Psychol ; 13: 869468, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35645926

RESUMO

This paper explores the differences in high-accuracy and low-accuracy learners' beliefs about corrective feedback when learning Chinese as a second language (henceforth, CSL). In this study, we collected data through a questionnaire survey and an oral test with 76 CSL learners in a Chinese university. The analysis revealed that both high- and low-accuracy CSL learners shared the same beliefs in whether and how the learner errors should be corrected but differed in their beliefs about when is the best time to correct, which error should be corrected, and who the corrector should be. Specifically, the discrepancy between high- and low-accuracy groups' beliefs about corrective feedback was found to be related to the participants' oral accuracy. Our results confirm that learners' CF beliefs can modulate their language accuracy. The corrective feedback beliefs held by high-accuracy groups have implications for improving low-accuracy groups' oral accuracy. Through comparison with findings on corrective feedback beliefs of English as a foreign/second language (henceforth, EFL/ESL) learners, this study suggested that language pedagogies developed from the research of EFL/ESL learners' CF beliefs should be able to shed light on this area and have significance for CSL learners. Implications for correcting learner errors in teaching CSL are also provided in the paper.

20.
Front Med (Lausanne) ; 9: 897392, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35646981

RESUMO

Heterotopic ossification (HO) occurs when bone forms within non-ossifying tissues, such as in muscle. Palovarotene, an activator of retinoic acid receptor γ (RAR-γ), has been shown to inhibit the formation of ectopic bone in HO model mice, but its specific mechanism of action remains unclear. This study will explore the target and molecular mechanism of Palovarotene's action on HO by network pharmacology study. We collected the relevant targets of Palovarotene and HO from the database, obtained the potential targets of Palovarotene acting on HO through Venn analysis, and constructed the protein-protein interaction (PPI) network. Then, Gene Ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment Analysis and Module-based Network Analysis were performed for potential targets, and in addition, PPI Network Topology Analysis and Gene-Phenotype Correlation Analysis were performed. The results suggested that MAPK1, MDM2, and other targets as well as P53 signaling pathway and PI3K-Akt signaling pathway may be closely related to Palovarotene treatment of HO. We carried out verification experiments to confirm our finding, alkaline phosphatase and alizarin red staining in vitro and Micro-CT as well as hematoxylin-eosin staining in vivo were performed to verify treatment for HO of Palovarotene, reverse transcription polymerase chain reaction was also used to explore the transcription changes of MAPK1, MDM2, and osteogenic genes. This study systematically elucidated the possible mechanism of Palovarotene in the treatment of HO through network pharmacology study, revealing a new direction for the further application of Palovarotene in the treatment of HO.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...