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1.
Molecules ; 29(6)2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38542935

RESUMO

The phase, mechanical properties, corrosion resistance, hydrophobicity, and interfacial contact resistance of Hastelloy X were investigated to evaluate its performance in proton exchange membrane fuel cells (PEMFCs). For comparison, the corresponding performance of 304 stainless steel (304SS) was also tested. Hastelloy X exhibited a single-phase face-centered cubic structure with a yield strength of 445.5 MPa and a hardness of 262.7 HV. Both Hastelloy X and 304SS exhibited poor hydrophobicity because the water contact angles were all below 80°. In a simulated PEMFC working environment (0.5 M H2SO4 + 2 ppm HF, 80 °C, H2), Hastelloy X exhibited better corrosion resistance than 304SS. At 140 N·cm-2, the interfacial contact resistance of Hastelloy X can reach as low as 7.4 mΩ·cm2. Considering its overall performance, Hastelloy X has better potential application than 304SS as bipolar plate material in PEMFCs.

2.
Shock ; 61(3): 454-464, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38412105

RESUMO

ABSTRACT: Immunosuppression, commonly accompanied by persistent inflammation, is a key feature in the later phase of sepsis. However, the pathophysiological mechanisms underlying this phenomenon remain unclear. Dendritic cells (DCs), specifically tolerogenic DCs (tolDCs), play a crucial role in this process by regulating immune responses through inducing T cell anergy and releasing anti-inflammatory cytokines. Nevertheless, the existing cell models are inadequate for investigating tolDCs during the immunosuppressive phase of sepsis. Therefore, this study aimed to develop a novel in vitro model to generate tolDCs under chronic inflammatory conditions. We have successfully generated tolDCs by exposing them to sublethal lipopolysaccharide (LPS) for 72 h while preserving cell viability. Considering that IL-10-induced tolDCs (IL-10-tolDCs) are well-established models, we compared the immunological tolerance between LPS-tolDCs and IL-10-tolDCs. Our findings indicated that both LPS-tolDCs and IL-10-tolDCs exhibited reduced expression of maturation markers, whereas their levels of inhibitory markers were elevated. Furthermore, the immunoregulatory activities of LPS-tolDCs and IL-10-tolDCs were found to be comparable. These dysfunctions include impaired antigen presenting capacity and suppression of T cell activation, proliferation, and differentiation. Notably, compared with IL-10-tolDCs, LPS-tolDCs showed a reduced response in maturation and cytokine production upon stimulation, indicating their potential as a better model for research. Overall, in comparison with IL-10-tolDCs, our data suggest that the immunological dysfunctions shown in LPS-tolDCs could more effectively elucidate the increased susceptibility to secondary infections during sepsis. Consequently, LPS-tolDCs have emerged as promising therapeutic targets for ameliorating the immunosuppressed state in septic patients.


Assuntos
Interleucina-10 , Sepse , Humanos , Interleucina-10/metabolismo , Células Dendríticas/metabolismo , Lipopolissacarídeos/farmacologia , Tolerância Imunológica , Sepse/metabolismo , Inflamação/metabolismo
3.
Dig Dis Sci ; 69(3): 798-810, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38334934

RESUMO

BACKGROUND: Currently, the mechanisms of impaired gut mucosal immunity in sepsis remain unclear. Gut immunoglobulin A (IgA) is an important defense mechanism against invasive pathogens, and CD4+ T cells regulate the IgA response. AIM: We aimed to verify the hypothesis indicating that CD4+ T pyroptosis induced by lipopolysaccharide (LPS) leads to an impaired gut IgA response and subsequent bacterial translocation and organ damage. METHODS: Cultured CD4+ T cells and mice were manipulated with LPS, and pyroptosis was improved by A438079 or adoptive CD4+ T cell transfer. The changes demonstrated in pyroptosis-related molecules, cytotoxicity and CD4+ T cells were examined to determine CD4+ T pyroptosis. The changes demonstrated in IgA+ B cells, AID (key enzyme for immunoglobulins) and IgA production and function were examined to evaluate the IgA response. Serum biomarkers, bacterial colonies and survival analysis were detected for bacterial translocation and organ damage. RESULTS: LPS attack induced CD4+ T pyroptosis, as evidenced by increased expression of P2X7, Caspase-11 and cleaved GSDMD, which elevated cytotoxicity and decreased CD4+ T cells. Decreased CD4+ T subsets (Foxp3+ T and Tfh cells) influenced the IgA response, as evidenced by lower AID expression, which decreased IgA+ B cells and IgA production and function. A438079 or cell transfer improved the IgA response but failed to reduce the translocation of gut pathogens, damage to the liver and kidney, and mortality of mice. CONCLUSION: LPS attack results in CD4+ T pyroptosis. Improvement of pyroptosis restores the mucosal IgA response but fails to ameliorate bacterial translocation and organ damage.


Assuntos
Imunoglobulina A , Lipopolissacarídeos , Camundongos , Animais , Lipopolissacarídeos/toxicidade , Piroptose , Translocação Bacteriana , Linfócitos T CD4-Positivos
4.
Plant Cell ; 36(3): 709-726, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38000892

RESUMO

Fruit softening, an irreversible process that occurs during fruit ripening, can lead to losses and waste during postharvest transportation and storage. Cell wall disassembly is the main factor leading to loss of fruit firmness, and several ripening-associated cell wall genes have been targeted for genetic modification, particularly pectin modifiers. However, individual knockdown of most cell wall-related genes has had minimal influence on cell wall integrity and fruit firmness, with the notable exception of pectate lyase. Compared to pectin disassembly, studies of the cell wall matrix, the xyloglucan-cellulose framework, and underlying mechanisms during fruit softening are limited. Here, a tomato (Solanum lycopersicum) fruit ripening-associated α-expansin (SlExpansin1/SlExp1) and an endoglucanase (SlCellulase2/SlCel2), which function in the cell wall matrix, were knocked out individually and together using clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9-mediated genome editing. Simultaneous knockout of SlExp1 and SlCel2 enhanced fruit firmness, reduced depolymerization of homogalacturonan-type pectin and xyloglucan, and increased cell adhesion. In contrast, single knockouts of either SlExp1 or SlCel2 did not substantially change fruit firmness, while simultaneous overexpression of SlExp1 and SlCel2 promoted early fruit softening. Collectively, our results demonstrate that SlExp1 and SlCel2 synergistically regulate cell wall disassembly and fruit softening in tomato.


Assuntos
Celulase , Solanum lycopersicum , Frutas/metabolismo , Solanum lycopersicum/genética , Celulase/genética , Celulase/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Pectinas/metabolismo , Parede Celular/metabolismo
5.
Biomolecules ; 13(12)2023 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-38136662

RESUMO

Pre-eclampsia (PE) is a severe pregnancy disorder that poses a significant health risk to both mother and fetus, with no preventive or therapeutic measures. Our previous research suggested an association between elevated SERPINA5 levels and PE features. This study investigated whether SERPINA5 could be a potential therapeutic target for PE. We established PE-like features in pregnant rats using L-NAME (75 mg/kg/d) treatment. Adenoviruses carrying overexpressed or suppressed SERPINA5 genes were intravenously injected into these PE rats on the fifth and seventh days of pregnancy. We evaluated the rats' systolic blood pressure, urine protein concentration, and placental and fetal metrics and histology. Placental gene expression following SERPINA5 overexpression was evaluated using mRNA sequencing. The L-NAME-induced PE rat model observed a significant increase in placental and peripheral SERPINA5 levels. The overexpression of SERPINA5 exacerbated L-NAME-induced hypertension and proteinuria in pregnant rats. A histology examination revealed a smaller placental junctional zone in L-NAME + overexpressing rats. Placental gene expression analysis in the L-NAME + overexpressing group indicated increased coagulation activation. L-NAME-induced hypertension and proteinuria were mitigated when SERPINA5 expression was suppressed. Additionally, placental development was improved in the SERPINA5-suppressed group. Our findings suggested that SERPINA5 may worsen L-NAME-induced PE-like features by promoting the activation of the coagulation cascade. Therefore, reducing SERPINA5 expression could potentially serve as a therapeutic strategy for PE.


Assuntos
Hipertensão , Pré-Eclâmpsia , Humanos , Ratos , Gravidez , Feminino , Animais , Pré-Eclâmpsia/induzido quimicamente , Pré-Eclâmpsia/genética , Placenta/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Proteinúria/metabolismo , Hipertensão/metabolismo , Inibidor da Proteína C/metabolismo , Inibidor da Proteína C/uso terapêutico
6.
NPJ Digit Med ; 6(1): 231, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38097771

RESUMO

The monitoring of physiological parameters is a crucial topic in promoting human health and an indispensable approach for assessing physiological status and diagnosing diseases. Particularly, it holds significant value for patients who require long-term monitoring or with underlying cardiovascular disease. To this end, Visual Contactless Physiological Monitoring (VCPM) is capable of using videos recorded by a consumer camera to monitor blood volume pulse (BVP) signal, heart rate (HR), respiratory rate (RR), oxygen saturation (SpO2) and blood pressure (BP). Recently, deep learning-based pipelines have attracted numerous scholars and achieved unprecedented development. Although VCPM is still an emerging digital medical technology and presents many challenges and opportunities, it has the potential to revolutionize clinical medicine, digital health, telemedicine as well as other areas. The VCPM technology presents a viable solution that can be integrated into these systems for measuring vital parameters during video consultation, owing to its merits of contactless measurement, cost-effectiveness, user-friendly passive monitoring and the sole requirement of an off-the-shelf camera. In fact, the studies of VCPM technologies have been rocketing recently, particularly AI-based approaches, but few are employed in clinical settings. Here we provide a comprehensive overview of the applications, challenges, and prospects of VCPM from the perspective of clinical settings and AI technologies for the first time. The thorough exploration and analysis of clinical scenarios will provide profound guidance for the research and development of VCPM technologies in clinical settings.

7.
Chem Commun (Camb) ; 59(88): 13147-13150, 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37850533

RESUMO

Herein, a septenary NiCoZnFeCuMnCe hydroxide nanoarray catalyst with a unique wire-on-sheet morphology and high-entropy feature was fabricated, which exhibits boosted pre-oxidation behavior and synergistically enhanced catalytic activity and durability towards the oxygen evolution reaction.

8.
Environ Pollut ; 336: 122458, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37633433

RESUMO

Chemicals are widely used and released into the environment, and their degradation, accumulation, migration, and transformation processes in the environment can pose a threat to the ecosystem. The advancement in analytical methods with high-throughput screening of biomolecules has revolutionized the way toxicologists used to explore the effects of chemicals on organisms. CRISPR/Cas is a newly developed tool, widely used in the exploration of basic science and biologically engineered products given its high efficiency and low cost. For example, it can edit target genes efficiently, and save loss of the crop yield caused by environmental pollution as well as gain a better understanding of the toxicity mechanisms from various chemicals. This review briefly introduces the development history of CRISPR/Cas and summarizes the current application of CRISPR/Cas in ecotoxicology, including its application on improving crop yield and drug resistance towards agricultural pollution, antibiotic pollution and other threats. The benefits by applying the CRISPR/Cas9 system in conventional toxicity mechanism studies are fully demonstrated here together with its foreseeable expansions in other area of ecotoxicology. Finally, the prospects and disadvantages of CRISPR/Cas system in the field of ecotoxicology are also discussed.

9.
Clin Ther ; 45(4): 316-332, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36973090

RESUMO

PURPOSE: Aspirin is widely used in patients in the intensive care unit (ICU); nonetheless, its effects on these patients remain controversial. This retrospective analysis of data from clinical practice investigated the effects of aspirin on 28-day mortality in ICU patients. METHODS: This retrospective study included data from patients in the Medical Information Mart for Intensive Care (MIMIC)-III database and the eICU-Collaborative Research Database (CRD). Patients aged 18 to 90 years and admitted to the ICU were eligible and were assigned to one of two groups according to whether they were given aspirin during their ICU stay. Multiple imputation was used for patients with >10% missing data. Multivariate Cox models and propensity score analysis were used to estimate the association of aspirin treatment with 28-day mortality among patients admitted to the ICU. FINDINGS: In total, 146,191 patients were enrolled in this study, and 27,424 (18.8%) used aspirin. Aspirin treatment in ICU patients, especially in nonseptic patients, was associated with a lower 28-day all-cause mortality on multivariate Cox analysis (eICU-CRD, hazard ratio [HR] = 0.81, [95% CI, 0.75-0.87]; MIMIC-III, HR = 0.72 [95% CI, 0.68-0.76]). Aspirin treatment was associated with lower 28-day all-cause mortality after propensity score matching (eICU-CRD, HR = 0.80 [95% CI, 0.72-0.88]; MIMIC-III, HR = 0.80 [95% CI, 0.76-0.85]). However, on subgroup analysis, aspirin therapy was not associated with a lower 28-day mortality in patients without systemic inflammatory response syndrome (SIRS) symptoms or with sepsis in either database. IMPLICATIONS: Aspirin treatment during the ICU stay was associated with a significantly reduced 28-day all-cause mortality, particularly in patients with SIRS symptoms but without sepsis. In patients with sepsis and with/without SIRS symptoms, beneficial effects were not clear, or more careful patient selection is required.


Assuntos
Cuidados Críticos , Sepse , Humanos , Estudos Retrospectivos , Síndrome de Resposta Inflamatória Sistêmica , Unidades de Terapia Intensiva , Aspirina/uso terapêutico
10.
Micromachines (Basel) ; 14(2)2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36838002

RESUMO

In this paper, we propose and investigate an electrically doped (ED) PNPN tunnel field effect transistor (FET), in which the drain side tunneling barrier width is effectively controlled to obtain a suppressed ambipolar current. We present that the proposed PNPN tunnel FETs can be realized without chemically doped junctions by applying the polarity bias concept to a doped N+/P- starting structure. Using numerical device simulations, we demonstrate how the tunneling barrier width on the drain side can be influenced by several design parameters, such as the gap length between the channel and the drain (Lgap), the working function of the polarity gate, and the dielectric material of the spacer. The simulation results show that an ED PNPN tunneling FET with an ED drain, which has been explored for the first time, exhibits a low ambipolar current of 5.87 × 10-16 A/µm at a gap length of 20 nm. The ambipolar current is reduced by six orders of magnitude compared to that which occurs with a conventional ED PNPN tunnel FET with a uniformly doped drain, while the average subthreshold slope and the ON state and OFF state currents remained nearly identical.

11.
Int J Oncol ; 62(3)2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36799168

RESUMO

Studies on clear cell renal cell carcinoma (ccRCC) are gaining momentum due to its high malignancy and potential to metastasize. F­box protein 30 (FBXO30) is a member of the F­box protein family; however, its role and mechanism in cancer remains to be fully elucidated. Western blotting, reverse transcription­quantitative PCR and immunohistochemsitry were performed to detect the expression levels of FBXO30 in ccRCC tissues and adjacent normal tissues. Tumor biological function assays and animal experiments were conducted to clarify the inhibitory effect of FBXO30 on the progression and metastasis of ccRCC. Protein half­life assay, MG132 inhibition assay, immunofluorescence assay and co­immunoprecipitation assay were performed to explore the ubiquitination mechanism of FBXO30 and HIF­1α. Zinc supplementation assay was used to verify the regulatory relationship between human ZRT, IRT­like protein 1 (hZIP1), FBXO30 and HIF­1α. The present study revealed that the expression levels of FBXO30 were lower in ccRCC tissues compared with those in normal adjacent tissues. In addition, FBXO30 inhibited the tumorigenesis and metastatic capacity of ccRCC cells in vivo and in vitro. FBXO30 mediated the ubiquitination and degradation of hypoxia­inducible factor­1α (HIF­1α) in ccRCC cells under normoxia, thereby inhibiting the oncogenic effect of HIF­1α. Notably, hZIP1 served as an upstream regulator of FBXO30, regulating the expression of FBXO30 and HIF­1α by recruiting Zn2+. In conclusion, the present data suggested that FBXO30 is a novel E3 ubiquitination ligase that can function as a tumor suppressor in ccRCC, and the hZIP1/Zn2+/FBXO30/HIF­1α axis may provide potential biomarkers or therapeutic targets for ccRCC.


Assuntos
Carcinoma de Células Renais , Proteínas F-Box , Neoplasias Renais , Animais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas F-Box/genética , Proteínas F-Box/metabolismo
12.
Front Cell Dev Biol ; 10: 977960, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36407113

RESUMO

Purpose: Accumulating evidence suggests that solute carrier family 39 member 1 (SLC39A1) conceivably function as a tumor suppressor, but the underlying mechanism in renal cell carcinoma (RCC) is poorly understood. Methods: OSRC-2 renal cancer cells were first transfected with SLC39A1 overexpressed vectors and empty vectors and then used in transcriptomics, proteomics, and metabolomics integrated analyses. Results: SLC39A1 significantly altered several metabolisms at transcriptional, protein and metabolic levels, including purine and pyrimidine metabolism, amino acids and derivatives metabolism, lactose metabolism, and free fatty acid metabolism. Additionally, SLC39A1 could promote ferroptosis, and triggered significant crosstalk in PI3K-AKT signal pathway, cAMP signal pathway, and peroxisome proliferators-activated receptor (PPAR) signal pathway. Conclusion: We found SLC39A1 transfection impaired tumor metabolism and perturbed tumor metabolism-related pathways, which was a likely cause of the alteration in cell proliferation, migration, and cell cycle progression in RCC cells. These multi-omics analyses results provided both a macroscopic picture of molecular perturbation by SLC39A1 and novel insights into RCC tumorigenesis and development.

13.
Front Plant Sci ; 13: 1022023, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36388545

RESUMO

Breeding cultivars that can maintain high production and water productivity (WP) under various growing conditions would be important for mitigating freshwater shortage problems. Experiments were carried out to assess the changes in yield and WP of different cultivars by breeding and traits related to the changes using tubes with 1.05 m depth and 19.2 cm inner diameter buried in the field located in the North China Plain. Six winter wheat cultivars released from the 1970s to 2010s were assessed under three water levels for three seasons. The results indicated that yield was on average improved by 19.9% and WP by 21.5% under the three water levels for the three seasons for the cultivar released in the 2010s as compared with that released in the 1970s. The performance of the six cultivars was relatively stable across the experimental duration. The improvement in yield was mainly attributed to the maintenance of higher photosynthetic capacity during the reproductive growth stage and greater above-ground biomass accumulation. These improvements were larger under wet conditions than that under dry conditions, indicating that the yield potential was increased by cultivar renewal. Traits related to yield and WP improvements included the increased harvest index and reduced root: shoot ratio. New cultivars reduced the redundancy in root proliferation in the topsoil layer, which did not compromise the efficient utilization of soil moisture but reduced the metabolic input in root growth. Balanced above- and below-ground growth resulted in a significant improvement in root efficiency at grain yield level up to 40% from the cultivars released in the 1970s to those recently released. The results from this study indicated that the improved efficiency in both the above- and below-parts played important roles in enhancing crop production and resource use efficiency.

14.
Front Pharmacol ; 13: 1019109, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36278213

RESUMO

Gut-vascular barrier (GVB) serves as the last barrier to limit the migration of intestinal toxins into the blood circulation. The efficacy of terlipressin (a vasopressin V1 receptor agonist) in reducing GVB and multiple organ damage in gut-derived sepsis is unknown. In this study, we hypothesized that, besides other intestinal barriers, GVB play a key role in gut-derived sepsis and terlipressin improve GVB damage and then reduce bacterial translocation and organ injuries. In vivo, a cecal ligation and puncture mouse model was established. The mice were subjected to examine the damage of GVB determined by intestinal plasmalemma vesicle-associated protein-1(PV-1) and vascular endothelial-cadherin. And the intestinal permeability was assessed by translocation of intestinal bacteria and macromolecules. In vitro, transendothelial electrical resistance (TER) during interleukin (IL)-1ß stimulation was measured on endothelial cells with or without small interfering RNA targeting ß-catenin (si ß-catenin). Terlipressin significantly improved GVB damage and reduced translocation of intestinal macromolecules and bacteria by activating PI3K signaling. Of note, intestinal PV-1 expression was significantly correlated with translocation of macromolecules, and dramatic increase of macromolecules was observed in intestinal tissues whereas fewer macromolecules and bacteria were observed in blood, liver and lung following terlipressin treatment. In vitro, terlipressin restored TER during IL-1ß stimulation and si ß-catenin transfection blocked the changes delivered by terlipressin. Collectively, terlipressin alleviated GVB damage and subsequent bacterial translocation via blood vessels after sepsis challenge, resulting in reduced distant organ injuries and the responsible mechanisms may involve the activation of PI3K/ß-catenin pathway.

15.
Cytotechnology ; 74(4): 491-502, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36110152

RESUMO

Proteasome 20S Subunit Beta 2 (PSMB2) has been suggested to play several roles in cancer. However, the role of PSMB2 and its underlying mechanisms in gastric cancer have not been studied. In this study, qRT-PCR was employed to detect the expression of genes that encode for 26 s proteasome subunit proteins. PSMB2 expression and its prognostic ability were assessed by collecting patient tissue samples and reviewing the TCGA and Kaplan-Meier Plotter databases. Immunofluorescence and western blotting experiments were performed to evaluate the expression of PSMB2 in human gastric cancer cells and normal gastric epithelial cells. Subsequently, PSMB2 was knocked down in HGC-27 and SNU-1 cells and overexpressed in N-87 and AGS cells. Proteasome activity assays, 5-Ethynyl-2'-deoxyuridine staining, and TUNEL assays were used to assess proteasome activity, cell proliferation, and apoptosis. Tumor xenograft assays were conducted to evaluate PSMB2 function in vivo. Our results showed that a total of 8 genes encoding for the 26 s proteasome subunit protein were highly expressed in a variety of gastric cancer cells. Next, PSMB2 was selected as the focus of subsequent studies which showed that PSMB2 was highly expressed in samples of gastric cancer tissue. Furthermore, a review of the TCGA database revealed that a high level of PSMB2 expression was associated with a poor clinical prognosis. Our results indicated that PSMB2 overexpression promoted proteasome activity, cell proliferation, and suppressed the apoptosis of gastric cancer cells, while those effects were reversed by treatment with a proteasome inhibitor (MG132). In contrast, PSMB2 knockdown produced the opposite effects and also blocked NRF1 activation. Moreover, PSMB2 knockdown inhibited tumor growth in vivo, decreased PSMB2 expression and cell proliferation, and promoted apoptosis in tumor tissues. Our findings revealed the role played by PSMB2 in gastric cancer and suggest PSMB2 as a new target molecule for use in diagnosing and treating gastric cancer.

16.
Arch Pharm (Weinheim) ; 355(10): e2200171, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35661405

RESUMO

In recent years, small-molecule inhibitors targeting the autotaxin (ATX)/lysophosphatidic acid axis gradually brought excellent disease management benefits. Herein, a series of imidazo[1,2-a]pyridine compounds (1-11) were designed as ATX inhibitors through a hybrid strategy by combining the imidazo[1,2-a]pyridine skeleton in GLPG1690 and the benzyl carbamate moiety in PF-8380. As indicated by FS-3-based enzymatic assay, the carbamate derivatives revealed moderate to satisfying ATX inhibitory potency (IC50 = 23-343 nM). Subsequently, the carbamate linker was altered to a urea moiety (12-19) with the aim of retaining ATX inhibition and improving the druglikeness profile. The binding mode analysis all over the modification process well rationalized the leading activity of urea derivatives in an enzymatic assay. Following further structural optimization, the diethanolamine derivative 19 exerted an amazing inhibitory activity (IC50 = 3.98 nM) similar to the positive control GLPG1690 (IC50 = 3.72 nM) and PF-8380 (IC50 = 4.23 nM). Accordingly, 19 was tested directly for in vivo antifibrotic effects through a bleomycin model (H&E staining), in which 19 effectively alleviated lung structural damage and fibrosis at an oral dose of 20 and 60 mg/kg. Collectively, 19 qualified as a promising ATX inhibitor for potential application in fibrosis-relevant disease treatment.


Assuntos
Diester Fosfórico Hidrolases , Piridinas , Bleomicina , Carbamatos , Fibrose , Humanos , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade , Ureia
17.
Wideochir Inne Tech Maloinwazyjne ; 17(1): 134-142, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35251398

RESUMO

INTRODUCTION: Patients who undergo video-assisted thoracic surgery (VATS) frequently experience moderate to severe postoperative pain. Serratus anterior plane block (SAPB) is a relatively novel technique that can block the lateral cutaneous branches of the intercostal nerves as well as the long thoracic nerve. AIM: To evaluate the analgesic efficiency of deep serratus plane block (DSPB) and superficial serratus anterior plane block (SSPB) as well as paravertebral nerve block (PVB) in patients undergoing VATS. MATERIAL AND METHODS: A total of 74 patients aged 16-80 undergoing VATS were randomized to receive either DSPB or SSPB as well as PVB. Ultrasound (US) guided DSPB or SSPB as well as PVB was performed preoperatively on the patients according to their groups. All patients were provided with patient-controlled intravenous analgesia (PCIA) for postoperative analgesia. The primary outcomes were the levels of postoperative pain at rest and on coughing evaluated by the visual analog scale (VAS), and intraoperative and postoperative opioid consumption. The secondary outcomes included PCIA pressing times, side effects and satisfaction with analgesia, duration of nerve block, intraoperative hemodynamic changes and vasoactive drug dosage. RESULTS: No significant differences of VAS score were found. During the operation, PVB reduced consumption of opioids (27.23 ±5.10 mg) compared to DSPB (31.20 ±3.80 mg) and SSPB (32.61 ±5.28 mg). The effective pressing times of PCIA in the SSPB group (0.18 ±0.65) were significantly lower compared to the PVB group (1.09 ±1.50) at 12 h postoperatively. Accordingly, SSPB also reduced the dosage of PCIA (26.55 ±4.72 ml) compared to PVB (31.45 ±7.60 ml). Time of the PVB procedure was longer (11.14 ±1.66 min) than DSPB (5.68 ±1.10 min) and SSPB (4.77 ±1.04 min). CONCLUSIONS: DSPB and SSPB are easy to perform and can serve as a promising alternative technique to PVB that may offer comparable analgesic effectiveness for patients undergoing VATS.

18.
Future Med Chem ; 14(6): 407-419, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35192400

RESUMO

Background: Colorectal cancer (CRC) is a malignancy with high mortality. TSPYL2 participates in tumor suppression but its role in CRC remains unknown. Methodology & results: TSPYL2 was downregulated and SIRT1 was upregulated in gefitinib drug-resistant (GEF-DR) tissues of patients with CRC. The GEF-resistant cells, HCT116 and HCT-15, were successfully established. The knockdown of TSPYL2 promoted resistance to GEF in CRC cells. Interestingly, immunofluorescence and western blot assays demonstrated that TSPYL2 inhibited DNA damage repair in HCT-15 and HCT116 GEF-resistant cells. Mechanically, TSPYL2 reduced the resistance to GEF and inhibited DNA damage repair via suppressing SIRT1-mediated FOXO3 deacetylation. TSPYL2 consistently inhibited tumor growth and decreased resistance to GEF in vivo. Conclusion: TSPYL2 reduced resistance to GEF and suppressed DNA damage through downregulating SIRT1-mediated FOXO3 deacetylation, indicating that TSPYL2 might be a novel therapeutic target in CRC.


Assuntos
Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Sirtuína 1 , Dano ao DNA , Proteína Forkhead Box O3 , Gefitinibe/farmacologia , Células HCT116 , Humanos
19.
J Hazard Mater ; 430: 128374, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35150992

RESUMO

From the perspective of environmental protection and resource recovery, recycling of spent lithium-ion batteries is a meaningful process. In this study, the removal of organics, liberatioin of electrode material, and reduction of high valence transition metal, as the key points in recycling efficiency of valuable metals, have been firstly achieved simultaneously by low temperature heat treatment recycling process. Pyrolysis characteristics of organics, phase transition behavior of spent cathode material and the thermal reduction mechanism were evaluated in the meantime. Results demonstrate that organics can be removed and the liberation of electrode materials can be improved by pyrolysis. High-valence transition metals in cathode materials are synchronously reduced to CoO, NiO, MnO, Ni, and Co based on the reducing action of organics, aluminum foil and conductive additives. At the same time, Li element exists in the form of Li2CO3, LiF and aluminum-lithium compound that can be recycled by water-leaching in the water impact crushing process while transition metals can be recycled by acid leaching without reducing agents. 81.26% of Li can be recycled from water-leaching process while the comprehensive recovery rate of Ni, Co, Mn is 92.04%, 93.01%, 92.21%, respectively. This study may provide an environmentally-friendly recycling flowchart of spent lithium-ion batteries.

20.
J Minim Access Surg ; 18(2): 241-247, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33885016

RESUMO

BACKGROUND: This study was to determine the analgesic effect of ultrasound-guided erector spinae plane block (ESPB) and paravertebral block (PVB) as well as the combination of PVB and ESPB (P + E) after video-assisted thoracoscopic surgery (VATS). PATIENTS AND METHODS: Patients were randomly assigned to receive ESPB, PVB or PVB combined with ESPB with 0.5% ropivacaine (20 ml). The primary outcomes were cumulative hydromorphone consumption and Visual Analogue Scale (VAS) scores at rest and while coughing at 0 h, 12 h, 24 h, 48 h and 72 h postoperatively. The secondary outcomes were effective PCA usage count and rescue analgesia requirement at the same time points. RESULTS: The median (interquartile range) hydromorphone consumption, including converted oxycodone, was significantly different at 48 h postoperatively among the three groups (ESPB, 10.24 [9.53-11.71] mg; PVB, 9.94 [9.19-10.75] mg; P + E, 9.44 [8.96-9.97] mg; P = 0.011). Hydromorphone consumption in P + E group was lower compared with that in ESPB group at 12 h, 24 h and 48 h (P < 0.001, P = 0.004 and P = 0.003, respectively). VAS scores at rest were significantly higher for ESPB group compared to P + E group at 0 h postoperatively (P = 0.009). VAS scores while coughing were significantly higher for ESPB group compared to P + E group at 0 h and 12 h postoperatively (P = 0.015 and P < 0.001) and to the PVB group at 12 h postoperatively (P = 0.002). The effective PCA usage count in P + E group was lower than in ESPB group in 0-12 h (P < 0.001). More patients needed rescue analgesia in ESPB group compared to those in P + E group in 0-12 h, 0-24 h and 0-48 h (P = 0.022, 0.035 and 0.035, respectively). CONCLUSIONS: Ultrasound-guided PVB combined with ESPB provided superior analgesia to ESPB for VATS. The combination of PVB and ESPB had a similar analgesic effect compared with PVB alone.

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