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2.
J Ethnopharmacol ; 334: 118539, 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38986754

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Anemarrhena asphodeloides Bunge (Ane) and Phellodendron chinense C. K. Schneid (Phe) is classical herb pair in traditional Chinese medicine, commonly used to ameliorate the symptoms of Benign Prostatic Hyperplasia (BPH). However, the mechanisms underlying this effect are remained indistinct. AIM OF THE STUDY: This study aimed to clarify potential therapeutic mechanisms of herb pair on BPH from a metabolic perspective. MATERIALS AND METHODS: Testosterone propionate-induced BPH rat model was established, prostatic parameters, histopathology and the levels of serum dihydrotestosterone (DHT) and testosterone (T) were used to evaluate the pharmacological effect of the herb pair on BPH. Subsequently, untargeted metabolomics of prostate tissues samples was performed by UHPLC-Q-Exactive-Orbitrap-MS, followed by multivariate statistical analysis. Targeted metabolomics by UHPLC-QQQ-MS was further utilized to verify and supplement the results of lipids and amino acids found by untargeted metabolomics, clarifying the relationship between disease, herbal pair and metabolism pathway. RESULTS: The study found that Ane-Phe could relieve the progression of BPH and regulate metabolic imbalances. The levels of 13 metabolites decreased and 11 increased in prostatic tissues including glycerolphospholipid, arachidonic acid, citric acid and so on, these altered metabolites were primarily associated with TCA cycle, arachidonic acid metabolism, lipid metabolism and amino acid metabolism. Furthermore, targeted metabolomics was fulfilled to further analyze the lipid metabolism disorders, the levels of 5 lipids in serum and 21 in prostatic tissues were changed in the herb pair group compared to the model group, which closely related to glycerophospholipid, sphingolipid and glycerolipid metabolism. Besides, amino acid metabolism may be regulated by activating arginine metabolism pathway. CONCLUSIONS: In this study, the combination of untargeted metabolomics and targeted metabolomics was applied to explore therapeutic mechanisms of Ane-Phe on BPH. In summary, Ane-Phe could improve the levels of endogenous metabolites by regulating multiple metabolic pathways and plays a role in energy supply, anti-inflammation and oxidative stress in BPH treatment.

3.
J Med Chem ; 2024 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-39031090

RESUMEN

Targeting the programmed cell death-1/ligand 1 (PD-1/PD-L1) pathway is one of the most promising cancer treatment strategies. Studies have shown that HDAC inhibitors can enhance the antitumor immune response by modulating the expression of PD-L1. Herein, we designed and synthesized a series of novel hydrazide-based small molecule HDAC inhibitors; among them, compound HQ-30 showed selective HDAC3 inhibition (IC50 = 89 nM) and remarkable PD-L1-degrading activity (DC50 = 5.7 µM, Dmax = 80% at 10 µM). Further studies revealed that HQ-30 induced the degradation of PD-L1 by regulating cathepsin B (CTSB) in the lysosomes. Further, HQ-30 could enhance the infiltration of CD3+ CD4+ helper T and CD3+ CD8+ cytotoxic T cells in tumors, thus activating the tumor immune microenvironment. Moreover, HQ-30 possessed a benign toxicity profile (LD50 > 1000 mg/kg) and favorable pharmacokinetic properties (F = 57%). Taken together, HQ-30 is worthy of further investigation as a small molecule-based epigenetic modulator of tumor immunotherapy.

4.
ACS Appl Mater Interfaces ; 16(24): 31294-31303, 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38838350

RESUMEN

Photodetector technology has evolved significantly over the years with the emergence of new active materials. However, there remain trade-offs between spectral sensitivity, operating energy, and, more recently, an ability to harbor additional features such as persistent photoconductivity and bidirectional photocurrents for new emerging application areas such as switchable light imaging and filter-less color discrimination. Here, we demonstrate a self-powered bidirectional photodetector based on molybdenum disulfide/gallium nitride (MoS2/GaN) epitaxial heterostructure. This fabricated detector exhibits self-powered functionality and achieves detection in two discrete wavelength bands: ultraviolet and visible. Notably, it attains a peak responsivity of 631 mAW-1 at a bias of 0V. The device's response to illumination at these two wavelengths is governed by distinct mechanisms, activated under applied bias conditions, thereby inducing a reversal in the polarity of the photocurrent. This work underscores the feasibility of self-powered and bidirectional photocurrent detection but also opens new vistas for technological advancements for future optoelectronic, neuromorphic, and sensing applications.

5.
J Pharm Biomed Anal ; 248: 116264, 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-38889577

RESUMEN

Anemarrhena asphodeloides Bunge-Phellodendron chinense Schneid (AAPC) is one of the most widely accepted herb pairs in Chinese medicine prescription for treating benign prostatic hyperplasia (BPH). However, the mechanisms underlying the combination of the two herbs for anti-BPH are still not completely clear. To uncover the potential mechanism of the AAPC herb pair in the treatment of BPH, chemical profiling, network pharmacology, serum metabonomics and experimental validation were integrated. UHPLC-Q-Exactive Orbitrap-MS was performed to characterize the chemical profiling of the herb pair extract, and network pharmacology was employed to forecast the potential effective components, core targets and key signaling pathways. Then, western blot and RT-PCR experiments were conducted to verify the PI3K/Akt/NF-κB signaling pathway predicted by network pharmacology. Finally, the serum differential metabolites and metabolic pathways were analyzed by serum non-targeted metabonomics, and these results were jointly analyzed by MetScape. 51 chemical components of the AAPC herb pair extract were identified, including phellodendrine, magnoflorine, berberine, mangiferin, anemarsaponin BIII, etc. In network pharmacology, the predicted core targets of these components include AKT1, TNF, EGFR, PTGS2, PIK3CA, etc. The KEGG pathway enrichment analysis indicated that PI3K-Akt, Rap1 and MAPK signaling pathways may play a key role in the AAPC herb pair for the treatment of BPH, and the results of animal experiments demonstrated that the herb pair could significantly inhibit the activation and expression of p-PI3K/PI3K, p-Akt/Akt, p-NF-κB/NF-κB in protein and mRNA levels. Furthermore, 31 serum differential metabolites and three main metabolic pathways were obtained by serum non-targeted metabonomics. And the crucial metabolic pathway of arachidonic acid (AA) was obtained by integrated analysis of network pharmacology and metabonomics results. In conclusion, the AAPC herb pair can improve BPH through inhibiting the activation and expression of the PI3K/Akt/NF-κB signaling pathway and AA metabolism.


Asunto(s)
Anemarrhena , Medicamentos Herbarios Chinos , Metabolómica , Farmacología en Red , Phellodendron , Hiperplasia Prostática , Transducción de Señal , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/sangre , Masculino , Anemarrhena/química , Metabolómica/métodos , Farmacología en Red/métodos , Phellodendron/química , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Transducción de Señal/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Extractos Vegetales/farmacología
6.
J Hazard Mater ; 472: 134555, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38728864

RESUMEN

This study aimed to isolate marine bacteria to investigate their stress response, inhibition mechanisms, and degradation processes under high-load conditions of salinity and enrofloxacin (ENR). The results demonstrated that marine bacteria exhibited efficient pollutant removal efficiency even under high ENR stress (up to 10 mg/L), with chemical oxygen demand (COD), total phosphorus (TP), total nitrogen (TN) and ENR removal efficiencies reaching approximately 88%, 83%, 61%, and 73%, respectively. The predominant families of marine bacteria were Bacillaceae (50.46%), Alcanivoracaceae (32.30%), and Rhodobacteraceae (13.36%). They responded to ENR removal by altering cell membrane properties, stimulating the activity of xenobiotic-metabolizing enzymes and antioxidant systems, and mitigating ENR stress through the secretion of extracellular polymeric substance (EPS). The marine bacteria exhibited robust adaptability to environmental factors and effective detoxification of ENR, simultaneously removing carbon, nitrogen, phosphorus, and antibiotics from the wastewater. The attapulgite carrier enhanced the bacteria's resistance to the environment. When treating actual mariculture wastewater, the removal efficiencies of COD and TN exceeded 80%, TP removal efficiency exceeded 90%, and ENR removal efficiency approached 100%, significantly higher than reported values in similar salinity reactors. Combining the constructed physical and mathematical models of tolerant bacterial, this study will promote the practical implementation of marine bacterial-based biotechnologies in high-loading saline wastewater treatment.


Asunto(s)
Antibacterianos , Enrofloxacina , Nitrógeno , Fósforo , Aguas Residuales , Contaminantes Químicos del Agua , Aguas Residuales/química , Enrofloxacina/metabolismo , Contaminantes Químicos del Agua/metabolismo , Antibacterianos/metabolismo , Fósforo/metabolismo , Fósforo/química , Nitrógeno/metabolismo , Biodegradación Ambiental , Bacterias/metabolismo , Acuicultura , Eliminación de Residuos Líquidos/métodos
7.
Environ Pollut ; 352: 124062, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38701963

RESUMEN

The leaching process of uranium tailings is a typical water-rock interaction. The release of 226Ra from uranium tailings depends on the nuclides outside the intrinsic properties of uranium tailings on the one hand, and is influenced by the water medium on the other. In this paper, a uranium tailings repository in southern China was used as a research object, and uranium tailings at different depths were collected by drilling samples and mixed to analyze the 226Ra occurrence states. Static dissolution leaching experiments of 226Ra under different pH conditions, solid-liquid ratio conditions, and ionic strength conditions were carried out, and the adsorption and desorption behaviours of 226Ra in five representative stratigraphic media were investigated. The results show that 226Ra has a strong adsorption capacity in representative strata, with adsorption distribution coefficient Kd values ranging from 1.07E+02 to 1.29E+03 (mL/g) and desorption distribution coefficients ranging from 4.97E+02 to 2.71E+03 (mL/g), but the adsorption is reversible. The 226Ra in uranium tailings exists mainly in the residual and water-soluble states, and the release of 226Ra from uranium tailings under different conditions is mainly from the water-soluble and exchangeable state fractions. Low pH conditions, low solid-liquid ratio conditions and high ionic strength conditions are favourable to the release of 226Ra from uranium tailings, so the release of 226Ra from uranium tailings can be reduced by means of adjusting the pH in the tailings and setting up a water barrier. The results of this research have important guiding significance for the management of existing uranium tailings ponds and the control of 226Ra migration in groundwater, which is conducive to guaranteeing the long-term safety, stability and sustainability of uranium mining sites.


Asunto(s)
Radio (Elemento) , Uranio , Uranio/química , Adsorción , Radio (Elemento)/análisis , Radio (Elemento)/química , China , Contaminantes Radiactivos del Suelo/análisis , Monitoreo de Radiación , Minería , Contaminantes Radiactivos del Agua/química , Contaminantes Radiactivos del Agua/análisis
8.
Bioorg Chem ; 147: 107376, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38640722

RESUMEN

The inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway with small molecules is a promising approach for cancer immunotherapy. Herein, novel small molecules compounds bearing various scaffolds including thiophene, thiazole, tetrahydroquinoline, benzimidazole and indazole were designed, synthesized and evaluated for their inhibitory activity against the PD-1/PD-L1 interaction. Among them, compound Z13 exhibited the most potent activity with IC50 of 189.6 nM in the homogeneous time-resolved fluorescence (HTRF) binding assay. Surface plasmon resonance (SPR) assay demonstrated that Z13 bound to PD-L1 with high affinity (KD values of 231 nM and 311 nM for hPD-L1 and mPD-L1, respectively). In the HepG2/Jurkat T co-culture cell model, Z13 decreased the viability rate of HepG2 cells in a concentration-dependent manner. In addition, Z13 showed significant in vivo antitumor efficacy (TGI = 52.6 % at 40 mg/kg) without obvious toxicity in the B16-F10 melanoma model. Furthermore, flow cytometry analysis demonstrated that Z13 inhibited tumor growth in vivo by activating the tumor immune microenvironment. These findings indicate that Z13 is a promising PD-1/PD-L1 inhibitor deserving further investigation.


Asunto(s)
Antineoplásicos , Antígeno B7-H1 , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Indazoles , Receptor de Muerte Celular Programada 1 , Humanos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Relación Estructura-Actividad , Indazoles/química , Indazoles/farmacología , Indazoles/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Animales , Estructura Molecular , Ratones , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Ratones Endogámicos C57BL , Células Hep G2 , Supervivencia Celular/efectos de los fármacos
9.
Sci Rep ; 14(1): 9411, 2024 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-38658579

RESUMEN

Matrix Metalloproteinases (MMPs) have been demonstrated to be essential in facilitating the migration and metastasis of clear cell renal cell carcinoma (ccRCC). However, the ability of the MMP family to predict clinical outcomes and guide optimal therapeutic strategies for ccRCC patients remains incompletely understood. In this investigation, we initially conducted a thorough examination of the MMP family in pan-cancer. Notably, MMPs exhibited distinctive significance in ccRCC. Following this, we undertook an extensive analysis to evaluate the clinical value of MMPs and potential mechanisms by which MMPs contribute to the progression of ccRCC. A novel stratification method and prognostic model were developed based on MMPs in order to enhance the accuracy of prognosis prediction for ccRCC patients and facilitate personalized treatment. By conducting multi-omics analysis and transcriptional regulation analysis, it was hypothesized that SAA1 plays a crucial role in promoting ccRCC migration through MMPs. Subsequently, in vitro experiments confirmed that SAA1 regulates ccRCC cell migration via the ERK-AP1-MMPs axis. In conclusion, our study has explored the potential value of the MMP family as prognostic markers for ccRCC and as guides for medication regimens. Additionally, we have identified SAA1 as a crucial factor in the migration of ccRCC.


Asunto(s)
Carcinoma de Células Renales , Movimiento Celular , Neoplasias Renales , Metaloproteinasas de la Matriz , Proteína Amiloide A Sérica , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Humanos , Movimiento Celular/genética , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Metaloproteinasas de la Matriz/genética , Pronóstico , Línea Celular Tumoral , Proteína Amiloide A Sérica/metabolismo , Proteína Amiloide A Sérica/genética , Regulación Neoplásica de la Expresión Génica , Sistema de Señalización de MAP Quinasas , Femenino , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Masculino , Transducción de Señal
10.
Opt Lett ; 49(3): 606-609, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38300070

RESUMEN

Luminescence thermometry is a promising non-contact temperature measurement technique, but improving the precision and reliability of this method remains a challenge. Herein, we propose a thermal sensing strategy based on a machine learning. By using Gd3Ga5O12: Er3+-Yb3+ as the sensing medium, a support vector machine (SVM) is preliminarily adopted to establish the relationship between temperature and upconversion emission spectra, and the sensing properties are discussed through the comparison with luminescence intensity ratio (LIR) and multiple linear regression (MLR) methods. Within a wide operating temperature range (303-853 K), the maximum and the mean measurement errors actualized by the SVM are just about 0.38 and 0.12 K, respectively, much better than the other two methods (3.75 and 1.37 K for LIR and 1.82 and 0.43 K for MLR). Besides, the luminescence thermometry driven by the SVM presents a high robustness, although the spectral profiles are distorted by the interferences within the testing environment, where, however, LIR and MLR approaches become ineffective. Results demonstrate that the SVM would be a powerful tool to be applied on the luminescence thermometry for achieving a high sensing performance.

11.
Mar Drugs ; 21(11)2023 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-37999422

RESUMEN

Two new compounds, named rhizoaspergillin A (1) and rhizoaspergillinol A (2), were isolated from the mangrove endophytic fungus Aspergillus sp. A1E3, associated with the fruit of Rhizophora mucronata, together with averufanin (3). The planar structures and absolute configurations of rhizoaspergillinol A (2) and averufanin (3) were established by extensive NMR investigations and quantum-chemical electronic circular dichroism (ECD) calculations. Most notably, the constitution and absolute configuration of rhizoaspergillin A (1) were unambiguously determined by single-crystal X-ray diffraction analysis of its tri-pivaloyl derivative 4, conducted with Cu Kα radiation, whereas those of averufanin (3) were first clarified by quantum-chemical ECD calculations. Rhizoaspergillin A is the first orsellinic acid-ribose-pyridazinone-N-oxide hybrid containing a unique ß-oxo-2,3-dihydropyridazine 1-oxide moiety, whereas rhizoaspergillinol A (2) and averufanin (3) are sterigmatocystin and anthraquinone derivatives, respectively. From the perspective of biosynthesis, rhizoaspergillin A (1) could be originated from the combined assembly of three building blocks, viz., orsellinic acid, ß-D-ribofuranose, and L-glutamine. It is an unprecedented alkaloid-N-oxide involving biosynthetic pathways of polyketides, pentose, and amino acids. In addition, rhizoaspergillinol A (2) exhibited potent antiproliferative activity against four cancer cell lines. It could dose-dependently induce G2/M phase arrest in HepG2 cells.


Asunto(s)
Aspergillus , Ribosa , Ribosa/metabolismo , Aspergillus/química , Antraquinonas/metabolismo , Estructura Molecular
12.
J Environ Manage ; 348: 119293, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-37827082

RESUMEN

In the Yellow River Basin (YRB), there exists a rich biodiversity of species that has been shaped by its unique geography, climate, and human activities. However, the high speed of economic development has resulted in the fragmentation and loss of habitats that are crucial for the survival of these species. To address this problem, constructing ecological networks has emerged as a promising approach for biodiversity preservation. In the study, we centered on the YRB and employed bird communities as an indicator species to identify ecological sources by combining bioclimatic variables and land use data with the Maximum Entropy (MaxEnt) and Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST) models. We generated a resistance surface using various data such as Digital Elevation Model (DEM), the Normalized Difference Vegetation Index (NDVI), Normalized Difference Water Index (NDWI), nighttime light, road density, railway density, and waterway density. So, we then simulated ecological corridors applying the Minimum Cumulative Resistance (MCR) model and constructed a bird diversity protection network. The results we found suggested that bird hotspots were predominantly clustered upstream and downstream in the YRB. We identified 475 sources covering a total area of 65,088 km2, 681 corridors with a total length of 11,495.05 km. This network served as a critical ecological facility to sustain and protect biodiversity. The bird ecological corridors in the YRB showed that a dense east-west pattern in the central area, with a short length in the west and east and a long length in the central area. Although the central region lacked ecological sources, the east and west were still connected as a tight whole. Two scenarios showed adding ecological stepping stones had a better optimization effect than enhancing ecological connectivity.


Asunto(s)
Conservación de los Recursos Naturales , Ecosistema , Animales , Humanos , Biodiversidad , China , Aves
13.
Appl Microbiol Biotechnol ; 107(21): 6421-6438, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37695342

RESUMEN

Hypocrellins (HYPs), a kind of natural perylenequinones (PQs) with an oxidized pentacyclic core, are important natural compounds initially extracted from the stromata of Hypocrella bambusae and Shiraia bambusicola. They have been widely concerned for their use as anti-microbial, anti-cancers, and anti-viral photodynamic therapy agents in recent years. Considering the restrictions of natural stromal resources, submerged fermentation with Shiraia spp. has been viewed as a promising alternative biotechnology for HYP production, and great efforts have been made to improve HYP production over the past decade. This article reviews recent publications about the mycelium fermentation production of HYPs, and their bioactivities and potential applications, and especially summarizes the progresses toward manipulation of fermentation conditions. Also, their chemical structure and analytic methods are outlined. Herein, it is worth mentioning that the gene arrangement in HYP gene cluster is revised; previous unknown genes in HYP and CTB gene clusters with correct function annotation are deciphered; the homologous sequences of HYP, CTB, and elc are systematically aligned, and especially the biosynthetic pathway of HYPs is full-scale proposed. KEY POINTS: • The mycelial fermentation process and metabolic regulation of hypocrellins are reviewed. • The bioactivities and potential applications of hypocrellins are summarized. • The biosynthesis pathway and regulatory mechanisms of hypocrellins are outlined.

14.
Sci Total Environ ; 901: 166371, 2023 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-37604368

RESUMEN

Soil heavy metal (HM) contamination around metal mining areas (MMAs) is a global concern that requires a cost-effective ecological risk assessment (ERA) method for preventive management. Traditional ERAs, comparing environmental HM concentrations with benchmarks, are labor- and cost-intensive in field investigations and chemical analyses, which challenge the management demands of numerous MMAs. In this study, a prospective ecological risk assessment method based on exposure and ecological scenario (ERA-EES) was developed to predict the eco-risk levels (low/medium/high) around MMAs prior to field sampling. Five exposure scenario indicators related to soil HM exposure and three ecological scenario indicators reflecting the soil bioreceptor response were selected and combined with the analytic hierarchy process and fuzzy comprehensive evaluation methods for ERA-EES development. Case application and performance evaluation with 67 MMAs in China demonstrated that the ERA-EES method had an overall effective and conservative performance when referring to potential ecological risk index (PERI) levels, with an accuracy of 0.87, kappa coefficient of 0.7, and low or medium eco-risk levels in PERI classified to high levels in ERA-EES. Overall, the selected scenario indicators could efficiently reflect the risk levels of soil HM pollution from mining activities. Besides, more regulatory efforts should be paid to the MMAs of nonferrous metals, underground and long-term mining and those located in southern China. This work provided a convenient and cost-effective prospective ERA method under the trend of ERA being tiered and refined, facilitating the risk management of various MMAs.

15.
Bioorg Chem ; 139: 106740, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37478546

RESUMEN

Programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1) is one of the most promising immune checkpoints (ICs) in tumor immunology and has been actively pursued as a target for anticancer drug discovery. Based on our previous research in small molecule PD-1/PD-L1 modulators, we designed and synthesized a series of resorcinol biphenyl ether-bearing macrocyclic compounds and evaluated their anti-PD-1/PD-L1 activities. Among them, compound 8d exhibited the highest inhibitory activity against PD-1/PD-L1 interaction with IC50 of 259.7 nM in the homogenous time-resolved fluorescence (HTRF) assay. In addition, 8d displayed in vitro immunomodulatory effects by promoting HepG2 cell death in a HepG2/Jurkat cell co-culture model. Furthermore, 8d effectively inhibited tumor growth (TGI = 74.6% at 40 mg/kg) in a melanoma tumor model in mice without causing obvious toxicity. Moreover, 8d exhibited favorable pharmacokinetics [e.g. high stability, reasonable half-life, and good oral bioavailability (F = 21.5%)]. Finally, molecular modeling studies showed that 8d bound to PD-L1 with high affinity. These results suggest that 8d may serve as a starting point for further development of macrocyclic small molecule-based PD-1/PD-L1 inhibitors for cancer treatment.


Asunto(s)
Antígeno B7-H1 , Neoplasias , Animales , Ratones , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Resorcinoles/farmacología , Resorcinoles/uso terapéutico , Éteres
16.
Talanta ; 265: 124924, 2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-37437393

RESUMEN

Point-of-care testing methods currently utilize rapid, portable, inexpensive, and multiplexed on-site detection. Microfluidic chips have become a very promising platform with broad development prospects due to their breakthrough improvement in miniaturization and integration. However, the conventional microfluidic chips still have disadvantages, such as difficulty in fabrication processing, long production time and high cost, which hinder its applications in the fields of POCT and in vitro diagnostics. In this study, a capillary-based microfluidic chip with the characteristics of low cost and easy fabrication was developed for the rapid detection of acute myocardial infarction (AMI). Several short capillaries, which were already conjugated with the capture antibodies respectively, were connected by peristaltic pump tubes and then formed the working capillary. Two working capillaries were encapsulated in the plastic shell and ready for the immunoassay. Multiplex detection of Myoglobin (Myo), cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) were chosen to demonstrate the feasibility and analytical performance of the microfluidic chip, which requires rapid and accurate detection during diagnosis and therapy for AMI. The capillary-based microfluidic chip required tens of minutes to prepared, and its cost was less than $1. The limit of detection (LOD) was 0.5 ng/mL for Myo, 0.1 ng/mL for cTnI and 0.5 ng/mL for CK-MB respectively. The capillary-based microfluidic chips with easy fabrication and low cost hold promise for the portable and low-cost detection of target biomarkers.


Asunto(s)
Microfluídica , Infarto del Miocardio , Humanos , Capilares , Infarto del Miocardio/diagnóstico , Troponina I , Forma MB de la Creatina-Quinasa , Biomarcadores , Mioglobina
17.
Appl Microbiol Biotechnol ; 107(11): 3745-3761, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37126084

RESUMEN

Perylenequinones (PQs) are a class of natural polyketides used as photodynamic therapeutics. Heat stress (HS) is an important environmental factor affecting secondary metabolism of fungi. This study investigated the effects of HS treatment on PQs biosynthesis of Shiraia sp. Slf14(w) and the underlying molecular mechanism. After the optimization of HS treatment conditions, the total PQs amount reached 577 ± 34.56 mg/L, which was 20.89-fold improvement over the control. Also, HS treatment stimulated the formation of intracellular nitric oxide (NO). Genome-wide analysis of Shiraia sp. Slf14(w) revealed iNOSL and cNOSL encoding inducible and constitutive NOS-like proteins (iNOSL and cNOSL), respectively. Cloned iNOSL in Escherichia coli BL21 showed higher nitric oxide synthase (NOS) activity than cNOSL, and the expression level of iNOSL under HS treatment was observably higher than that of cNOSL, suggesting that iNOSL is more responsible for NO production in the HS-treated strain Slf14(w) and may play an important role in regulating PQs biosynthesis. Moreover, the putative biosynthetic gene clusters for PQs and genes encoding iNOSL and nitrate reductase (NR) in the HS-treated strain Slf14(w) were obviously upregulated. PQs biosynthesis and efflux stimulated by HS treatment were significantly inhibited upon the addition of NO scavenger, NOS inhibitor, and NR inhibitor, indicating that HS-induced NO, as a signaling molecule, triggered promoted PQs biosynthesis and efflux. Our results provide an effective strategy for PQs production and contribute to the understanding of heat shock signal transduction studies of other fungi.Key points• PQs titer of Shiraia sp. Slf14(w) was significantly enhanced by HS treatment.• HS-induced NO was first reported to participate in PQs biosynthetic regulation.• Novel inducible and constitutive NOS-like proteins (iNOSL and cNOSL) were obtained and their NOS activities were determined.


Asunto(s)
Ascomicetos , Óxido Nítrico , Óxido Nítrico/metabolismo , Ascomicetos/metabolismo , Quinonas/metabolismo , Respuesta al Choque Térmico
18.
Front Neurorobot ; 17: 1119231, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36845064

RESUMEN

Lightweight semantic segmentation promotes the application of semantic segmentation in tiny devices. The existing lightweight semantic segmentation network (LSNet) has the problems of low precision and a large number of parameters. In response to the above problems, we designed a full 1D convolutional LSNet. The tremendous success of this network is attributed to the following three modules: 1D multi-layer space module (1D-MS), 1D multi-layer channel module (1D-MC), and flow alignment module (FA). The 1D-MS and the 1D-MC add global feature extraction operations based on the multi-layer perceptron (MLP) idea. This module uses 1D convolutional coding, which is more flexible than MLP. It increases the global information operation, improving features' coding ability. The FA module fuses high-level and low-level semantic information, which solves the problem of precision loss caused by the misalignment of features. We designed a 1D-mixer encoder based on the transformer structure. It performed fusion encoding of the feature space information extracted by the 1D-MS module and the channel information extracted by the 1D-MC module. 1D-mixer obtains high-quality encoded features with very few parameters, which is the key to the network's success. The attention pyramid with FA (AP-FA) uses an AP to decode features and adds a FA module to solve the problem of feature misalignment. Our network requires no pre-training and only needs a 1080Ti GPU for training. It achieved 72.6 mIoU and 95.6 FPS on the Cityscapes dataset and 70.5 mIoU and 122 FPS on the CamVid dataset. We ported the network trained on the ADE2K dataset to mobile devices, and the latency of 224 ms proves the application value of the network on mobile devices. The results on the three datasets prove that the network generalization ability we designed is powerful. Compared to state-of-the-art lightweight semantic segmentation algorithms, our designed network achieves the best balance between segmentation accuracy and parameters. The parameters of LSNet are only 0.62 M, which is currently the network with the highest segmentation accuracy within 1 M parameters.

19.
Chemosphere ; 313: 137390, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36436578

RESUMEN

The adsorption behavior of phosphorus on raw sediment (RS), attapulgite (AT), purified attapulgite (PAT) and AT/PAT-amended sediments conforms to the Langmuir, pseudo first-order kinetics and liquid film diffusion model. The adsorption process is spontaneous and monolayer adsorption, and the adsorption rate is mainly controlled by liquid film diffusion. The addition of attapulgite improved the adsorption capacity of phosphorus in the sediments of mariculture ponds. The results of long-term sediment core incubation showed that the average reduction rates of total phosphorus (TP) and soluble reactive phosphorus (SRP) in overlying water and SRP in pore water by adding 20% purified attapulgite (S/PAT20) were 62.11%, 70.83% and 56.32% respectively, and the phosphorus flux in sediments decreased by 53.81%. The addition of attapulgite reduces the risk of phosphorus release in sediments, and changes sediments from "source" to "pool". The specific surface area and pore volume of PAT increased to 203.254 cm2/g and 0.395 cm3/g respectively, but the phosphorus adsorption capacity was only increased by 2 times compared with AT (1431.3-2671.8 mg P/kg), indicating that the changes of mineral structure and chemical composition jointly determine the phosphorus adsorption effect. Adsorption mechanisms include physical adsorption, surface chemical precipitation, ligand effects, electrostatic attraction and ion exchange. Therefore, seeking modification methods with low energy consumption, low production cost, no damage to rod crystal, expansion of pore volume, increase of hydroxyl and other functional groups, and great retention of effective components are issues that need to be considered to improve the phosphorus adsorption capacity of attapulgite.


Asunto(s)
Fósforo , Contaminantes Químicos del Agua , Fósforo/química , Sedimentos Geológicos/química , Adsorción , Contaminantes Químicos del Agua/análisis , Lagos/química , Agua de Mar , Agua
20.
Environ Sci Pollut Res Int ; 30(12): 34573-34584, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36515880

RESUMEN

Exploring the impact of air quality ranking on energy efficiency and its spatial spillovers will help improve the pollution and carbon reduction effects of environmental governance policies. Based on the panel data of 285 cities at or above prefecture level in China during 2009-2019, this study pioneers in adopting difference-in-differences (DID) model with multiple time periods, spatial DID (SDID) model with multiple time periods, and mediating effect to explore the direct influence of ranking on China's energy efficiency, as well as its spatial effect and influence mechanism. Results show that air quality ranking is of significant positive impact on energy efficiency, proved by parallel trend hypothesis, placebo control, and policy heterogeneity. With spatial effect considered, such impact still exists, and ranking of the experimental group has significant positive spatial spillover effect on efficiency of the control group, meaning the ranking also promotes the efficiency of nearby cities in control groups via spatial spillover effect. In addition, air quality ranking greatly elevates energy efficiency via industrial structure and technological innovation, the mechanism of which is of significant positive spatial spillover effect. Based on the above results, some policy recommendations on environmental competition policy, industrial structure adjustment, and low-carbon applicable technology promotion were proposed to promote the energy efficiency of China.


Asunto(s)
Contaminación del Aire , Conservación de los Recursos Energéticos , Conservación de los Recursos Naturales , Política Ambiental , Carbono , China , Ciudades , Desarrollo Económico , Eficiencia
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