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1.
Eur J Med Chem ; 216: 113322, 2021 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-33652353

RESUMEN

In this paper, the 2,5-disubstituted furan derivatives containing 1,3,4-thiadiazole were synthesized and screened for their inhibitory activity against α-glucosidase and ß-glucuronidases to obtain potent α-glucosidase inhibitor 9 (IC50 = 0.186 µM) and E. coli ß-glucuronidase inhibitor 26 (IC50 = 0.082 µM), respectively. The mechanisms of the compounds were studied. The kinetic study revealed that compound 9 is a competitive inhibitor against α-glucosidase (Ki = 0.05 ± 0.003 µM) and molecular docking simulation showed several key interactions between 9 and the target including hydrogen bond and p-π stacking interaction. Derivative 26 (Ki = 0.06 ± 0.005 µM) displayed uncompetitive inhibition behavior against EcGUS. Furthermore, the result of docking revealed the furan ring of 26 may be a key moiety in obstructing the active domain of EcGUS. In addition, compound 15 exhibited significant inhibitory activity against these two enzymes, with potential therapeutic effects against diabetes and against CPT-11-induced diarrhea. At the same time, their low toxicity against normal liver tissue LO2 cells lays the foundation for in vivo studies and the development of bifunctional drug.

2.
Int J Nanomedicine ; 16: 1423-1434, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33654394

RESUMEN

Background: Interleukin-1ß (IL-1)-treated mesenchymal stem cells (MSCs) and IL-1-MSCs-conditioned medium (CM) exert anti-inflammatory roles. Astrocytes are essential for the modulation of synaptic activity and neuronal homeostasis in the brain. Exosomes are the critical mediators in intercellular communication. However, the mechanism underlying the anti-inflammatory effect of IL-1-treated MSCs remains unknown. Methods: In this study, exosomes (IL-1-Exo) were isolated from IL-1-treated MSCs. In addition, lipopolysaccharide (LPS)-treated hippocampal astrocytes and status epilepticus (SE) mice were treated with IL-1-Exo. Inflammatory activity, astrogliosis, and cognitive performance were measured to determine the effect of IL-1-Exo on inflammation. Results: The results revealed that IL-1-Exo significantly inhibited LPS-induced astrogliosis and inflammatory responses of astrocytes. Also, IL-1-Exo reversed the LPS-induced effect on calcium signaling. The Nrf2 signaling pathway was associated with the effect of IL-1-Exo in LPS-treated astrocytes. Furthermore, IL-1-Exo reduced the inflammatory response and improved the cognitive performance of SE mice. Conclusion: The results suggest that IL-1-Exo inhibited LPS-induced inflammatory responses in astrocytes and SE mice and that the effect of IL-1-Exo was primarily mediated through the Nrf-2 signaling pathway. This study provides a new understanding of the molecular mechanism of inflammation-associated brain diseases and an avenue to develop nanotherapeutic agents for the treatment of inflammatory conditions in the brain.

3.
Toxicol Sci ; 2021 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-33662127

RESUMEN

The idiosyncratic characteristics and severity of acetaminophen (APAP) overdose-induced hepatotoxicity render identifying the predisposing factors and mechanisms of APAP-induced liver toxicity necessary and urgent. Farnesoid X receptor (FXR) controls bile acid homeostasis and modulates the progression of various liver diseases. While global FXR deficiency in mice enhances APAP intoxication, the mechanism remains elusive. In this study, an increased sensitivity to APAP-induced toxicity was found in global Fxr-null (Fxr-/-) mice, but was not observed in hepatocyte-specific or macrophage-specific Fxr-null mice, suggesting that global FXR deficiency enhances APAP hepatotoxicity via disruption of systematic bile acid homeostasis. Indeed, more bile acid accumulation was found in global Fxr-/- mice, while 2% cholestyramine diet feeding decreased serum bile acids and alleviated APAP hepatotoxicity in global Fxr-/- mice, suggesting that bile acid accumulation contributes to APAP toxicity. Bile acids were suspected to induce macrophage to release tumor necrosis factor α (TNFα), which is known to enhance the APAP hepatotoxicity. In vitro, deoxycholic acid (DCA), a secondary bile acid metabolite, significantly induced Tnfa mRNA and dose-dependently enhanced TNFα release from macrophage, while the same dose of DCA did not directly potentiate APAP toxicity in cultured primary hepatocytes. In vivo, DCA enhanced TNFα release and potentiated APAP toxicity, both of which were abolished by the specific TNFα antagonist infliximab. These results reveal an FXR-DCA-TNFα axis that potentiates APAP hepatotoxicity, which could guide the clinical safe use of APAP.

4.
BMC Geriatr ; 21(1): 155, 2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33663402

RESUMEN

BACKGROUND: The systemic immune-inflammation index (SII), based on peripheral platelet, neutrophil and lymphocyte counts, has been proven to be a promising prognostic indicator in various diseases. Hip fracture is a common injury among the older adults, and has become a global public health problem with high mortality and disability rates. However, the relationship between SII and the prognosis of hip fracture is not yet well-known. The aim of the this study was to explore the predictive value of SII in older adults with hip fracture undergoing surgery. METHODS: This was a prospective cohort study performed from January 2014 to December 2018 at a orthopaedic center, China. The SII was calculated as platelet×neutrophil/lymphocyte counts. Univariable and multivariable Cox proportional hazard models were used to assess the association between SII and all-cause mortality. RESULTS: A total of 290 older adults with hip fracture were included, and the mean (SD) age was 77.6 (8.6) years, and 189 (65.2%) were female. The median (IQR) SII was 759.4 (519.0-1128.7) × 109/L. After a median follow-up time of 33.4 months, 13 (4.5%), 26 (9.0%) and 54 (18.6%) patients died within the 30-day, 1-year and last follow-up, respectively. Multivariable Cox analysis revealed that each increase of 100 units of SII was associated with a 8% increased hazard of death at 1-year follow-up (HR = 1.08, 95% CI: 1.01-1.17, p = 0.033), and 9% increased hazard of death at last follow-up (HR = 1.09, 95% CI: 1.03-1.15, p = 0.003). CONCLUSIONS: SII is associated with poor all-cause mortality in older adults with hip fracture undergoing surgery, and deserves further investigation and application in clinical practice.

5.
Zhongguo Zhong Yao Za Zhi ; 46(1): 118-124, 2021 Jan.
Artículo en Chino | MEDLINE | ID: mdl-33645060

RESUMEN

To establish the HPLC fingerprint and multi-component determination method of fried Glycyrrhizae Radix et Rhizoma pieces. HPLC analysis was performed on Thermo Acclaim ~(TM)120 C_(18) column(4.6 mm×250 mm, 5 µm). Acetonitrile-0.1% phosphoric acid aqueous solution was taken as the mobile phase for gradient elution. The flow rate was 1 mL·min~(-1),the column temperature was maintained at 30 ℃, and the detection wavelength was 237 nm and 360 nm. The similarity of 15 batches of fried Glycyrrhizae Radix et Rhizoma pieces was higher than 0.849, and 17 common peaks were identified. Liquiritin, isoliquiritin apioside, isoliquiritin, liquiritigenin, isoliquiritigenin and glycyrrhizic acid were identified; among them, the mass fractions of Liquiritin, isoliquiritin apioside, isoliquiritin, liquiritigenin, glycyrrhizic acid were were 0.519%-3.058%, 0.227%-0.389%, 0.070%-0.439%, 0.038%-0.173%, 1.381%-4.252%, respectively. According to the cluster analysis, the 15 batches of decoction pieces were classified into three categories; principal component analysis screened out four principal components, with the cumulative variance contribution rate of 86.630%, indicating that the principal components contained most information of original data. Partial least squares discriminant ana-lysis marked 6 differential components in the decoction pieces. The established fingerprint and multicomponent determination are stable and reliable, and can provide a reference for the quality control of Radix Glycyrrhizae Radix et Rhizomae and fried Glycyrrhizae Radix et Rhizoma pieces.


Asunto(s)
Medicamentos Herbarios Chinos , Cromatografía Líquida de Alta Presión , Extractos Vegetales , Control de Calidad
6.
Zhongguo Zhong Yao Za Zhi ; 46(4): 966-971, 2021 Feb.
Artículo en Chino | MEDLINE | ID: mdl-33645103

RESUMEN

This study is to provide the basis of establishing a quality evaluation system, based on the differences in appearance and internal components of Astragali Radix from different sources. The diameter of 18 batches of Astragali Radix, the content of alcohol(water) extract and 7 kinds of flavonoids were determined. The peak area ratio of flavonoid aglycon to aglycone was calculated. PCA and CA were carried out by synthesizing various indexes. The results of PCA and CA showed that Astragali Radix was obviously clustered into three types. Alcohol extract, formononetin/formosan glycosides,(pilose isoflavones+astragalus flavonoid A)/pilose isoflavone glucoside are the most significant differences in the variable importance projection index(VIP) of Astragali Radix. Combining the diameter, alcohol(water) extract, flavonoid aglycon to aglycone peak area ratio can provide an analysis method for the establishment of the grade evaluation system of Astragali Radix.


Asunto(s)
Astrágalo (Planta) , Medicamentos Herbarios Chinos , Glucósidos , Glicósidos , Raíces de Plantas
7.
Acupunct Med ; : 964528421997155, 2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33657871

RESUMEN

BACKGROUND: To evaluate the antidepressant effects of auricular intradermal acupuncture (AIA) of areas innervated by both the auricular branch of the vagus nerve and the trigeminal nerve. METHODS: Forty-nine patients with depression were randomly allocated into an AIA group (n = 25) and a sham AIA group (n = 24). Both groups received selective serotonin reuptake inhibitors (SSRIs) as conventional treatment. The AIA group received AIA stimulation, and the sham AIA group received sham AIA, which constituted being subjected to an attached needle that did not penetrate the skin. The needles were retained for 4 h each session, with five sessions a week for a total duration of 2 weeks. The outcomes were assessed by the 17-item Hamilton depression rating scale (HAMD-17), five factors (sleep disorder, retardation, cognitive dysfunction, anxiety/somatization, and weight) and self-rating depression scale (SDS) at weeks 0, 1, and 2. RESULTS: Fifty-four patients were randomly assigned to the AIA (n = 27) and sham AIA group (n = 27), of whom 25 patients in the AIA and 24 patients in the sham AIA group were analyzed. AIA-treated patients displayed a significantly greater reduction from baseline in HAMD-17 scores (p = 0.03) and SDS scores (p = 0.02) at week 2 compared to patients receiving sham AIA. The AIA intervention also produced a higher rate of clinically significant responses in sleep disorders (p = 0.07) compared to sham AIA. No adverse events occurred in either group. CONCLUSION: According to the findings of this preliminary study, AIA appears to have additional value compared to SSRIs alone in treating patients with depressive disorder.

8.
Zhongguo Zhong Yao Za Zhi ; 46(2): 388-390, 2021 Jan.
Artículo en Chino | MEDLINE | ID: mdl-33645126

RESUMEN

Two phloroglucinol compounds(1-2) were isolated and purified from 95% ethanol extract of Dryopteris fragrans through various column chromatographies on silica gel, Sephadex LH-20, medium pressure column chromatography, and preparative HPLC. Their structures were elucidated as 2',4',6'-trihydroxy-5'-methyl acetate-3'-methyl-1'-butyrophenone(1) and aspidinol B(2) based on their chemical and physicochemical methods and spectroscopic data. Compound 1 is a new phloroglucinol compound named "dryofraginol".


Asunto(s)
Dryopteris , Cromatografía Líquida de Alta Presión , Etanol , Floroglucinol , Extractos Vegetales
9.
Hum Vaccin Immunother ; : 1-7, 2021 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-33651653

RESUMEN

To evaluate rotavirus (RV) disease burden and circulating strains of RV among Chinese children younger than 5-years old who had diarrhea from 2011 to 2018. PubMed, Web of Science, Embase, CNKI and WANFANG databases were systematically searched to identify studies that reported RV prevalence in mainland China. After data extraction, a fixed-effects model or a random-effects model was applied to estimate RV positivity and proportions of G and P types. Statistical analysis was conducted using R software. We initially reviewed 1323 studies, and identified 69 studies that were eligible. The overall proportion of RV gastroenteritis (RVGE) among children under 5-years old who presented with diarrhea and sought medical care was 34.0% (95% CI: 31.3, 36.8), and RV positivity was higher among inpatients (39.7%) than outpatients (23.9%). Western areas of China had the highest proportion of RVGE (42.7%), and RV positivity was highest for children who were 6 months-old to 2 years-old. The most prevalent G types were G3 (26.1%), G9 (17.5%), and G1 (12.8%), the most prevalent P type was P[8] (56.8%) and the most prevalent G-P combination was G9P[8] (20.9%). RV continues to be a main cause of acute gastroenteritis in Chinese children who are younger than 5 years old. Following the introduction of an RV vaccine in 2011, monitoring of the disease burden of RV diarrhea and circulating strains in China remain important for assessments of vaccine efficacy.

10.
J Nanosci Nanotechnol ; 21(5): 3065-3071, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33653481

RESUMEN

Towards addressing water pollution issues, the development of multifunctional chlorella with applications ranging from sensing pollutants to heavy metal and oil removal is described. The use of chlorella cells, which are widely abundant natural structures, leads to simple and low-cost mass production of effective functional materials. Bioinspired surface modification approaches mediated by polydopamine can endow chlorella with enhanced adsorption capacity for heavy metals, as well as superhydrophobic, fluorescence and magnetic properties according to the desired application. The resulting chlorella exhibits excellent heavy metal and oil removal ability, while magnetic propulsion and guidance allow directional motion over long distances for implementation in situ removal. Moreover, it is further demonstrated that chlorella can be used as a biosensor to detect metal ions by taking advantage of the fluorescence properties of carbon dots. Such use of chlorella provides a new way for the large-scale production of functional materials to tackle water pollution.

11.
J Sep Sci ; 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33646632

RESUMEN

In this work, a new quantitative analysis method of multi-components analysis via a single marker strategy coupled with HPLC analysis, was proposed to analyze nine nucleosides (cytidine, uridine, 2'-deoxyuridine, inosine, guanosine, 2'-deoxyguanosine, thymidine, adenosine and 2'-deoxyadenosine) as quality control markers in Rhizoma Paridis. Guanosine was set as the internal reference substance, whose content in Rhizoma Paridis was determined using conventional external standard method. Then, relative correction factors between guanosine and other eight nucleosides were measured respectively. The amounts of the other eight components were calculated according to the relative correction factors by the quantitative analysis of multi-components via a single marker method. Finally, the result of vector angle cosine analysis showed that there was no significant difference of the contents between the external standard method and the quantitative analysis of multi-components via a single marker method, indicating that the quantitative analysis of multi-components via a single marker method can be applied for the quality control of Rhizoma Paridis. As far as we know, this is also the first report to analyze nucleosides by the quantitative analysis of multi-components via a single marker method, providing an efficient and promising quality assessment method for other traditional Chinese medicine containing nucleosides. This article is protected by copyright. All rights reserved.

12.
Mol Med ; 27(1): 21, 2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658002

RESUMEN

BACKGROUND: Studies have found that circular RNAs (circRNAs) play key roles in cardiovascular diseases. However, the function of circROBO2 in acute myocardial infarction (AMI) is unclear. This study aimed to investigate the pathogenesis of circROBO2 in AMI. METHODS: qRT-PCR and Western blot were used to determine the expression levels of circROBO2, miR-1184, and TRADD in AMI and sham-operated mouse models at mRNA and protein level, respectively. The relationship among miR-1184, circROBO2 and TRADD was evaluated by RNA immunoprecipitation (RIP) analysis and luciferase reporter gene analysis. The roles of circROBO2, miR-1184, and TRADD in myocardial cell apoptosis were evaluated using flow cytometry. Ultrasound echocardiography, serum creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH), myocardial infarction area, and myocardial cell apoptosis were measured to examine the effects of circROBO2 on myocardial injury. RESULTS: The expression levels of miR-1184 were significantly reduced, and the expression levels of circROBO2 and TRADD were significantly increased in MI group. CircROBO2 acted as a sponge for miR-1184 by upregulating the expression of TRADD. In addition, overexpression of miR-1184 enhanced the protective effect of knockdown of circROBO2 by partially inhibiting the expression of TRADD in vivo and in vitro. CONCLUSION: Knockdown of circROBO2 reduced the apoptosis of cardiomyocytes by increasing the expression levels of miR-1184, which in turn decreased the expression levels of TRADD in the myocardium post-MI.

13.
J Ethnopharmacol ; 271: 113914, 2021 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-33571617

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Shengmai San (SMS) has been commonly used as a traditional Chinese medicine for the treatment of cardiovascular disorders, of which drug interactions need to be assessed for the safety concern. There is little evidence for the alterations of hepatic and intestinal drug-metabolizing enzymes after repeated SMS treatments to assess drug interactions. AIM OF THE STUDY: The studies aim to illustrate the effects of repeated treatments with SMS on cytochrome P450s (CYPs), reduced nicotinamide adenine dinucleotide (phosphate)-quinone oxidoreductase (NQO), uridine diphosphate-glucuronosyltransferase (UGT), and glutathione S-transferase (GST) using in vivo rat model. MATERIALS AND METHODS: The SMS was prepared using Schisandrae Fructus, Ginseng Radix, and Ophiopogonis Radix (OR) (1:2:2). Chromatographic analyses of decoctions were performed using ultra-performance liquid chromatography (UPLC) and LC-mass spectrometry. Sprague-Dawley rats were orally treated with the SMS and its component herbal decoctions for 2 or 3 weeks. Hepatic and intestinal enzyme activities were determined. CYP3A expression and the kinetics of intestinal nifedipine oxidation (NFO, a CYP3A marker reaction) were determined. RESULTS: Schisandrol A, schisandrin B, ginsenoside Rb1 and ophiopogonin D were identified in SMS. SMS selectively suppressed intestinal, but not hepatic, NFO activity in a dose- and time-dependent manner. Hepatic and intestinal UGT, NQO and GST activities were not affected. A 3-week SMS treatment decreased the maximal velocity of intestinal NFO by 50%, while the CYP3A protein level remained unchanged. Among SMS component herbs, the decoction of OR decreased intestinal NFO activity. CONCLUSIONS: These findings demonstrate that 3-week treatment with SMS and OR suppress intestinal, but not hepatic CYP3A function. It suggested that the potential interactions of SMS with CYP 3A drug substrates should be noticed, especially the drugs whose bioavailability depends heavily on intestinal CYP3A.

14.
Lancet Oncol ; 22(3): 351-360, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33581774

RESUMEN

BACKGROUND: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. METHODS: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. FINDINGS: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. INTERPRETATION: Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. FUNDING: Jiangsu Hengrui Medicine and National Key R&D Program of China. TRANSLATIONS: For the Chinese translation of the abstract see Supplementary Materials section.

15.
Water Res ; 194: 116894, 2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33592355

RESUMEN

Phosphorus (P) release from sediment is a key process affecting the effectiveness of eutrophication mitigation. We hypothesized that high nitrate (NO3-) input may have dual effect on sediment P release: reduce the sediment P release by improving the oxidation of sediment or promote P release by stimulating the growth of phytoplankton and increase the decomposition rates and oxygen consumption at the sediment water interface. To test the effect of different NO3- concentrations, we conducted a three-month experiment in 15 cement tanks (1 m3), with five targeted concentrations of NO3-: control, 2 mg L-1, 5 mg L-1, 10 mg L-1, and 15 mg L-1. The results showed that: i) when NO3- was maintained at high levels: NO3-≥5-7 mg L-1 (range of median values), there was no effect of NO3- on net P release from the sediment, likely because the positive effects of NO3- (increasing oxidation) was counteracted by a promotion of phytoplankton growth. ii) after NO3- addition was terminated NO3- dropped sharply to a low level (NO3-≤0.4 mg L-1), followed by a minor P release in the low N treatments but a significant P release in the high N treatments, which likely reflect that the inhibition effect of NO3- on P release decreased, while the promotion effects at high NO3- concentrations continued. The results thus supported our hypotheses of a dual effect on sediment P release and suggest dose-dependent effect of NO3- loading on stimulating P release from the sediment, being clear at high NO3- exceeding 5-7 mg L-1.

16.
Cancer Res ; 2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33619116

RESUMEN

Fusion genes including NPM-ALK can promote T cell transformation, but the signals required to drive a healthy T cell to become malignant remain undefined. In this study, we introduce NPM-ALK into primary human T cells and demonstrate induction of the epithelial-to-mesenchymal transition (EMT) program, attenuation of most T cell effector programs, re-emergence of an immature epigenomic profile, and dynamic regulation of c-Myc, E2F, and PI3K/mTOR signaling pathways early during transformation. A mutant of NPM-ALK failed to bind several signaling complexes including GRB2/SOS, SHC1, SHC4, and UBASH3B and was unable to transform T cells. Lastly, TCR-generated signals were required to achieve T cell transformation, explaining how healthy individuals can harbor T cells with NPM-ALK translocations. These findings describe the fundamental mechanisms of NPM-ALK-mediated oncogenesis, and may serve as a model to better understand factors that regulate tumor formation.

17.
Environ Int ; 151: 106444, 2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33621917

RESUMEN

Oral bioavailability of arsenic (As) determines levels of As exposure via ingestion of As-contaminated soil, however, the role of gut microbiota in As bioavailability has not evaluated in vivo although some in vitro studies have investigated this. Here, we made a comparison in As relative bioavailability (RBA) estimates for a contaminated soil (3913 mg As kg-1) using a mouse model with and without penicillin perturbing gut microbiota and metabolites. Compared to soil exposure alone (2% w/w soil in diets), addition of penicillin (100 or 1000 mg kg-1) reduced probiotic Lactobacillus and sulfate-reducing bacteria Desulfovibrio, enriched penicillin-resistant Enterobacter and Bacteroides, and decreased amino acid concentrations in ileum. With perturbed gut microbiota and metabolic profile, penicillin and soil co-exposed mice accumulated 2.81-3.81-fold less As in kidneys, excreted 1.02-1.35-fold less As in urine, and showed lower As-RBA (25.7-29.0%) compared to mice receiving diets amended with soil alone (56 ± 9.63%). One mechanism accounted for this is the decreased concentrations of amino acids arising from the gut microbiota shift which resulted in elevated iron (Fe) and As co-precipitation, leading to reduced As solubilization in the intestine. Another mechanism was conversion of bioavailable inorganic As to less bioavailable monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) by the antibiotic perturbed microflora. Based on in vivo mouse model, we demonstrated the important role of gut microbiota and gut metabolites in participating soil As solubilization and speciation transformation then affecting As oral bioavailability. Results are useful to better understand the role of gut bacteria in affecting As metabolism and the health risks of As-contaminated soils.

18.
Biosens Bioelectron ; 178: 113036, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33548656

RESUMEN

Recent advancements in super-resolution nanoscopy allowed the study of mitochondrial biology at nanoscale and boosted the understanding its correlated cellular processes those were previously poorly understood. Nevertheless, studying mitochondrial ultrastructure remains a challenge due to the lack of probes that could target specific mitochondrial substances (e.g. cristae or mtDNA) and survive under harsh super-resolution optical conditions. Herein, in this work, we have rationally constructed a pyridine-BODIPY (Py-BODIPY) derivative that could target mitochondrial membrane in living cells without interfering its physiological microenvironments. Furthermore, we found Py-BODIPY is a membrane potential independent probe, hence it is not limit to live-cell staining but also showed a strong internalization into pre-fixed and stimulus disrupted sample. Importantly, its cristae specificity and superb photostability allow the observation of mitochondrial dynamic nano-structures with an unprecedented resolution, allow demonstrating how mitochondrial 3D ultrastructure evolved under oxidative phosphorylation condition.

19.
ChemMedChem ; 2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33527731

RESUMEN

Pancreatic lipase (PL), a key target for the prevention and treatment of obesity, plays crucial roles in the hydrolysis and absorption of in dietary fat. In this study, a series of pyrazolones was synthesized, and their inhibitory effects against PL were assayed by using 4-methylumbelliferyl oleate (4-MUO) as optical substrate for PL. Comprehensive structure-activity relationship analysis of these pyrazolones led us to design and synthesize a novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as a potent mixed-competitive inhibitor of PL (IC50 =0.30 µM). In addition, P32 displayed some selectivity over other known serine hydrolases. A molecular docking study for P32 demonstrated that the inhibitory activity of P32 towards PL could be attributed to the π-π interactions of 2-naphthyl unit (R1 ) and hydrophobic interactions of phenyl moiety (R3 ) with the active site of PL. Thus, P32 could serve as promising lead compound for the development of more efficacious and selective pyrazolones-type PL inhibitors for biomedical applications.

20.
ACS Nano ; 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33625842

RESUMEN

Hypoxia is a critical cause of tumor immunosuppression, and it significantly limits the efficacy of many anticancer modalities. Herein, we report an amphiphilic F11-derivative-based oxygen-delivering polyfluorocarbon nanovehicle loading photodynamic DiIC18(5) and reactive oxygen species (ROS)-sensitive prodrug of chemo-immunomodulatory gemcitabine (PF11DG), aimed at relieving tumor hypoxia and boosting antitumor immunity for cancer therapy. We optimized F11-based polyfluorocarbon nanovehicles with a 10-fold enhancement of tumor oxygenation. PF11DG exhibited intriguing capabilities, such as oxygen-dissolving, ROS production, and responsive drug release. In tumors, PF11DG exhibited flexible intratumoral permeation and boosted robust antitumor immune responses upon laser irradiation. Notably, the treatment of PF11DG plus laser irradiation (PF11DG+L) significantly retarded the tumor growth with an 82.96% inhibition in the 4T1 breast cancer model and a 93.6% inhibition in the PANC02 pancreatic cancer model with better therapeutic benefits than non-oxygen-delivering nanovehicles. Therefore, this study presents an encouraging polyfluorocarbon nanovehicle with deep tumor-penetrating and hypoxia-relieving capacity to boost antitumor immunity for cancer treatment.

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