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1.
Chin J Nat Med ; 19(5): 351-363, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33941340

RESUMO

Digestive system cancers, including liver, gastric, colon, esophageal and pancreatic cancers, are the leading cause of cancers with high morbidity and mortality, and the question of their clinical treatment is still open. Previous studies have indicated that Ziyuglycoside II (ZYG II), the major bioactive ingredient extract from Sanguisorba officinalis L., significantly inhibits the growth of various cancer cells. However, the selective anti-tumor effects of ZYG II against digestive system cancers are not systemically investigated. In this study, we reported the anti-cancer effect of ZYG II on esophageal cancer cells (OE21), cholangiocarcinoma cells (HuCCT1), gastric cancer cells (BGC-823), liver cancer cells (HepG2), human colonic cancer cells (HCT116), and pancreatic cancer cells (PANC-1). We also found that ZYG II induced cell cycle arrest, oxidative stress and mitochondrial apoptosis. Network pharmacology analysis suggested that UBC, EGFR and IKBKG are predicted targets of ZYG II. EGFR signaling was suggested as the critical pathway underlying the anti-cancer effects of ZYG II and both docking simulation and western blot analysis demonstrated that ZYG II was a potential EGFR inhibitor. Furthermore, our results showed synergistic inhibitory effects of ZYG II and chemotherapy 5-FU on the growth of cancer cells. In summary, ZYG II are effective anti-tumor agents against digestive cancers. Further systemic evaluation of the anti-cancer activities in vitro and in vivo and characterization of underlying mechanism will promote the development of novel supplementary therapeutic strategies based on ZYG II for the treatment of digestive system cancers.

2.
Semin Cancer Biol ; 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33962020

RESUMO

Cancer therapeutic strategies include surgeries, radiotherapy, chemotherapy, targeted therapy and immunotherapies. However, current cancer treatment still faces challenges such as postoperative residuals, postoperative recurrence, chemoradiotherapy resistance and lack of drugs with high specificity, due to the complexity of the cancer environment. Extracellular vesicles (EVs) are lipid-capsuled membrane vesicles secreted from cells, communicating vital messages between cells and regarding function in tumorigenesis and metastasis. Investigation of compositions and functions of EVs may open unprecedented, promising avenues for cancer therapeutics. This review brings new perspectives from both researchers and clinicians in the EV field, emphasizing the ties between basic research and ongoing clinical trials. In sum, our review summarizes the roles EVs play in cancer therapy, ranging from mechanisms to applications in cancer treatment. In particular, it focuses on their therapeutic potential with an eye toward clinical relevance.

4.
J Pharm Biomed Anal ; 200: 114079, 2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33901755

RESUMO

A total of 49 limonoids derivatives were rapidly identified by UNIFI software and three new limonoids derivatives, named dasycarinone (1, DAS), isodictamdiol C (2) and dasycarinone A (3), along with nineteen known compounds, were isolated from the root bark of Dictamnus dasycarpus, named as "Baixianpi" in Chinese. Their structures were elucidated on the basis of spectroscopic data (UV, IR, HR-ESI-MS, NMR, CD spectra and OR). All the compounds were tested for anti-inflammatory activities by suppressing the nitric oxide (NO) production in lipopolysaccharide (LPS) induced BV-2 cells. DAS exhibited a strong anti-inflammatory activity with IC50 value of 1.8 µM. Nuclear Factor kappa B (NF-κB) luciferase assay and enzyme-linked immune sorbent assay indicated that DAS can suppress the release of inflammatory cytokines such as Tumor Necrosis Factor α (TNF-α), interleukin 6 (IL-6) via inactivating NF-κB signaling pathways. Moreover, we found that anti-inflammatory activities of obacunone-class are better than those of limonin-class by analyzing structure-activity relationship. Our results suggested that obacunone derivatives play an important role on anti-inflammation of Baixianpi. As a representative among them, DAS showed a strong anti-inflammatory activity via suppressing NF-κB signaling pathways.

5.
Bioorg Med Chem ; 39: 116166, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33910157

RESUMO

Constitutive activation of Hedgehog (Hh) pathway is intimately related with the occurrence and development of several malignancies, such as medulloblastoma (MB) and other tumors. Therefore, small molecular inhibitors of Hh pathway are urgently needed. In this study, three new steroidal alkaloids, ⊿5 (20R, 24R) 23-oxo-24-methylsolacongetidine, ⊿5 (20S, 24R) 23-oxo-24-methylsolacongetidine and veralinine 3-O-α-l-rhamnopyranosyl-(1 â†’ 2)-ß-D-glucopyranoside, together with six known alkaloids, 20-epi-verazine, verazine, protoverine 15-(l)-2'-methylbutyrate, jervine, veramarine and ß1-chaconine, were isolated and determined from Veratrum grandiflorum Loes. The dual-luciferase bioassay indicated that all compounds exhibited significant inhibitions of Hh pathway with IC50 values of 0.72-14.31 µM against Shh-LIGHT 2 cells. To determine whether these Hh pathway inhibitors act with the Smoothened (Smo) protein, which is an important oncoprotein and target for this pathway, BODIPY-cyclopamine (BC) competitive binding assay was preferentially performed. Compared with BC alone, all compounds obviously reduced the fluorescence intensities of BC binding with Smo in Smo-overexpression HEK293T cells through fluorescence microscope and flow cytometer. By directly interacting with Smo, it revealed that they were actually novel natural Smo inhibitors. Then, their anti-tumor effects were investigated against the human MB cell line DAOY, which is a typical pediatric brain tumor cells line with highly expressed Hh pathway. Interestingly, most of compounds had slight proliferation inhibitions on DAOY cells after treatment for 24 h same as vismodegib, while ß1-chaconine showed the strongest inhibitory effect on the growth of DAOY with IC50 value of 5.35 µM. In conclusion, our studies valuably provide several novel natural Smo inhibitors for potential targeting treatment of Hh-dependent tumors.

6.
J Dig Dis ; 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33928766

RESUMO

AIM: Emperipolesis, the cell-in-cell structure, is one of the pathological diagnostic standard of AIH. We have already identified that CD8+ T cells participated in the emperipolesis process in liver tissue of AIH patients. In this study, we aimed to clarify the characteristics and molecular mechanisms of emperipolesis in the patients with AIH in vitro and in mice with α-GalCer-induced acute hepatitis. METHODS: Peripheral blood mononuclear cell (PBMC) of patients with variant chronic liver diseases and healthy controls were co-cultured with hepatic cell line to induce emperipolesis in vitro. Confocal staining was performed to illustrate the cellular types and potential mechanisms of emperipolesis in AIH. In addition, the mouse model of α-GalCer-induced acute hepatitis which mimics human AIH in several features, was used to confirm the role of CD44/p-ERM/F-actin in the emperipolesis process in vivo. RESULTS: In co-culture system with PBMC and hepatic cell line, emperipolesis was observed most common in the patients with AIH. CD8+ T cells were the major cells participated in the emperipolesis process, and penetrated into hepatocytes actively via CD44/p-ERM/F-actin pathway. As a result, most CD8+ T cells engulfed in hepatocytes undergo self-apoptosis. In α-GalCer-induced acute hepatitis model, emperipolesis was observed around the inflammatory foci, and was inhibited by Ezrin phosphorylation inhibitor NSC668394. Similarly, activated murine CD8+ T cells penetrated into primary hepatocytes via CD44/p-ERM/F-actin pathway in vitro. CONCLUSIONS: CD8+ T cells penetrated into hepatocytes actively via CD44/p-ERM/F-actin signaling pathway and undergo apoptosis, may be a compensative mechanism to attenuate overwhelming immune attack in AIH. This article is protected by copyright. All rights reserved.

7.
J Sci Food Agric ; 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33856705

RESUMO

BACKGROUND: Food processing induces various modifications that affect the structure, physical and chemical properties of food products and hence the acceptance of the product by the consumer. In this work, the evolution of volatile components, 2-thiobarbituric acid reactive substances (TBARS), moisture content (MC) and microstructural changes of pork was investigated by hyperspectral (HSI) and confocal imaging (CLSM) techniques in synergy with gas chromatography-ion mobility spectrometry (GC-IMS). Models based on partial least squares regression (PLSR) were developed using the full HSI spectrum variables as well as optimum variables selected through a competitive adaptive reweighted sampling algorithm. RESULTS: Prediction results for MC and TBARS using multiplicative scatter correction pre-processed spectra models demonstrated greater efficiency and predictability with determination coefficient of prediction of 0.928, 0.930 and root mean square error of prediction of 0.114, 1.002, respectively. Major structural changes were also observed during CLSM imaging, which were greatly pronounced in pork samples oven cooked for 15 and 20 h. These structural changes could be related to the denaturation of the major meat components, which could explain the loss of moisture and the formation of TBARS visualized from the HSI chemical distribution maps. GC-IMS identified 35 volatile components, including hexanal and pentanal, which are also known to have a higher lipid oxidation specificity. CONCLUSION: The synergistic application of HSI, CLSM and GC-IMS enhanced data mining and interpretation and provided a convenient way for analyzing the chemical, structural and volatile changes occurring in meat during processing. © 2021 Society of Chemical Industry.

8.
Sheng Li Xue Bao ; 73(2): 275-285, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33903889

RESUMO

This study aimed to explore the positive inotropic effect of phosphodiesterase type 9 (PDE9) inhibitor PF-04449613 in ratsand its cellular and molecular mechanisms. The heart pressure-volume loop (P-V loop) analysis was used to detect the effects of PF-04449613 on rat left ventricular pressure-volume relationship, aortic pressures and peripheral vessel resistance in healthy rats. The Langendorff perfusion of isolated rat heart was used to explore the effects of PF-04449613 on heart contractility. The cardiomyocyte sarcoplasmic reticulum (SR) Ca2+ transients induced by field stimulation and caffeine were used to analyze the mechanism underlying the effect of PF-04449613 using Fluo-4 AM as a Ca2+ indicator. The results indicated as follows: (1) PF-04449613 (5.5 mg/kg, ip) significantly increased the stroke work, cardiac output, stroke volume, end-systolic pressure and ejection fraction (P < 0.05), and decreased the end-systolic volume, end-diastolic volume and end-diastolic pressure (P < 0.05). Meanwhile, the systolic blood pressure was increased and diastolic blood pressure and arterial elastance were decreased after PF-04449613 treatment (P < 0.05). (2) PF-04449613 (0.001, 0.01, 0.1, 1 µmol/L) significantly increased the left ventricular developed pressure (LVDP) in a concentration-dependent manner in vitro (P < 0.05). (3) PF-04449613 (5 µmol/L) significantly increased the amplitude of SR Ca2+ transients mediated by facilitating sarcoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) (P < 0.05). (4) PF-04449613 (5 µmol/L) decreased the SR Ca2+ leak rate via ryanodine receptor 2 (RyR2) (P < 0.05). In conclusion, PF-04449613 exerted positive inotropic effect both in vivo and in vitro by enhancing SERCA2a activity.


Assuntos
Cálcio , Inibidores de Fosfodiesterase , Animais , Cálcio/metabolismo , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Diester Fosfórico Hidrolases , Ratos , Canal de Liberação de Cálcio do Receptor de Rianodina , Retículo Sarcoplasmático
9.
Artigo em Inglês | MEDLINE | ID: mdl-33900854

RESUMO

High-sodium-intake (HS) inhibited epithelial-sodium-channel (ENaC) in the aldosterone-sensitive-distal-nephron (ASDN) and Na+-Cl--cotransporter (NCC) by suppressing basolateral Kir4.1/Kir5.1 in the distal-convoluted-tubule (DCT) thereby increasing renal Na+ excretion but not affecting K+ excretion. The aim of the present study is to explore whether the deletion of Kir5.1 compromises the inhibitory effect of HS on NCC expression/activity and renal K+-excretion. Patch-clamp experiments demonstrated that HS failed to inhibit DCT-basolateral K+ channels and did not depolarize K+-currents (IK) reversal-potential of the DCT in Kir5.1 knockout (Kir5.1 KO) mice. Moreover, deletion of Kir5.1 not only increased the expression of Kir4.1, phosphor-NCC (pNCC) and total NCC (tNCC) but also abolished the inhibitory effect of HS on the expression of Kir4.1, pNCC and tNCC, and thiazide-induced natriuresis. Also, LS-induced stimulation of NCC expression/activity and the basolateral K+ channels in the DCT was absent in Kir5.1 KO mice. The deletion of Kir5.1 decreased ENaC currents in DCT2 and HS further inhibited ENaC activity in Kir5.1 KO mice. Finally, the measurement of basal renal K+ excretion rate with modified renal clearance method demonstrated that long-term HS inhibited renal K+ excretion rate and steadily increased plasma K+ levels in Kir5.1 KO mice but not in WT mice. We conclude that Kir5.1 plays an important role in mediating the effect of HS intake on the basolateral K+ channels in the DCT and NCC activity/expression. Kir5.1 is involved in maintaining renal ability of K+ excretion during HS intake.

10.
Science ; 372(6538): 171-175, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33833120

RESUMO

Sexual reproduction in angiosperms relies on precise communications between the pollen and pistil. The molecular mechanisms underlying these communications remain elusive. We established that in Arabidopsis, a stigmatic gatekeeper, the ANJEA-FERONIA (ANJ-FER) receptor kinase complex, perceives the RAPID ALKALINIZATION FACTOR peptides RALF23 and RALF33 to induce reactive oxygen species (ROS) production in the stigma papillae, whereas pollination reduces stigmatic ROS, allowing pollen hydration. Upon pollination, the POLLEN COAT PROTEIN B-class peptides (PCP-Bs) compete with RALF23/33 for binding to the ANJ-FER complex, leading to a decline of stigmatic ROS that facilitates pollen hydration. Our results elucidate a molecular gating mechanism in which distinct peptide classes from pollen compete with stigma peptides for interaction with a stigmatic receptor kinase complex, allowing the pollen to hydrate and germinate.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Flores/metabolismo , Peptídeos/metabolismo , Pólen/fisiologia , Polinização , Proteínas Quinases/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Estado de Hidratação do Organismo , Espécies Reativas de Oxigênio/metabolismo
11.
J Int Med Res ; 49(4): 3000605211009689, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33906531

RESUMO

OBJECTIVE: The serum glucose/potassium ratio (GPR) is a potential prognostic predictor for acute brain injury-related diseases. We calculated the serum GPR in patients with acute intracerebral hemorrhage (ICH) and explored its prognostic value for long-term prognoses and ICH severity. METHODS: This retrospective cohort study consecutively included 92 patients with ICH and 92 healthy controls. The National Institutes of Health Stroke Scale (NIHSS) score, Glasgow coma scale (GCS) score, and hematoma volume were used to assess severity. A modified Rankin Scale score > 2 at 90 days post-stroke was defined as a poor outcome. RESULTS: The serum GPR was significantly higher in patients than controls. The serum GPR was weakly correlated with the NIHSS score, GCS score, and hematoma volume. The serum GPR, GCS score, and hematoma volume were independently associated with poor outcomes. In the receiver operating characteristic curve analysis, the serum GPR remarkably discriminated patients at risk of poor outcomes at 90 days. The serum GPR significantly improved the prognostic predictive capability of hematoma volume and tended to increase that of the GCS score. CONCLUSION: Serum GPR is an easily obtained clinical variable for predicting clinical outcomes after ICH.

12.
Dalton Trans ; 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33908538

RESUMO

The Ti-based metal-organic framework (Ti-MOF) MIL-125 with tunable crystalline size in the range of ca. 50 nm to 1500 nm was synthesized by the coordination modulation method using trans-cinnamic acid (CA) as a modulator. The coordination modulation also induced hierarchical porosity and structure defects on the nanocrystals. A significant size-dependent catalytic activity towards the oxidative desulfurization (ODS) reaction was observed for these MIL-125 nanocrystals. In particular, the MIL-125 nanocrystals with a mean size of ca. 50 nm exhibit dramatically enhanced catalytic performance for the bulky sulfur compound 4,6-dimethyldibenzothiophene (4,6-DMDBT) compared to the microcrystals. It is demonstrated that the size modulation of MIL-125 is an effective approach to promote its performance for the catalysis of bulky molecules.

13.
Zhongguo Zhen Jiu ; 41(3): 257-62, 2021 Mar 12.
Artigo em Chinês | MEDLINE | ID: mdl-33798306

RESUMO

OBJECTIVE: To evaluate the clinical efficacy of acupuncture at different timings in acute stage for limb dysfunction in patients with cerebral infarction. METHODS: A total of 101 patients with cerebral infarction limb dysfunction were divided into an early exposure group (n=51) and a late exposure group (n=50) according to the time of first acupuncture treatment during the acute phase. SPSS 25.0 software was used to balance the baseline between the two groups, and 31 pairs of matched patients were included, including 31 cases in the early exposure group and 31 cases in the late exposure group. The two groups were treated with Xingnao Kaiqiao acupuncture at Shuigou (GV 26), Neiguan (PC 6), Sanyinjiao (SP 6), Jiquan (HT 1), Chize (LU 5), Weizhong (BL 40), etc., once a day, and the course of treatment was not limited. In the early exposure group, acupuncture was started after 1 to 3 days of onset; in the late exposure group, acupuncture was started after 11 to 14 days of onset. The modified Rankin scale (mRS) grade was recorded before treatment, 30 and 60 days after onset; Fugl-Meyer assessment (FMA) grade was observed before treatment and 30 days after onset; the effect of acupuncture timing on the patients was analyzed by logistic analysis. RESULTS: Compared before treatment, the mRS grade at 30 and 60 days after onset in the early exposure group was improved (P<0.05), which was superior to the late exposure group (P<0.05); compared before treatment, the FMA grade at 30 days after onset in the early exposure group was improved (P<0.05), which was superior to the late exposure group (P<0.05). The timing of acupuncture was independently correlated with the disability status and the severity of motor dysfunction at 30 days after onset, and the disability status at 60 days after onset (P<0.05). Compared with the late exposure group, the possibility of becoming non-disabled at 30 days after onset (OR=22.882, 95%CI: 4.034-129.778), normal limb motor dysfunction (OR=22.320, 95%CI: 3.454-144.213) and non-disabled at 60 days after onset (OR=8.650, 95%CI: 2.437-30.696) in the early exposure group was increased. CONCLUSION: The timing of acupuncture is an independent factor affecting the disability status and limb motor dysfunction in patients with cerebral infarction, and the effect of early intervention may be better than late intervention.


Assuntos
Terapia por Acupuntura , Acidente Vascular Cerebral , Pontos de Acupuntura , Infarto Cerebral/complicações , Infarto Cerebral/terapia , Humanos , Projetos Piloto , Estudos Prospectivos , Resultado do Tratamento
14.
J Vasc Interv Radiol ; 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33819601

RESUMO

PURPOSE: To evaluate the performance of the Integrated Liver Inflammatory Score (ILIS) in predicting survival in hepatocellular carcinoma (HCC) patients who received transarterial chemoembolization (TACE), and to compare ILIS to other prognostic scoring systems and inflammatory indices. MATERIALS AND METHODS: This study included 192 patients with unresectable HCC who underwent TACE from three medical centers. The potential risk factors of patients' overall survival (OS) were determined by multivariate Cox regression analysis. The predictive performances of ILIS in 1-, 2-, 3-, 4-, and 5-year survivals were evaluated using receiver operating characteristic (ROC) curves. The discriminatory power in the OS of ILIS and the other known scoring systems or inflammatory indices were determined by C-statistic. RESULTS: Multivariate regression analysis showed that high ILIS (P=0.047), low lymphocyte count (P=0.034), beyond up-to-seven criteria (P=0.021), and non-responder to the first TACE session (P=0.039) were risk factors for poor prognosis after TACE. The predictive performances of ILIS for 1-, 2-, 3-, 4-, and 5-year survivals were fairly good, with AUCs of 0.627, 0.631, 0.621, 0.577, and 0.681, respectively. ILIS outperformed other standard scoring systems and inflammatory indices in predicting OS, with a C-statistic of 0.625. CONCLUSION: ILIS is a powerful prognostic index for survival of HCC patients after TACE, suggesting that pretreatment ILIS should be considered during the patient evaluation process.

15.
Arch Immunol Ther Exp (Warsz) ; 69(1): 11, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33856572

RESUMO

Visfatin is a multifunctional protein involved in inflammatory immune stress. The aim of current study was to explore the role of visfatin in lipopolysaccharide (LPS)-induced intestinal mucosal inflammation and to confirm its cellular effect in inflammatory immune response through silencing of Toll-like receptors (TLRs). We divided Kunming mice into three groups: Saline group, LPS group, and LPS + visfatin group and performed hematoxylin and eosin staining, immunohistochemistry, quantitative polymerase chain reaction, Western blot, enzyme linked immunosorbent assay and RNA-seq analysis. Pretreatment of visfatin improves LPS-stimulated reduction of tight junction protein 1 (ZO-1) and secretory immunoglobulin A, inhibits overexpression of Claudin-1 and vascular endothelial growth factor, and reduces intestinal mucosal damage and inflammation. RNA-seq analysis of cellular transcriptomes indicated that visfatin is involved in down-regulation of mRNA level of TLR4 as well as attenuation of protein levels of TLR8 and nucleotide-binding oligomerization domain-containing protein 2, revealing that visfatin could reduce intestinal mucosal inflammation through TLR signaling pathway in mice ileum. In RAW264.7 cells, the genes silencing of Toll/IL-1R family, such as TLR4, TLR2, and IL-1R1, was accompanied by decreased expressions of inflammatory factors (TNF-α, IL-1ß, IL-6 and MCP-1) along with lower cellular visfatin levels. Hence, visfatin maintains the intestinal mucosal barrier structure and attenuates the intestinal mucosal inflammation through the TLR signaling pathway. Likewise, the Toll/IL-1R family regulates the release of visfatin, which can participate in the inflammatory reaction through the regulation of inflammatory factors.

16.
Pharmacol Res ; : 105610, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33857625

RESUMO

During pregnancy, various physiological changes occur that can alter the pharmacokinetics of antiepileptic drugs, such as lamotrigine (LTG). Anticipating the change in LTG dose required to achieve a pre-pregnancy target concentration is challenging. This study aimed to develop a refined population pharmacokinetic (PopPK) model of LTG in pregnant women with epilepsy (WWE) to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen. On that basis, a coarsened model containing only clinical variables was also developed to examine its predictive performance compared to the refined model. In total, 322 concentration-time points from 51 pregnant WWE treated with LTG were employed to establish a refined PopPK model that included endogenous estrogen profiles, variants of candidate genes for LTG-metabolizing enzymes and -transporter proteins, and other clinical variables and a coarsened model that included only clinical variables, respectively. Data from an additional 11 patients were used for external validation of these two models. A nonlinear mixed-effect modeling approach was used for PopPK analysis of LTG. The standard goodness-of-fit method, bootstrap, normalized prediction distribution errors and external evaluation were adopted to estimate the stability and predictive performance of the candidate models. Akaike information criterion (AIC) was used to compare the goodness of fit between these two models. A lower AIC indicates a better fit of the data and the preferred model. Recommended dosing regimens for pregnant WWE were selected using Monte Carlo simulation based on the established optimal model. In the refined PopPK model, the population mean of apparent LTG clearance (CL/F) in pregnant WWE was estimated to be 2.82L/h, with an inter-individual variability of 23.6%. PopPK analysis indicated that changes in estrogen profile during pregnancy were the predominant reason for the significant variations in LTG-CL/F. Up to the 3rd trimester, the concentration accumulation effect of E2 increased LTG-CL/F by 5.109L/h from baseline levels. Contrary to effect of E2, E3 as the main circulating estrogen in pregnancy with a peak value of 34.41ng/mL is 1000-fold higher than that in non-pregnancy reduced LTG-CL/F by 1.413L/h. In addition, the UGT2B7 rs4356975 C>T and ABCB1 rs1128503 A>G variants may contribute to a better understanding of the inter-individual variability in LTG-CL/F. LTG-CL/F was 1.66-fold higher in UGT2B7 rs4356975 CT or TT genotype carriers than in CC genotype carriers. In contrast, ABCB1 rs1128503 GG genotype carriers had only 71.9% of the LTG-CL/F of AA or AG genotype carriers. In the coarsened PopPK model, the gestational age was a promising predictor of changes in LTG-CL/F. When comparing these two models, the refined PopPK model was favored over the coarsened PopPK model (AIC = -30.899 vs. -20.017). Monte Carlo simulation based on optimal PopPK model revealed that the LTG dosage administered to carriers of the UGT2B7 rs4356975 CT or TT genotype required a 33% to 50% increase to reach the pre-pregnancy target concentration, and carriers of the ABCB1 rs1128503 GG genotype required a 33% to 66% lower dose of LTG than carriers of the ABCB1 rs1128503 AA or AG genotype. Changes in estrogen profile during pregnancy was a better predictor of variations in LTG-CL/F than gestational age. The developed model based on estrogen profile and pharmacogenetics can serve as a foundation for further optimization of dosing regimens of LTG in pregnant WWE.

17.
ACS Appl Mater Interfaces ; 13(14): 15973-15982, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33793212

RESUMO

Encapsulation of probiotic bacteria can enhance their functionality when used in combination with antibiotics for treating intestinal tract infections. The interaction strength of encapsulating shells, however, varies among the encapsulation methods and impacts encapsulation. Here, we compared the protection offered by encapsulating shells with different interaction strengths toward probiotic Bifidobacterium breve against simulated gastric fluid and tetracycline, including protamine-assisted SiO2 nanoparticle yolk-shell packing (weak interaction across a void), alginate gelation (intermediate interaction due to hydrogen binding), and ZIF-8 mineralization (strong interaction due to coordinate covalent binding). The presence of encapsulating shells was demonstrated using X-ray-photoelectron spectroscopy, particulate microelectrophoresis, and dynamic light scattering. Strong interaction upon ZIF-8 encapsulation caused demonstrable cell wall damage to B. breve and slightly reduced bacterial viability, delaying the growth of encapsulated bacteria. Cell wall damage and reduced viability did not occur upon encapsulation with weakly interacting yolk-shells. Only alginate-hydrogel-based shells yielded protection against simulated gastric acid and tetracycline. Accordingly, only alginate-hydrogel-encapsulated B. breve operated synergistically with tetracycline in killing tetracycline-resistant Escherichia coli adhering to intestinal epithelial layers and maintained surface coverage of transwell membranes by epithelial cell layers and their barrier integrity. This synergy between alginate-hydrogel-encapsulated B. breve and an antibiotic warrants further studies for treating antibiotic-resistant E. coli infections in the gastrointestinal tract.

18.
Haematologica ; 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33853293

RESUMO

Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression is a common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) is used in combination with azacitidine (AZA), a DNA-methyltransferase inhibitor (DNMTi), to treat patients with AML. Despite promising response rates to VEN/AZA, resistance to the agent is common. One identified mechanism of resistance is the upregulation of myeloid cell leukemia-1 protein (MCL1). Pevonedistat (PEV), a novel agent that inhibits NEDD8-activating enzyme, and AZA both upregulate NOXA (PMAIP1), a BCL2 family protein that competes with effector molecules at the BH3 binding site of MCL1. We demonstrate that PEV/AZA combination induces NOXA to a greater degree than either PEV or AZA alone, which enhances VEN-mediated apoptosis. Herein, using AML cell lines and primary AML patient samples ex vivo, including in cells with genetic alterations linked to treatment resistance, we demonstrate robust activity of the PEV/VEN/AZA triplet. These findings were corroborated in preclinical systemic engrafted models of AML. Collectively, these results provide preclinical rational for combining PEV/VEN/AZA as a novel therapeutic approach in overcoming AML resistance current therapies.

19.
Plant Dis ; 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33851863

RESUMO

Bletilla striata (Thunb.) Rchb. f. (Orchidaceae), a perennial plant, is a traditional Chinese herb (known as baiji) used to treat hemorrhage, scalding injuries, gastric ulcers, pulmonary diseases, and inflammation (Zu et al. 2019). In May 2019, foliar blight symptoms were observed on approximately 25% of B. striata (cv. Guiji No.1) plants in three plantations (∼4.5 hectares in total) in Ziyuan County, Guangxi Province, China. Initial symptoms were light brown, irregular, water-soaked spots on the plant leaves. Several spots often merged, forming large, irregular, lesions that extended onto the stem after a week and led to leaf abscission, and even plant death. To determine the causal agent, 5-mm squares cut from the margin of 6 infected leaves were surface disinfected in 1% sodium hypochlorite solution for 2 min, rinsed three times with sterile distilled water, plated on potato dextrose agar (PDA), and incubated at 28°C (12-h light-dark cycle) for 3 days. The emerging hyphal tip of a single mycelium was transferred to PDA to obtain pure cultures of the isolates. Twenty isolates were obtained, and 10 isolates (50%) were initially white before turning light brown (∼4 days). Septate hyphae were 4.29 to 10.75 µm (average 6.42 µm) in diameter and branched at right angles with a constriction at the origin of the branch point. Staining with 1% safranin O and 3% KOH solution (Bandoni 1979) revealed multinucleated cells (3 to 9 nuclei per cell, n = 142). This morphology was typical of Rhizoctonia solani Kühn (Meyer et al. 1990). For species confirmation by molecular identification, three isolates (BJ101.6, BJ101.11, and BJ102.2) were cultured on PDA for 4 days, then DNA was extracted from the mycelium using the CTAB method (Guo et al. 2000), and the ribosomal ITS1-5.8S-ITS2 region was amplified by PCR using the universal fungal primers ITS1 and ITS4 (White et al. 1990). Internal transcribed spacer (ITS) sequences of strains BJ101.6, BJ101.11, and BJ102 (deposited in GenBank under accession nos MT406271, MT892815, and MT892814, respectively) had over 99% similarity with those of R. solani AG-2-2 IIIB in GenBank (accession nos JX913810 and AB054858) (Carling et al. 2002; Hong et al. 2012). Phylogenetic analysis using ITS sequences showed that the isolates clustered monophyletically with strains of R. solani AG-2-2 IIIB. The AG of the isolates was confirmed by their ability to grow well on PDA at 35°C, which separates AG-2-2 IIIB from AG-2-2 IV (Inokuti et al. 2019). Based on morphological characteristics and nucleotide sequence analysis, the isolates were identified as R. solani AG-2-2 IIIB. Pathogenicity was tested using 1.5-year-old B. striata (cv. Guiji No.1) plants grown in a perlite and peat moss mixture (1:3) in 7-cm pots. Healthy leaves on plants were inoculated with an aqueous suspension (approximately 1 × 105 hyphal fragments/mL, 100 µL) prepared from cultures of strains BJ101.6, BJ101.11, and BJ102.2, each isolate was inoculated onto three plants; three other plants with sterile water served as controls. All plants were enclosed in transparent plastic bags and incubated in a greenhouse at 28°C for 14 days (12-h photoperiod). Three days post-inoculation, leaves exposed to the mycelial fragments had symptoms similar to those originally observed in the field. No symptoms were detected on control plants. Experiments were replicated three times with similar results. To fulfill Koch's postulates, R. solani AG-2-2 IIIB was re-isolated on PDA from symptomatic leaves and confirmed by sequencing, whereas no fungus was isolated from the control plants. To our knowledge, this is the first report of R. solani AG-2-2 IIIB causing foliar blight on B. striata in China, and these findings will be useful for further control strategies and research.

20.
Int J Biol Macromol ; 182: 612-625, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33838200

RESUMO

As generally accepted, inhibiting the bacterial invasion at initial stage and promoting the behavior of related osteogenesis cells afterwards is crucial to achieve favorable osteointegration after dental implantation. In this study, a novel combined structured hydrogel composed of chitosan and pore-closed poly(lactic-co-glycolic acid) microparticles was prepared and characterized. In vitro and in-vivo studies have identified that this biocompatible material can rapidly release vancomycin at initial 2 days and then sustainedly release recombinant human bone morphogenetic protein-2 for about 12 days, thus respectively accomplish antibacterial and osteogenesis functions. This sequential drug release system can be used as a promising coating material to improve the surface conditions of dental implant to enhance the osteointegration after surgery.

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