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1.
Food Chem ; 371: 131278, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34808763

RESUMO

α-Amylase inhibition of chlorogenic acid (CHA) and its component moieties including quinic acid (QA) and caffeic acid (CA) were characterized by IC50, inhibition kinetics, fluorescence quenching, isothermal titration calorimetry, differential scanning calorimetry and molecular docking. QA was found with the highest inhibitory activity in a competitive-mode, and caffeoyl substitution significantly decreased its inhibition but maintained inhibition type. Interestingly, QA hardly quenched α-amylase fluorescence, while CA quenched that significantly without inhibitory activity. This resulted from lack of aromatic ring in QA that can form π-conjugation with α-amylase fluorescent residues. Besides, the binding constant of QA with α-amylase was higher than CHA. Additionally, QA and CA decreased but CHA remained α-amylase thermal stability, indicating that change in α-amylase spatial structure was related with enzyme residue sites involved in interactions with inhibitors, instead of with inhibition effect. Conclusively, caffeoyl substitution decreased α-amylase inhibition of QA through reducing its binding affinity to the enzyme.


Assuntos
Ácido Clorogênico , Ácido Quínico , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , alfa-Amilases
2.
Food Chem ; 367: 129846, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34399273

RESUMO

The inhibition of α-glucosidase by nine galloyl-based polyphenols with free and unfree galloyl moieties (GMs) was studied. The results show that the inhibitory activity increased with the free GM number increasing. For the compounds with unfree GMs, ellagic acid and hexahydroxydiphenoyl group contributed to the enzyme inhibition. Free GMs could bind not only with the active site of α-glucosidase (competitive inhibition character), but also with the non-active sites (uncompetitive one); however, the former binding interaction was stronger than the latter one. All polyphenols that had inhibitory effects quenched α-glucosidase fluorescence in a static mode through forming a polyphenol-enzyme complex. The number of amino acid residues involved in polyphenol-enzyme binding interactions (hydrogen bonding and π-conjugations) increased with the inhibitory activity increasing. Additionally, two polyphenols with 5 free GMs showing certain hypoglycemic effects in maltose-loading test suggests that GM may be an advisable functional factor for alleviation of type II diabetes symptoms.


Assuntos
Diabetes Mellitus Tipo 2 , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases , Humanos , Simulação de Acoplamento Molecular , Polifenóis
3.
J Cancer Res Ther ; 17(5): 1269-1274, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34850777

RESUMO

Objectives: The objective of the study was to assess the clinical efficacy of computed tomography (CT)-guided cryoablation as a means to treat adrenal metastasis (AM) secondary to lung cancer. Materials and Methods: This study was a single-center retrospective study that analyzed 39 consecutive patients with AM secondary to lung cancer who underwent CT-guided cryoablation in our center. The rates of complete ablation, local recurrence, local recurrence-free survival (RFS), and overall survival (OS) were analyzed. Results: The rates of primary and secondary complete ablation were 94.9% and 100%, respectively, and none of the patients suffered from a hypertensive crisis associated with the treatment. Over the follow-up period, 20.5% of the patients experienced local recurrence, and the median RFS duration was 26 months. The cumulative 1-, 3-, and 5-year local RFS rates in this study were 84.6%, 51.3%, and 5.9%, respectively. Extra-adrenal gland metastases were detected in five patients. Over the course of follow-up, 26 patients died. The mean OS duration was 34 months with cumulative 1-, 3-, and 5-year OS rates of 89.7%, 53.4%, and 8.3%, respectively. Advanced age (P = 0.001), primary adenocarcinoma (P = 0.006), other primary lung cancers (P = 0.038), and primary Stage III lung cancers (P = 0.007) were all found to be independent predictive factors of poor OS in these patients. Conclusion: CT-guided cryoablation can be safely and effectively used to control AM secondary to lung cancer, and patients with AM secondary to lung squamous cell carcinoma may be best suited for this form of treatment.

4.
Diabetol Metab Syndr ; 13(1): 137, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34801077

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is a common complication of diabetes mellitus. Accumulating studies suggest that the deregulation of circular RNA (circRNA) is involved in DN pathogenesis. This study aimed to investigate the role of circSMAD4 in DN models. METHODS: Mice were treated with streptozotocin to establish DN models in vivo. Mouse glomerulus mesangial cells (SV40-MES13) were treated with high glucose to establish DN models in vitro. The expression of circSMAD4, miR-377-3p and bone morphogenetic protein 7 (BMP7) mRNA was measured by quantitative real-time PCR (qPCR). The releases of inflammatory factors were examined by ELISA. The protein levels of fibrosis-related markers, apoptosis-related markers and BMP7 were checked by western blot. Cell apoptosis was monitored by flow cytometry assay. The predicted relationship between miR-377-3p and circSMAD4 or BMP7 was validated by dual-luciferase reporter assay or pull-down assay. RESULTS: CircSMAD4 was poorly expressed in DN mice and HG-treated SV40-MES13 cells. HG induced SV40-MES13 cell inflammation, extracellular matrix (ECM) deposition and apoptosis. CircSMAD4 overexpression alleviated, while circSMAD4 knockdown aggravated HG-induced SV40-MES13 cell injuries. MiR-377-3p was targeted by circSMAD4, and miR-377-3p enrichment partly reversed the effects of circSMAD4 overexpression. BMP7 was a target of miR-377-3p, and circSMAD4 regulated BMP7 expression by targeting miR-377-3p. MiR-377-3p overexpression aggravated HG-induced injuries by suppressing BMP7. CONCLUSION: CircSMAD4 alleviates HG-induced SV40-MES13 cell inflammation, ECM deposition and apoptosis by relieving miR-377-3p-mediated inhibition on BMP7 in DN progression.

5.
Psychol Res Behav Manag ; 14: 1805-1821, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34754250

RESUMO

Purpose: The purpose of our study is to explore the antecedents and consequences of team flexibility in an organizational change context. In this regard, we considered team flexibility as an important theoretical mechanism under which the insiders would adapt to organizational change. Participants and Methods: A sample of 602 individual data that was nested in 108 teams and 43 organizations was used in this study, collecting from 43 enterprises located in mainland China through questionnaires. We adopted HLM 6.08 to testify all the hypothesized relationships and used the Monte Carlo method to create the confidence intervals for all the indirect effects. Results: The empirical results show that 1) balance dimension of ambidexterity and change leadership have a significant positive effect on team flexibility; 2) balance dimension of ambidexterity only has marginal significant effects on employee change-specific adaptive behavior, change-specific proactive behavior, and change fairness. And change leadership has significant positive effects on the three outcomes; 3) team flexibility has a positive influence on the three outcomes. 4) Team flexibility plays a significant mediating role in the links between the balance dimension of ambidexterity and the three outcomes. In addition, team flexibility only has a significant indirect effect on the relationship between change leadership and change-specific adaptive behavior and proactive behavior. Conclusion: The current study reveals how team flexibility is established and how such flexibility is associated with employee-level change-specific behavior and perception under an organizational change context. The study indicates that team flexibility is contingent on two factors across two levels: change leadership at team level and balanced ambidexterity at organizational level, which also contributes to individual outcomes of organizational change.

6.
Int J Mol Sci ; 22(22)2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34829990

RESUMO

Low-intensity pulsed ultrasound (LIPUS) has been proved to promote the proliferation of myoblast C2C12. However, whether LIPUS can effectively prevent muscle atrophy has not been clarified, and if so, what is the possible mechanism. The aim of this study is to evaluate the effects of LIPUS on muscle atrophy in hindlimb unloading rats, and explore the mechanisms. The rats were randomly divided into four groups: normal control group (NC), hindlimb unloading group (UL), hindlimb unloading plus 30 mW/cm2 LIPUS irradiation group (UL + 30 mW/cm2), hindlimb unloading plus 80 mW/cm2 LIPUS irradiation group (UL + 80 mW/cm2). The tails of rats in hindlimb unloading group were suspended for 28 days. The rats in the LIPUS treated group were simultaneously irradiated with LIPUS on gastrocnemius muscle in both lower legs at the sound intensity of 30 mW/cm2 or 80 mW/cm2 for 20 min/d for 28 days. C2C12 cells were exposed to LIPUS at 30 or 80 mW/cm2 for 5 days. The results showed that LIPUS significantly promoted the proliferation and differentiation of myoblast C2C12, and prevented the decrease of cross-sectional area of muscle fiber and gastrocnemius mass in hindlimb unloading rats. LIPUS also significantly down regulated the expression of MSTN and its receptors ActRIIB, and up-regulated the expression of Akt and mTOR in gastrocnemius muscle of hindlimb unloading rats. In addition, three metabolic pathways (phenylalanine, tyrosine and tryptophan biosynthesis; alanine, aspartate and glutamate metabolism; glycine, serine and threonine metabolism) were selected as important metabolic pathways for hindlimb unloading effect. However, LIPUS promoted the stability of alanine, aspartate and glutamate metabolism pathway. These results suggest that the key mechanism of LIPUS in preventing muscle atrophy induced by hindlimb unloading may be related to promoting protein synthesis through MSTN/Akt/mTOR signaling pathway and stabilizing alanine, aspartate and glutamate metabolism.

7.
Anal Biochem ; : 114403, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34610335

RESUMO

The antibody of Cry1Ab-51 was immobilized orientationly in a simple and effective way on Colloidal gold nanoparticles(CGNP) by The staphylococcal protein A(SPA) affinity with the FC fragement of mouse IgG.The lateral flow detection test strip assembled with the probe by orientational labeled method at the optimum operational conditons (new probe) is 10 times more sensitive than the test strip assembled with the probe labeled by Adsorption(conventionally probe). The affinity experiment have shown that the affinity of the new probe is much higher than the conventionally probe. The Immunochromatography gold strip(ICG strip) assembled by the new probe was highly specific to Cry1Ab with no cross-reaction with other transgenic proteins. And it was proved that the specificity of the new probe have no significant change. Furthermore, the ICG strips assembled by the new probe could be stored for 12 months under dry conditions without significant loss of sensitivity.The Orientational labeling the antibodies with Staphylococcus A protein on Colloidal gold proved to be suitable for improving the sensitivity of the ICG strips.

8.
Cancer Sci ; 2021 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-34657342

RESUMO

TCF1+CD8+T cells are reported to exhibit stem-like properties with the ability to self-renew and differentiate into terminal effector T cells (TCF1-CD8+T cells) to enhance antitumor response. Previous studies indicated that TCF1+CD8+ tumor-infiltrating lymphocytes (TILs) are related to response to immunotherapy. However, their role in predicting prognosis for patients with primary small cell carcinoma of the esophagus (PSCCE) remains unclear. In this study, the expression of TCF1+CD8+T was analyzed by multiplex fluorescence immunohistochemistry in tumor tissues of 79 patients with PSCCE. High infiltration of TCF1+CD8+T cells had longer overall survival (OS) than low infiltration (P = .009, hazard ratio [HR] = 0.506). High TCF1+CD8/CD8 ratio (>21%) showed superior OS compared with low ratio (≤21%) (P < .001, HR = 0.394). In the validation set (n = 20), the prognostic value of TCF1+CD8+T cells on OS was also verified. TCF1+CD8+T cells are strong prognostic predictors.

9.
Front Nutr ; 8: 766756, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34692755

RESUMO

The inhibition mechanism of four caffeic and tartaric acid derivates, including caffeic acid (CA), tartaric acid (TA), caftaric acid (CFA) and chicoric acid (CHA) against α-glucosidase was characterized by substrate depletion, fluorescence quenching, isothermal titration calorimetry (ITC) and molecular docking. TA and CA were found with the highest and no inhibition effect respectively, and caffeoyl substitution at 2 and/or 3-OH of TA significantly decreased its inhibition. The enzyme inhibition effects of organic acids were not in an inhibitor concentration-dependent mode, and there was a rush increase in inhibition at a respective acidic pH value, especially for CFA and CHA, suggesting the important role of acidic pH in the enzyme inhibition for both compounds. Besides, CA, CFA and CHA were shown with strong quenching effects on α-glucosidase fluorescence because of π-conjugations between aromatic ring of caffeoyl moiety and that of enzyme fluorescent residues. However, no fluorescence quenching effect was observed for TA due to lack of aromatic ring. Additionally, a direct binding interaction behavior was observed for TA with α-glucosidase according to the fitted independent binding model in ITC, but not for CFA and CHA. Therefore, both acidic pH and binding interactions of TA with α-glucosidase resulted in the enzyme inhibition.

10.
J Therm Biol ; 100: 103080, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34503768

RESUMO

High mortality is a frequent occurrence during live transport of shrimp species and the biochemical mechanism remains unknown. This study aimed to explore the influence of combined stress of acute cold exposure (AC) and waterless duration (WD) on survivability and biochemical response of shrimp L. vannamei during live transport. The shrimps in NC and AC groups remained the total survivability throughout the experiment while the shrimps exposed to AC + WD stress exhibited significantly higher mortality since 6h afterwards (P < 0.05) and the median survival time was calculated at 10.46 h. Moreover, the typical combined stress points at AC + WD3h, AC + WD6h and AC + WD9h were assigned for exploring the immunological and antioxidative responses. For immunity response, the total hemocyte counts (THC) decreased with the prolongation of duration time and the activities of non-specific immunity enzymes such as phenol oxidase (PO), acid phosphatase (ACP), alkaline phosphatase (AKP), aspartate aminotransferase (AST) and alanine transaminase (ALT) were significantly elevated in AC + WD9h groups (P < 0.05). Moreover, compared with that in NC group, the significant accumulation of reactive oxygen species (ROS) was observed in AC group and then reduced in combined stress groups (P < 0.05), with the highest level of malonaldehyde (MDA) in AC and AC + WD3h groups. Overall, the significant elevation of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and total antioxidant capacity (T-AOC) was detected in AC + WD9h group (P < 0.05). Furthermore, the accumulative pathological impairment on hepatopancreas tissue revealed the cytoskeleton degradation. In addition, correlation analyses visualized the correlation between oxidative stress and biochemical response. This study not only deepens our understanding on the biochemical mechanism of shrimp mortality induced by combined stress, but also provides a potential strategy for improving the management of L. vannamei during live transport.

11.
J Physiol Biochem ; 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34453705

RESUMO

Weight-bearing training, as one of resistance exercises, is beneficial to bone health. Myostatin (MSTN) is a negative regulator of skeletal muscle growth and development. Animals lacking MSTN show increased bone mineral density (BMD). The aim of this study was to investigate the preventive effect of weight-bearing training on bone loss in ovariectomized rats and whether it was related to MSTN. In this study, the rats were randomly assigned to three group: Sham-ovariectomized (Sham), ovariectomized (OVX), ovariectomized and weight-bearing training (OWT). The rats in the OWT group ran at 20-m/min bearing with 35% of their body weight for 6 days/week. After 10 weeks, compared with the OVX group, weight-bearing training increased the BMD of total femur and trabecular bone by 8.13% and 57.44%, respectively. The OVX-induced destruction of bone microarchitecture including the thickness and number of trabeculae and bone volume fraction was all significantly improved (9.26%, 47.68%, 63.03%) in the OWT group. The OVX-induced degradation of bone mechanical properties was significantly enhanced in the OWT group (maximum load increased by 35.46%, stiffness increased by 89.19%, energy absorption increased by 53.4%; elastic modulus increased by 26.3%). Ten-week weight-bearing training also significantly upregulated the mRNA and protein expression of Wnt1 and ß-catenin, which is crucial in bone development. Compared with the Sham group, MSTN in serum and muscle increased in the OVX group, but it decreased in the OWT group compared with the OVX group. Its receptor ActRIIB and downstream molecules Smad2/3 in the OVX group were downregulated in bone by weight-bearing training. The results indicated that MSTN is an important myokine for weight-bearing training to attenuate bone loss in ovariectomized rats.

12.
Bioorg Chem ; 115: 105235, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34388484

RESUMO

α-Glucosidase inhibition of 11 flavonoids, including myricetins, quercetins and catechins were studied through initial reaction velocity, IC50 value, inhibition kinetics, fluorescence quenching and molecular docking. It was found that C4 = O, C2 = C3, 3-OH and 5'-OH were essential moieties for α-glucosidase inhibition of myricetin that was shown with the highest inhibitory activity. The trans-conformational catechins was shown with stronger inhibition effects than the cis-conformational ones. Further, gallocatechin was an uncompetitive inhibitor, while myricetin, myricetrin, quercetin and catechin were competitive ones. 3-OH and 5'-OH promoted myricetin to bind with the enzyme active site through hydrogen bondings. The presence of C4 = O and C2 = C3 increased electron delocalization in ring A-C for myricetin and quercetin, and this enhanced stability of π-conjugations with aromatic residues of amino acids. However, 5'-OH decreased the quenching effects because it limited π-conjugations of ring B with key fluorescent residues. Notably, for same flavonoid sort, the constants that indicate binding affinity of flavonoids to α-glucosidase, including reciprocal of competitive inhibition constant, fluorescence quenching constant and binding energy followed same order as the inhibitory activity, indicating that α-glucosidase inhibition of the flavonoids resulted from binding interactions between them, and that the methods above can be combined reasonably to characterize flavonoid-enzyme binding interactions.

13.
Brain Cogn ; 152: 105771, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34217125

RESUMO

Tension is a bridge between music structure and emotion. It is known that tension is affected by prediction in music listening as music unfolds. Combining behavioral and neural responses, the current research investigated how musical predictions influence tension in the process of prediction build-up based on musical context (anticipatory stage) and its integration with upcoming stimuli (integration stage). The results showed that, at the anticipatory stage, compared with high-prediction conditions, in low-prediction conditions tension curve changed faster and unstable, and a larger N5 in ERP response was elicited. Furthermore, at the integration stage, compared with congruent conditions, in incongruent conditions the behavioral rating of tension were higher regardless of the predictability of the final chord; a right negativity and P600 were elicited, and the amplitude of P600 was modulated by the predictability of the final chord. These results indicated that the effect of prediction on tension was modulated by contextual predictability. The findings provide a more comprehensive view on how musical prediction affects musical tension.


Assuntos
Música , Estimulação Acústica , Percepção Auditiva , Eletroencefalografia , Emoções , Humanos
14.
RSC Med Chem ; 12(6): 902-914, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34223158

RESUMO

The arylhydrocarbon receptor (AHR) is a ligand activated transcription factor that controls the expression of a number of immunosuppressive signaling molecules, including the immune checkpoint proteins PD-1/L1 and cytokine IL-10. AHR activation also stimulates the formation and recruitment of tolerogenic dendritic cells, tumor associated macrophages, and regulatory T cells in the tumor microenvironment, which restrains antitumoral immune response. Overexpression of AHR has been observed in a number of different types of cancer and suggested to contribute to immune dysfunction and cancer progression. One prominent endogenous ligand of AHR is the oncometabolite kynurenine, a product of tryptophan metabolism catalyzed by the dioxygenases IDO1 and TDO that are often aberrantly activated in cancer. AHR has gained significant interest as a drug target for the development of novel small molecule cancer immunotherapies, as evidenced by the advancement of two clinical candidates into phase 1 clinical trials in patients with advanced cancer. Discussed in this Review is a brief background of AHR in immuno-oncology and the recent progress in the discovery and development of AHR antagonists.

15.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34074794

RESUMO

The DNA-sensing enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) regulates inflammation and immune defense against pathogens and malignant cells. Although cGAS has been shown to exert antitumor effects in several mouse models harboring transplanted tumor cell lines, its role in tumors arising from endogenous tissues remains unknown. Here, we show that deletion of cGAS in mice exacerbated chemical-induced colitis and colitis-associated colon cancer (CAC). Interestingly, mice lacking cGAS were more susceptible to CAC than those lacking stimulator of interferon genes (STING) or type I interferon receptor under the same conditions. cGAS but not STING is highly expressed in intestinal stem cells. cGAS deficiency led to intestinal stem cell loss and compromised intestinal barrier integrity upon dextran sodium sulfate-induced acute injury. Loss of cGAS exacerbated inflammation, led to activation of STAT3, and accelerated proliferation of intestinal epithelial cells during CAC development. Mice lacking cGAS also accumulated myeloid-derived suppressive cells within the tumor, displayed enhanced Th17 differentiation, but reduced interleukin (IL)-10 production. These results indicate that cGAS plays an important role in controlling CAC development by defending the integrity of the intestinal mucosa.


Assuntos
Neoplasias do Colo/enzimologia , Mucosa Intestinal/enzimologia , Proteínas de Neoplasias/metabolismo , Nucleotidiltransferases/metabolismo , Animais , Neoplasias do Colo/genética , Camundongos , Camundongos Knockout , Células Supressoras Mieloides/enzimologia , Proteínas de Neoplasias/genética , Nucleotidiltransferases/genética , Células-Tronco/enzimologia , Células Th17/enzimologia
16.
Foods ; 10(6)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071531

RESUMO

The effects of mixing orders of tannic acid (TA), starch, and α-amylase on the enzyme inhibition of TA were studied, including mixing TA with α-amylase before starch addition (order 1), mixing TA with pre-gelatinized starch before α-amylase addition (order 2) and co-gelatinizing TA with starch before α-amylase addition (order 3). It was found that the enzyme inhibition was always highest for order 1 because TA could bind with the enzyme active site thoroughly before digestion occurred. Both order 2 and 3 reduced α-amylase inhibition through decreasing binding of TA with the enzyme, which resulted from the non-covalent physical adsorption of TA with gelatinized starch. Interestingly, at low TA concentration, α-amylase inhibition for order 2 was higher than order 3, while at high TA concentration, the inhibition was shown with the opposite trend, which arose from the difference in the adsorption property between the pre-gelatinized and co-gelatinized starch at the corresponding TA concentrations. Moreover, both the crystalline structures and apparent morphology of starch were not significantly altered by TA addition for order 2 and 3. Conclusively, although a polyphenol has an acceptable inhibitory activity in vitro, the actual effect may not reach the expected one when taking processing procedures into account.

17.
Clin Genet ; 100(3): 340-347, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34101167

RESUMO

PKD2 gene variants account for 4.5% to 20% of patients with autosomal dominant polycystic kidney disease (ADPKD). Little is known about the clinical characteristics of PKD2 variants in Chinese patients with ADPKD. Herein, we performed a comprehensive search for variants of PKD2 gene in 44 Chinese ADPKD pedigrees and a total of 37 variants were identified. Of these 37 variants, 18 were nonsense variants, 10 frameshift variants, 4 missense variants, and 5 splice site variants. 11/37 variants were detected for the first time. The median age at diagnosis was 30.5 years, and positive family history was detected in 77.27% patients, liver cysts in 68.18%, hypertension in 45.45%, nephrolithiasis in 31.82%, macro-hematuria in 22.73%, and proteinuria in 13.63%. The level of estimated glomerular filtration rate in 8/39 patients were blow 60 ml/min/1.73m2 . 11/17 patients were classified as rapid progression by Mayo Clinic classification. The end stage renal disease (ESRD) events were reported in 9/22 pedigrees, and the presence of nephrolithiasis and macro-hematuria were significantly associated with ESRD in the pedigrees with PKD2 variants. The identified variants and clinical features will facilitate the early diagnosis and prognosis prediction in Chinese ADPKD patients with PKD2 variants.

18.
Blood ; 138(13): 1182-1193, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-33945603

RESUMO

Events mediated by the P-selectin/PSGL-1 pathway play a critical role in the initiation and propagation of venous thrombosis by facilitating the accumulation of leukocytes and platelets within the growing thrombus. Activated platelets and endothelium express P-selectin, which binds P-selectin glycoprotein ligand-1 (PSGL-1) that is expressed on the surface of all leukocytes. We developed a pegylated glycomimetic of the N terminus of PSGL-1, PEG40-GSnP-6 (P-G6), which proved to be a highly potent P-selectin inhibitor with a favorable pharmacokinetic profile for clinical translation. P-G6 inhibits human and mouse platelet-monocyte and platelet-neutrophil aggregation in vitro and blocks microcirculatory platelet-leukocyte interactions in vivo. Administration of P-G6 reduces thrombus formation in a nonocclusive model of deep vein thrombosis with a commensurate reduction in leukocyte accumulation, but without disruption of hemostasis. P-G6 potently inhibits the P-selectin/PSGL-1 pathway and represents a promising drug candidate for the prevention of venous thrombosis without increased bleeding risk.

19.
BMC Infect Dis ; 21(1): 500, 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34051748

RESUMO

BACKGROUND: Cryptococcal Meningitis (CM) is a common opportunistic infection in the late stage of acquired immunodeficiency syndrome (AIDS). Despite the wide use of effective antiretroviral and antifungal therapy in AIDS patients, CM is still a major morbidity and mortality cause. Understanding the immune response in cryptococcal infection may help to improve the treatment strategies. METHODS: We established a prospective cohort of twelve AIDS patients with CM (HIV + CM+) admitted to the hospital from 2019 to 2020. All patients were examined at the baseline, 2 weeks, and 4 weeks thereafter. The level of 19 cytokines in cerebrospinal fluid (CSF) were recorded to analyze the characteristics and dynamic changes of Th1/Th2 immune response. Meanwhile, six AIDS patients without CM (HIV + CM-) and seventeen healthy subjects (HIV-CM-) were included as control groups for CSF assessment. RESULTS: The HIV+ CM+ group had higher CSF IFN-γ, TNF-α, IL-6, IL-7, IL-8, IL-10, IL-12 (P40), IL-15, IL-18, CCL2 levels but lower IL-4 when compared with the HIV-CM- group at baseline. And they also had a higher level of IL-12 (P40) and IL-17A compared with HIV + CM- patients. Except one patient dropped out of the study, eleven HIV + CM+ patients received induction antifungal therapy and regular CSF testing, and the mortality rate was 9.1% (1/11) and 18.2% (2/11) respectively at week 2 and week 4. Compared with baseline CSF cytokines, IL-2, IL-13, IL-17A, and VEGF-A decreased in week 2, and the VEGF-A levels further decreased in week 4. But there was no difference in the levels of all cytokines between survivors and the dead. CONCLUSION: No evidence of Th1/Th2 imbalance was found in AIDS patients with CM. However, the CSF cytokine network may provide new clues for the treatment of AIDS patients with CM. TRIAL REGISTRATION: This trial was prospectively registered in 2019.7.16. The registered number is ChiCTR1900024565 .


Assuntos
Síndrome de Imunodeficiência Adquirida/imunologia , Citocinas/líquido cefalorraquidiano , Meningite Criptocócica/líquido cefalorraquidiano , Meningite Criptocócica/imunologia , Síndrome de Imunodeficiência Adquirida/complicações , Síndrome de Imunodeficiência Adquirida/microbiologia , Adulto , Comorbidade , Cryptococcus , Citocinas/imunologia , Feminino , Humanos , Imunidade Celular , Masculino , Meningite Criptocócica/complicações , Pessoa de Meia-Idade , Estudos Prospectivos , Equilíbrio Th1-Th2 , Fator A de Crescimento do Endotélio Vascular
20.
J Dev Orig Health Dis ; : 1-8, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33971999

RESUMO

The effects of supraphysiological estradiol (E2) on neonatal outcomes and the significance of specific E2 concentrations remain unclear. The purpose of this study was to investigate whether supraphysiological E2 levels on the human chorionic gonadotropin (hCG) trigger day are associated with small size for gestational age (SGA) in singletons born from fresh embryo transfer (ET) cycles. Patients with singleton pregnancies who delivered after the transfer of fresh embryos, during the period from July 2012 to December 2017, at our center were included. We excluded cycles involving a vanishing twin, maternal age >35 years, basal follicle-stimulating hormone ≥10 mIU/ml, or anti-Müllerian hormone ≤1 ng/ml. We then divided all cycles into five groups by E2 level on trigger day: group A, <2000 pg/ml (reference group); group B, 2000 pg/ml≤E2<2999 pg/ml; group C, 3000 pg/ml≤E2<3999 pg/ml; group D, 4000 pg/ml≤E2<4999 pg/ml; and group E, ≥5000 pg/ml. The prevalence of SGA among singletons from fresh ET was the primary outcome. The SGA rate significantly increased when the E2 level was ≥4000 pg/ml, as observed by comparing groups D (odds ratio [OR]: 1·79, 95% confidence interval [CI]: 1·16-2·76, P = 0·01) and E (OR: 1·68, 95% CI: 1·10-2·56, P = 0·02) with the reference group. Multivariate logistic regression indicated that a serum E2 level of at least 4000 pg/ml on the hCG trigger day was associated with increased SGA and with significant differences for groups D (adjusted OR [AOR]: 1·65, 95% CI: 1·05-2·59, P = 0·03) and E (AOR: 1·60, 95% CI: 1·03-2·53, P = 0·04) relative to the reference group. In conclusion, in fresh ET cycles, the supraphysiological E2 ≥4000 pg/ml on the hCG trigger day increases the risk of SGA.

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