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1.
Dis Colon Rectum ; 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35485833

RESUMO

BACKGROUND: Colorectal cancer patients with mismatch repair deficiency are usually less aggressive and associated with lower risk of distant metastasis. Immune checkpoint inhibition, rather than traditional chemoradiotherapy, has shown great advantages in treating such patients. OBJECTIVE: This study aimed to verify our hypothesis that locally very advanced (T4b) CRC without distant metastases might present with higher probability of dMMR and be more sensitive to neoadjuvant immune checkpoint inhibition. DESIGN: This study was designed as a single center retrospective observational study. SETTINGS: The study was conducted in a tertiary referral center in China. PATIENTS: Patients clinically diagnosed as T4bM0 CRC from 2008 to 2019 were included. MAIN OUTCOME MEASURES: Clinicopathological characteristics, MMR status and survival outcomes of dMMR patients were analyzed. RESULTS: A total of 268 patients were included. The incidence of dMMR in T4bM0 population was 27.6% (75/268), with 84.0% (63/75) in colon and 16.0% (12/75) in rectum. For tumors located in proximal colon, 45.0% (50/111) exhibited dMMR, while the incidence of dMMR in sigmoid colon cancer and rectal cancer was only 15.9% (25/157). Neoadjuvant immune checkpoint inhibition significantly reduced open surgery and multivisceral resection rate (p = 0.000 and p = 0.025, respectively). The pCR rate in neoadjuvant immune checkpoint inhibition group was significantly higher than that in neoadjuvant chemoradiotherapy/ chemotherapy group (70.0% v.s. 0%, p = 0.004). No tumor downstaging was observed after neoadjuvant chemotherapy. Neoadjuvant immune checkpoint inhibition provided significantly better disease-free survival (p = 0.0078) and relatively longer overall survival (p = 0.15) than other groups. LIMITATIONS: This study is limited by the possible selection bias and small sample size. CONCLUSIONS: Our data depicted the high incidence of dMMR in T4bM0 CRC and the effectiveness of neoadjuvant immune checkpoint inhibition group in organ preservation. Precision oncology requires identification of MMR protein status at initial diagnosis to make rational treatment decision for these special patients. See Video Abstract at http://links.lww.com/DCR/B952.

2.
J Cell Mol Med ; 26(8): 2438-2450, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35297206

RESUMO

Cytochrome P450 26A1 (CYP26A1) plays a vital role in early pregnancy in mice. Our previous studies have found that CYP26A1 affects embryo implantation by modulating natural killer (NK) cells, and that there is a novel population of CYP26A1+ NK cells in the uteri of pregnant mice. The aim of this study was to investigate the effects of CYP26A1 on the subsets and killing activity of NK cells. Through single-cell RNA sequencing (scRNA-seq), we identified four NK cell subsets in the uterus, namely, conventional NK (cNK), tissue-resident NK (trNK) 1 and 2, and proliferating trNK (trNKp). The two most variable subpopulations after uterine knockdown of CYP26A1 were trNKp and trNK2 cells. CYP26A1 knockdown significantly downregulated the expression of the NK cell function-related genes Cd44, Cd160, Vegfc, and Slamf6 in trNK2 cells, and Klra17 and Ogn in trNKp cells. Both RNA-seq and cytotoxicity assays confirmed that CYP26A1+ NK cells had low cytotoxicity. These results indicate that CYP26A1 may affect the immune microenvironment at the maternal-foetal interface by regulating the activity of NK cells.


Assuntos
Implantação do Embrião , Células Matadoras Naturais , Animais , Implantação do Embrião/fisiologia , Feminino , Camundongos , Subfamília A de Receptores Semelhantes a Lectina de Células NK/metabolismo , Gravidez , Ácido Retinoico 4 Hidroxilase/metabolismo , Útero/metabolismo
3.
Mar Drugs ; 20(3)2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35323502

RESUMO

Through activity-guided fractionation, a new triterpene (asperflagin, 1) was isolated as a PPAR-γ agonist from the jellyfish-derived fungus Aspergillus flavus. Asperflagin displayed selective and moderate transactivation effects on PPAR-γ in Ac2F rat liver cells. Based on further biological evaluation and molecular docking analysis, we postulated that asperflagin might function as a PPAR-γ partial agonist. This compound was calculated to display a typical PPAR-γ ligand-receptor interaction that is distinct from that of full agonistic antidiabetics such as rosiglitazone, and may retain the antidiabetic effect without accompanying weight gain. Weight gain and obesity are typical side effects of the PPAR-γ full agonist rosiglitazone, and lead to suboptimal outcomes in diabetic patients. Compared to rosiglitazone, asperflagin showed higher glucose uptake in HepG2 human liver cells at concentrations of 20 and 40 µM but induced markedly lower adipogenesis and lipid accumulation in 3T3-L1 preadipocytes. These results suggest that asperflagin may be utilized for further study on advanced antidiabetic leads.


Assuntos
Aspergillus flavus , Glucose/metabolismo , PPAR gama/agonistas , Triterpenos/farmacologia , Adipogenia/efeitos dos fármacos , Animais , Linhagem Celular , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , PPAR gama/metabolismo , Ratos , Triterpenos/química
4.
Front Chem ; 10: 841956, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35211457

RESUMO

Tailoring the structure and properties of lignin is an important step toward electrochemical applications. In this study, lignin/polypyrrole (PPy) composite electrode films with microporous and mesoporous structures were designed effectively by electrostatic spinning, carbonization, and in situ polymerization methods. The lignin can not only reduce the cost of carbon fiber but also increase the specific surface area of composite films due to the removal of carbonyl and phenolic functional groups of lignin during carbonization. Besides, the compact three-dimensional (3D) conductive network structures were constructed with PPy particles densely coated on the lignin nanofibers, which was helpful to improve the conductivity and fast electron transfer during the charging and discharging processes. The synthesized lignin carbon fibers/PPy anode materials had good electrochemical performance in 1 M H2SO4 electrolyte. The results showed that, at a current density of 1 A g-1, the lignin carbon nanofibers/PPy (LCNFs/PPy) had a larger specific capacitance of 213.7 F g-1 than carbon nanofibers (CNFs), lignin carbon nanofibers (LCNFs), and lignin/PPy fiber (LPAN/PPy). In addition, the specific surface area of LCNFs/PPy reached 872.60 m2 g-1 and the average pore size decreased to 2.50 nm after being coated by PPy. Therefore, the independent non-binder and self-supporting conductive film is expected to be a promising electrode material for supercapacitors with high performance.

5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 30(1): 146-151, 2022 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-35123618

RESUMO

OBJECTIVE: To investigate the expressions of CD33 and CD13 in newly diagnosed multiple myeloma (MM) patients and its relationship with prognosis. METHODS: It was retrospectively observed that the expression of CD33 and CD13 in 121 MM patients who were newly diagnosed from January 2014 to January 2020, and the relationship between the expressions of CD33 and CD13 and patients prognosis was analyzed. RESULTS: Among the 121 newly diagnosed MM patients, there were 30 patients (24.8%) in the CD33+ group and 12 patients (9.9%) in the CD13+ group. Kaplan-Meier analysis showed that, compared with the CD33- group, the progression-free survival (PFS) time and overall survival (OS) time were significantly shortened in MM patients in CD33+ group (PFS 17.5 vs 23 months, P=0.000; OS 18.5 vs 25 months, P=0.000); and the PFS time and OS time of MM patients in the CD13+ group were also significantly shortened than those in CD13- group (PFS 21 vs 22 months, P=0.012; OS 25 vs 26 months, P=0.006). Cox regression analysis showed that CD33 and CD13 were independent adverse prognostic factors in MM patients (CD33: P=0.000;CD13: P=0.003). CONCLUSION: CD33 and CD13 are prognostic risk factors in patients with MM.


Assuntos
Mieloma Múltiplo , Antígenos CD13 , Contagem de Células , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Estudos Retrospectivos , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico
6.
Commun Biol ; 5(1): 100, 2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-35087210

RESUMO

Glycosyltransferases typically display acceptor substrate flexibility but more stringent donor specificity. BsGT-1 is a highly effective glycosyltransferase to glycosylate macrolides, including epothilones, promising antitumor compounds. Here, we show that BsGT-1 has three major regions significantly influencing the glycodiversification of epothilone B based on structural molecular docking, "hot spots" alanine scanning, and site saturation mutagenesis. Mutations in the PSPG-like motif region and the C2 loop region are more likely to expand donor preference; mutations of the flexible N3 loop region located at the mouth of the substrate-binding cavity produce novel epothilone oligosaccharides. These "hot spots" also functioned in homologues of BsGT-1. The glycosides showed significantly enhanced water solubility and decreased cytotoxicity, although the glycosyl appendages of epothilone B also reduced drug permeability and attenuated antitumor efficacy. This study laid a foundation for the rational engineering of other GTs to synthesize valuable small molecules.


Assuntos
Epotilonas/metabolismo , Glucosiltransferases/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Epotilonas/química , Regulação Enzimológica da Expressão Gênica , Células Hep G2 , Hepatócitos , Humanos , Simulação de Acoplamento Molecular , Mutação , Engenharia de Proteínas
7.
J Inflamm Res ; 15: 163-176, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35035227

RESUMO

PURPOSE: To investigate if a traditional Chinese medicine formulation, called "Yiqihuoxue" (YQHX), could improve diabetic atherosclerosis (DA) and explore potential mechanisms based on DNA methylation. METHODS: Apolipoprotein E-knockout mice were administered streptozotocin (50 mg/d, i.p.) for 5 days and fed a high-fat diet for 16 weeks. Mice were divided randomly into DA model, rosiglitazone, as well as low-, medium-, and high-dose YQHX groups. Ten healthy C57BL/6J mice were the control group. Serum levels of fasting insulin, blood glucose, homeostasis model-insulin resistance index (HOMA-IR), serum lipids, and inflammatory factors were analyzed after the final treatment. Aorta tissues were collected for staining (hematoxylin and eosin, and Oil red O). Genomic DNA was extracted for methyl-capture sequencing (MC-seq). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) databases were used to analyze differentially methylated genes. Pyrosequencing was used to verify MC-seq data. RESULTS: Low-dose and high-dose YQHX could reduce the HOMA-IR (P < 0.05). Low-dose YQHX reduced expression of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), TNF-α, andI L-6 in serum compared with that in the model group (P < 0.05). Medium-dose YQHX decoction inhibited the expression level of TNF-α (P < 0.05). High-dose YQHX decreased the expression level of IL-6 (P < 0.05). Staining also showed the anti-atherosclerosis effects of YQHX (P < 0.05). MC-seq revealed many abnormally hypermethylated and hypomethylated genes in DA mice compared with those in the control group. KEGG database analysis showed that the hypermethylated genes induced by YQHX treatment were related to pathways in cancer, Hippo signaling, and mitogen activated protein kinase. The network analysis suggested that the hypermethylated genes epidermal growth factor receptor(Egfr) and phosphoinositide-3-kinase regulatory subunit 1(Pik3r1) induced by YQHX treatment had important roles in DA. Pyrosequencing revealed that YQHX treatment increased methylation of AKT1, Nr1h3 and Fabp4 significantly (P < 0.05). CONCLUSION: YQHX decoction had positive treatment effects against DA, because it could regulate aberrant hypomethylation of DNA.

8.
Diabetol Metab Syndr ; 14(1): 8, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35033170

RESUMO

BACKGROUND: Body composition alterations may participate in the pathophysiological processes of type 2 diabetes (T2D). A sedentary lifestyle may be responsible for alterations of body composition and adverse consequences, but on which body composition of patients with T2D and to what extent the sedentary lifestyle has an effect have been poorly investigated. METHODS: We recruited 402 patients with T2D for this cross-sectional study. All patients received questionnaires to evaluate sedentary time and were further divided into three subgroups: low sedentary time (LST, < 4 h, n = 109), middle sedentary time (MST, 4-8 h, n = 129) and high sedentary time (HST, > 8 h, n = 164). Each patient underwent a dual energy X-ray absorptiometry (DXA) scan to detect body composition, which included body fat percentage (B-FAT), trunk fat percentage (T-FAT), appendicular skeletal muscle index (ASMI), lumbar spine bone mineral density (BMD) (LS-BMD), femoral neck BMD (FN-BMD), hip BMD (H-BMD) and total BMD (T-BMD). Other relevant clinical data were also collected. RESULTS: With increasing sedentary time (from the LST to HST group), B-FAT and T-FAT were notably increased, while ASMI, LS-BMD, FN-BMD, H-BMD and T-BMD were decreased (p for trend < 0.01). After adjustment for other relevant clinical factors and with the LST group as the reference, the adjusted mean changes [B (95% CI)] in B-FAT, T-FAT, ASMI, LS-BMD, FN-BMD, H-BMD and T-BMD in the HST group were 2.011(1.014 to 3.008)%, 1.951(0.705 to 3.197)%, - 0.377(- 0.531 to - 0.223) kg/m2, - 0.083(- 0.124 to - 0.042) g/cm2, - 0.051(- 0.079 to - 0.024) g/cm2, - 0.059(- 0.087 to - 0.031) g/cm2 and - 0.060(- 0.088 to - 0.033) g/cm2, p < 0.01, respectively. CONCLUSIONS: A sedentary lifestyle may independently account for increases in trunk and body fat percentage and decreases in appendicular skeletal muscle mass and BMD of the lumbar spine, femoral neck, hip and total body in patients with T2D.

9.
J Cancer Res Clin Oncol ; 148(5): 1159-1169, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34181096

RESUMO

PURPOSE: This retrospective study aimed to evaluate the combined effect of anti-PD-1 inhibitor and nanoparticle albumin-bound (nab)-paclitaxel for refractory melanoma among Chinese patients. METHODS: Data from January 2018 to March 2021 were retrospectively collected and analyzed. Sixty-four patients were eligible for analysis from a single Chinese cancer center. RESULTS: The median follow-up was 16.0 months at data cutoff. The objective response rate (ORR) was 29.7%, and the disease control rate (DCR) was 67.2% in all patients. Treatment-naïve patients had significantly higher ORR than pretreated patients (42.9% vs 13.8%, p = 0.011). Cutaneous melanoma patients with NRAS gene mutation benefited more than non-mutated patients (DCR of 100% vs. 54.5%) (p = 0.030). The median progression-free survival (mPFS) of all patients was 5.2 months and the duration of response was 10.8 months. Median duration of disease control was 7.7 months. Prior treatment-naïve patients had significantly longer PFS than those who accepted prior treatments (7.2 vs. 5.1 months, p = 0.024). Patients with abnormally high LDH level had shorter mPFS (3.6 months vs. 6.6 months, p = 0.020). Median overall survival was not reached in this study. Most patients experienced adverse events (AEs), but only 17.2% of patients experienced grade 3 severe AEs. The most common AEs were alopecia (89.1%), neutropenia (18.8%), pruritus (15.6%), and arthralgia (14.1%). Some patients had immune related AEs (irAEs). No grade 4 or 5 AEs were observed. Patients with ≥ 3 AEs or with irAEs had longer mPFS (p < 0.05). CONCLUSION: Nab-paclitaxel combined with PD-1 antibody is a well-tolerated and effective regimen for Chinese patients with refractory melanoma.


Assuntos
Melanoma , Neoplasias Cutâneas , Albuminas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , China , Humanos , Inibidores de Checkpoint Imunológico , Melanoma/tratamento farmacológico , Melanoma/genética , Paclitaxel/efeitos adversos , Estudos Retrospectivos , Neoplasias Cutâneas/etiologia
10.
Acta Pharmacol Sin ; 43(3): 624-633, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34163023

RESUMO

Vascular calcification (VC) is characterized by pathological depositions of calcium and phosphate in the arteries and veins via an active cell-regulated process, in which vascular smooth muscle cells (VSMCs) transform into osteoblast/chondrocyte-like cells as in bone formation. VC is associated with significant morbidity and mortality in chronic kidney disease (CKD) and cardiovascular disease, but the underlying mechanisms remain unclear. In this study we investigated the role of large-conductance calcium-activated potassium (BK) channels in 3 experimental VC models. VC was induced in vascular smooth muscle cells (VSMCs) by ß-glycerophosphate (ß-GP), or in rats by subtotal nephrectomy, or in mice by high-dosage vitamin D3. We showed that the expression of BK channels in the artery of CKD rats with VC and in ß-GP-treated VSMCs was significantly decreased, which was functionally confirmed by patch-clamp recording. In ß-GP-treated VSMCs, BK channel opener NS1619 (20 µM) significantly alleviated VC by decreasing calcium content and alkaline phosphatase activity. Furthermore, NS1619 decreased mRNA expression of ostoegenic genes OCN and OPN, as well as Runx2 (a key transcription factor involved in preosteoblast to osteoblast differentiation), and increased the expression of α-SMA protein, whereas BK channel inhibitor paxilline (10 µM) caused the opposite effects. In primary cultured VSMCs from BK-/- mice, BK deficiency aggravated calcification as did BK channel inhibitor in normal VSMCs. Moreover, calcification was more severe in thoracic aorta rings of BK-/- mice than in those of wild-type littermates. Administration of BK channel activator BMS191011 (10 mg· kg-1 ·d-1) in high-dosage vitamin D3-treated mice significantly ameliorated calcification. Finally, co-treatment with Akt inhibitor MK2206 (1 µM) or FoxO1 inhibitor AS1842856 (3 µM) in calcified VSMCs abrogated the effects of BK channel opener NS1619. Taken together, activation of BK channels ameliorates VC via Akt/FoxO1 signaling pathways. Strategies to activate BK channels and/or enhance BK channel expression may offer therapeutic avenues to control VC.


Assuntos
Canais de Potássio Ativados por Cálcio de Condutância Alta/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Calcificação Vascular/patologia , Fosfatase Alcalina/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Benzimidazóis/farmacologia , Colecalciferol/farmacologia , Modelos Animais de Doenças , Glicerofosfatos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nefrectomia , Osteocalcina/efeitos dos fármacos , Osteopontina/efeitos dos fármacos , Fragmentos de Peptídeos/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
11.
J Colloid Interface Sci ; 608(Pt 1): 820-829, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34785459

RESUMO

Sensitive strain sensors have attracted more attention due to their applications in health monitoring and human-computer interaction. However, the problems existing in conventional hydrogels, such as inherent brittleness, freezing at low temperature, low toughness, and water evaporation, have greatly hindered the practical applications. In order to solve the above problems, herein, we designed dual network multifunctionality organohydrogels using polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA) covalent cross-linking polymer as the first network, the bacterial celluloses (BCs) and calcium chloride by ligand binding as the second network. The prepared organohydrogels showed good conductivity and sensitivity over a wide temperature range (-20 âˆ¼ 40 ℃), and maintained long-term stability (>15 days) in the air. In addition, the dynamic combination of BCs-Ca2 + and hydrogen bonds in the binary system further endows the organohydrogels with excellent tensile strength (≈1.0 MPa), tensile strain (≈1300%), toughness (≈6.2 MJ m-3), conductivity (3.4 S m-1), gauge factor (≈1.24), adhesion (≈0.3 MPa), and self-healing properties (self-healing tensile strain to 632%). Therefore, this organohydrogel has potential candidates for flexible electronic skin, motion monitoring, and soft robotics.


Assuntos
Celulose , Dispositivos Eletrônicos Vestíveis , Condutividade Elétrica , Humanos , Hidrogéis , Álcool de Polivinil
12.
Comput Struct Biotechnol J ; 19: 5931-5942, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34849197

RESUMO

Glycoside hydrolases (GHs) are greatly diverse in sequences and functions, but systematic studies of GH relationships based on structural information are lacking. Here, we report that GHs have multiple evolutionary origins and are structurally derived from 27 homologous superfamilies and 16 folds, but GHs are highly biased to distribute in a few superfamilies and folds. Six of these superfamilies are widely encoded by archaea, bacteria, and eukaryotes, indicating that they may be the most ancient in origin. Most superfamilies vary in enzyme function, and some, such as the superfamilies of (ß/α)8-barrel and (α/α)6-barrel structures, exhibit extreme functional diversity; this is highly positively correlated with sequence diversity. More than one-third of glycosidase activities show a phenomenon of convergent evolution, especially the degradation functions of GHs on polysaccharides. The GHs of most superfamilies have relatively narrow environmental distributions, normally with the highest abundance in host-associated environments and a distribution preference for moderate low-temperature and acidic environments. Overall, our expanded analysis facilitates an understanding of complex GH sequence-structure-function relationships and may guide our screening and engineering of GHs.

13.
J Phys Chem B ; 125(46): 12753-12762, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34766766

RESUMO

Tricationic ionic liquid (TIL) electrolytes have been successfully employed in supercapacitors with graphene electrodes, but the low power density of the TILs-based supercapacitors caused by strong cations-anions associations requires enhancement by adding organic solvents to the liquid. In this paper, the role of the solvents acetonitrile (ACN) and ethylene carbonate (EC) on the ion diffusion, the conductivity of the TIL [C6(mim)3](Tf2N)3, and the structures and the capacitances of the electrical double layers (EDLs) in TIL/ACN and TIL/EC electrolytes were probed by molecular dynamics (MD) simulations. The results indicate that adding organic solvents to the liquid significantly reduces interactions between ions, thereby greatly improving the ion diffusion coefficients and the conductivity of the TIL, and the maximum conductivity is found at the 0.55 M TIL/ACN electrolyte concentration. Moreover, the reduced packing of counterions and the strong expulsion of coions near charged electrodes are observed in the organic electrolytes, especially in the TIL/EC electrolyte. Further analyses on EDLs affirm that the asymmetric camel-shaped differential capacitance-voltage (C-V) curve in the pure TIL electrolyte is weakly changed by the solvent ACN or EC. Besides, the EDL capacitance in the TIL-based hybrid electrolytes is improved slightly by the organic solvents. Comparing the integral capacitances in TIL/ACN and TIL/EC with different solvent contents, it is found that reducing the solvent polarity may be more beneficial to promote the EDL capacitance. Comprehensively, in this work, the 0.55 M TIL/ACN electrolyte is the optimal choice for the high-performance supercapacitor. Hence, solvating TIL electrolytes in supercapacitors by suitable solvents can effectively enhance the power density without compromising energy density.

14.
Front Immunol ; 12: 763067, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712245

RESUMO

Uterine M1/M2 macrophages activation states undergo dynamic changes throughout pregnancy, and inappropriate macrophages polarization can cause adverse pregnancy outcomes, especially during the peri-implantation period. Our previous studies have confirmed that Cytochrome P450 26A1 (CYP26A1) can affect embryo implantation by regulating uterine NK cells and DCs. The aim of this study was to investigate whether CYP26A1 regulates the polarization of uterine macrophages in early pregnancy. Here, we observed that Cyp26a1 was significantly upregulated in M1 as compared with M2 of uterine macrophages, Raw264.7 and iBMDM. Knockdown of CYP26A1 in mice uterine significantly decreased the number of embryo implantation sites and the proportion of CD45+F4/80+CD206 - M1-like uterine macrophages. Primary uterine macrophages treated with anti-CYP26A1 antibody expressed significantly lower levels of M1 markers Nos2, Il1b, Il6 and Tnf-a. In CYP26A1 knockout Raw264.7 cells, the protein levels of M1 markers TNF-α, IL-6 and CD86 were significantly decreased as compared with the wild type cells. Moreover, CYP26A1 deficiency decreased the ability to produce nitric oxide and increased the phagocytosis capacity of Raw264.7 cells under M1 stimulation state. The re-introduction of CYP26A1 partially reversed the polarization levels of M1 in CYP26A1 knockout Raw264.7 cells. CYP26A1 may regulate the polarization of uterine macrophages to M1 through Stap1 and Slc7a2. In summary, these results indicate that CYP26A1 plays a significant role in macrophage polarization, and knockdown of CYP26A1 can cause insufficient M1 polarization during the peri-implantation period, which has adverse effects on blastocyst implantation.


Assuntos
Implantação do Embrião , Macrófagos/fisiologia , Ácido Retinoico 4 Hidroxilase/fisiologia , Útero/imunologia , Animais , Polaridade Celular , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Macrófagos/enzimologia , Camundongos , Camundongos Endogâmicos BALB C
15.
Diabetol Metab Syndr ; 13(1): 102, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556157

RESUMO

BACKGROUND: Deterioration of sleep quality has been reported to contribute to the incidence of diabetes and may be responsible for glycemic status in diabetes. The present study explored the relationship between sleep quality and glycemic variability in patients with type 2 diabetes (T2D). METHODS: We recruited 111 patients with T2D for this cross-sectional study. Each patient underwent flash glucose monitoring for 14 days to obtain glycemic variability parameters, such as standard deviation of glucose (SD), coefficient of variation of glucose (CV), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD), and time in glucose range of 3.9-10 mmol/L (TIR3.9-10). After 14 days of flash glucose monitoring, each patient received a questionnaire on the Pittsburgh Sleep Quality Index (PSQI) to evaluate subjective sleep quality. HbA1c was also collected to assess average glucose. RESULTS: HbA1c was comparable among the subgroups of PSQI score tertiles. Across ascending tertiles of PSQI scores, SD, CV and MAGE were increased, while TIR3.9-10 was decreased (p for trend < 0.05), but not MODD (p for trend = 0.090). Moreover, PSQI scores were positively correlated with SD, CV, MODD and MAGE (r = 0.322, 0.361, 0.308 and 0.354, respectively, p < 0.001) and were inversely correlated with TIR3.9-10 (r = - 0.386, p < 0.001). After adjusting for other relevant data by multivariate linear regression analyses, PSQI scores were independently responsible for SD (ß = 0.251, t = 2.112, p = 0.041), CV (ß = 0.286, t = 2.207, p = 0.033), MAGE (ß = 0.323, t = 2.489, p = 0.018), and TIR3.9-10 (ß = - 0.401, t = - 3.930, p < 0.001) but not for MODD (ß = 0.188, t = 1.374, p = 0.177). CONCLUSIONS: Increased glycemic variability assessed by flash glucose monitoring was closely associated with poor subjective sleep quality evaluated by the PSQI in patients with T2D.

16.
Signal Transduct Target Ther ; 6(1): 329, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471087

RESUMO

It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86-19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82-20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06-15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).


Assuntos
Angina Estável/tratamento farmacológico , Fármacos Cardiovasculares/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Adolescente , Adulto , Idoso , Angina Estável/genética , Angina Estável/patologia , Método Duplo-Cego , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
17.
Mar Drugs ; 19(8)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34436256

RESUMO

Peroxisome proliferator-activated receptor (PPAR) expression has been implicated in pathological states such as cancer, inflammation, diabetes, and neurodegeneration. We isolated natural PPAR agonists-eight 2,5-diketopiperazines-from the jellyfish-derived fungus Aspergillus flavus. Cyclo-(L-Pro-L-Phe) was the most potent PPAR-γ activator among the eight 2,5-DKPs identified. Cyclo-(L-Pro-L-Phe) activated PPAR-γ in Ac2F rat liver cells and SH-SY5Y human neuroblastoma cells. The neuroprotective effect of this partial PPAR-γ agonist was examined using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, lactate dehydrogenase release, and the Hoechst 33342 staining assay in SH-SY5Y cells. Our findings revealed that cyclo-(L-Pro-L-Phe) reduced hydrogen peroxide-induced apoptosis as well as the generation of reactive oxygen species. Rhodamine 123 staining and western blotting revealed that cyclo-(L-Pro-L-Phe) prevented the loss of mitochondrial membrane potential and inhibited the activation of mitochondria-related apoptotic proteins, such as caspase 3 and poly (ADP-ribose) polymerase. Moreover, cyclo-(L-Pro-L-Phe) inhibited the activation and translocation of nuclear factor-kappa B. Thus, the partial PPAR-γ agonist cyclo-(L-Pro-L-Phe) demonstrated potential neuroprotective activity against oxidative stress-induced neurodegeneration in SH-SY5Y cells.


Assuntos
Aspergillus flavus/química , Fármacos Neuroprotetores/farmacologia , Cifozoários/microbiologia , Animais , Organismos Aquáticos , Linhagem Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Humanos , Neuroblastoma/metabolismo , Ratos
18.
Zhongguo Zhen Jiu ; 41(8): 906-12, 2021 Aug 12.
Artigo em Chinês | MEDLINE | ID: mdl-34369703

RESUMO

OBJECTIVE: To observe the changes of functional connectivity of brain pain-emotion regulation region in patients with cervical spondylosis of cervical type by functional magnetic resonance imaging (fMRI). METHODS: Thirty-two subjects were selected. Of them, 16 patients with cervical spondylosis of cervical type were divided into an observation group and 16 healthy subjects into a control group. The patients in the observation group were treated with acupuncture at Tianzhu (BL 10), Jingbailao (EX-HN 15), Jianzhongshu (SI 15) and ashi points for 30 min. The rest-state fMRI data was collected before and after acupuncture in the observation group. The subjects in the control group received no treatment, and the rest-state fMRI data was collected once. The visual analogue scale (VAS) score before and after treatment and the pain catastrophizing scale (PCS) score before treatment in the observation group were recorded. The resting-state brain functional imaging characteristics between the observation group and control group before treatment, between the observation group before and after treatment, were compared. Based on the brain functional connectivity of region of interest (ROI) the changes of functional connectivity in insula and ventral tegmental area (VTA) in emotional regulation brain region were observed, and the correlation between functional connectivity changes and VAS、PCS scores in patients of the observation group was analyzed. RESULTS: In the observation group, the VAS score was (1.94±1.12) after the treatment, which was lower than (5.62±1.20) before treatment (P<0.05). The PCS score before treatment was (19.18±8.42) in the observation group. Compared with the control group, the areas with increased functional connectivity with insula in the observation group before acupuncture included bilateral dorsolateral prefrontal lobe and right middle cingulate gyrus, and the areas with increased functional connectivity with VTA included right central posterior gyrus and right insula. In the observation group, the connectivity coefficient of left insula and left dorsolateral prefrontal lobe (r=0.438, P<0.05), the connectivity coefficient of right insula and right dorsolateral prefrontal lobe (r=0.483, P<0.05) were positively associated with the VAS score. In the observation group, the connectivity coefficient between the right insula and the right middle cingulate gyrus (r=-0.560, P<0.05), the connectivity coefficient between the right VTA and the right insula (r=-0.525, P<0.05) were negatively associated with the PCS score. After acupuncture, the areas with decreased functional connectivity with insula included bilateral posterior central gyrus, right anterior central gyrus, middle cingulate gyrus and left corpus callosum, while the bilateral suboccipital gyrus and left cerebellum showed increased functional connectivity with right insula. The areas with decreased functional connectivity with VTA included bilateral dorsomedial prefrontal cortex, left anterior cingulate gyrus, right middle temporal gyrus and left anterior cingulate gyrus. After acupuncture in the observation group, the functional connectivity of left VTA left dorsomedial prefrontal cortex and left anterior cingulate cortex (r=-0.548, P<0.05), the functional connectivity of right VTA-bilateral dorsomedial prefrontal cortex and left anterior cingulate cortex (r=-0.547, P<0.05) were negatively associated with the PCS score. CONCLUSION: Pain involves the formation and expression of "pain-emotion-cognition". Acupuncture can systematically regulate the brain functional connections between cognitive regions such as dorsal prefrontal lobe and anterior cingulate gyrus and emotional regions such as insula and VTA in patients with cervical spondylosis of cervical type, suggesting that acupuncture has a multi-dimensional and comprehensive regulation effect on pain.


Assuntos
Terapia por Acupuntura , Espondilose , Encéfalo/diagnóstico por imagem , Emoções , Humanos , Imageamento por Ressonância Magnética , Dor , Espondilose/diagnóstico por imagem , Espondilose/terapia
19.
Autophagy ; 17(12): 4323-4340, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33977871

RESUMO

Macroautophagy/autophagy plays an important role during the development of human cancer. BECN1 (beclin 1), a core player in autophagy regulation, is downregulated in many kinds of malignancy. The underlying mechanism, however, has not been fully illuminated. Here, we found that CUL3 (cullin 3), an E3 ubiquitin ligase, could interact with BECN1 and promote the K48-linked ubiquitination and degradation of this protein; In addition, CUL3 led to a decrease in autophagic activity through downregulating BECN1. We also found that KLHL38 was a substrate adaptor of the CUL3 E3 ligase complex-mediated ubiquitination and degradation of BECN1. In breast and ovarian cancer, CUL3 could promote the proliferation of tumor cells, and the expression of CUL3 was related to poor prognosis in patients. Our study reveals the underlying mechanism of BECN1 ubiquitination and degradation that affects autophagic activity and subsequently leads to tumor progression, providing a novel therapeutic strategy that regulates autophagy to combat cancer.Abbreviations: ATG: autophagy-related BECN1: beclin 1 CHX: cycloheximide CoIP: co-immunoprecipitation CUL3: cullin 3 IP: immunoprecipitation MS: mass spectrometry PtdIns3K: phosphatidylinositol 3-kinase UPS: ubiquitin-proteasome system.


Assuntos
Autofagia , Proteínas Culina , Autofagia/fisiologia , Proteína Beclina-1/metabolismo , Proteínas Culina/metabolismo , Humanos , Ubiquitina/metabolismo , Ubiquitinação
20.
J Geriatr Cardiol ; 18(4): 261-270, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33995505

RESUMO

BACKGROUND: The efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors were confirmed by several clinical trials, but its effectiveness in routine clinical practice in China has not been evaluated. This study aims to describe the real world effectiveness of PCSK-9 inhibitors combined with statins compared with statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease (ASCVD). METHODS: This is a multi-center observational study, enrolled patients from 32 hospitals who underwent percutaneous coronary intervention (PCI) from January to June in 2019. There are 453 patients treated with PCSK-9 inhibitors combined with statins in PCSK-9 inhibitor group and 2,610 patients treated with statins-based lipid lowering therapies in statins-based group. The lipid control rate and incidence of major adverse cardiovascular events (MACE) over six months were compared between two groups. A propensity score-matched (PSM) analysis was used to balance two groups on confounding factors. Survival analysis using Kaplan-Meier methods was applied for MACE. RESULTS: In a total of 3,063 patients, 89.91% of patients had received moderate or high-intensity statins-based therapy before PCI, but only 9.47% of patients had low-density lipoprotein cholesterol (LDL-C) levels below 1.4 mmol/L at baseline. In the PSM selected patients, LDL-C level was reduced by 42.57% in PCSK-9 inhibitor group and 30.81% (P < 0.001) in statins-based group after six months. The proportion of LDL-C ≤ 1.0 mmol/L increased from 5.29% to 29.26% in PCSK-9 inhibitor group and 0.23% to 6.11% in statins-based group, and the proportion of LDL-C ≤ 1.4 mmol/L increased from 10.36% to 47.69% in PCSK-9 inhibitor group and 2.99% to 18.43% in statins-based group ( P < 0.001 for both). There was no significant difference between PCSK-9 inhibitor and statins-based treatment in reducing the risk of MACE (hazard ratio = 2.52, 95% CI: 0.49-12.97, P = 0.250). CONCLUSIONS: In the real world, PCSK-9 inhibitors combined with statins could significantly reduce LDL-C levels among patients with very high risk of ASCVD in China. The long-term clinical benefits for patients received PCSK-9 inhibitor to reduce the risk of MACE is still unclear and requires further study.

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