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1.
J Ethnopharmacol ; 282: 114639, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34530093

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Luohanguo (LHG) extract major contenting mogrosides, as a nonnutritive sweetener, has been reported to exert a hypoglycemic effect on diabetic patients and animals. As the pharmacokinetics and pharmacodynamics of drugs were changed with diabetes, it may lead to the different pharmacological of mogrosides between diabetic and normal subjects. AIMS OF THE STUDY: To characterise the pharmacokinetic profiles of mogrosides in T2DM rats. STUDY DESIGN AND METHODS: High-fat diet and streptozocin induced type 2 diabetic mellitus rats were used to investigate the pharmacokinetic behavior of mogroside V and mogrosides IIIA1, IIA1, and IA1 after T2DM rats orally administrated with mogroside V and 1-3 glucose residues' mogrosides, respectively. The validated convenient UPLC-QTOF/MS and UPLC-MS/MS methods were established to use in the pharmacokinetic studies of mogrosides in normal and T2DM rats. Additionally, the expression of the intestinal tight junction protein zonula occludens-1 (ZO-1) was also detected by immunohistochemical analysis, which assessed the function of passive intestinal permeability in T2DM rats. RESULTS: The results showed that for rats treated with mogroside V, its metabolite mogroside IIIA1 has a significant increase (p < 0.05) in maximum plasma concentration (Cmax, 163.80 ± 25.56 ng/mL) and area under the plasma concentration (AUC0-t, 2327.44 ± 474.63 h·ng/mL) in T2DM rats compared with in normal rats. The mean residence time (MRT0-t, 12.04 ± 0.97 h) of mogroside V showed a significant decrease (p < 0.05) in T2DM rats. However, the mogrosides IIIA1, IIA1and IA1 showed no statistical differences in the normal and T2DM rats after administered with 1-3 glucose residues' mogrosides. Furthermore, the expression level of ZO-1 in the duodenum and colon of T2DM rats were downregulated. CONCLUSION: The pharmacokinetic profiles of mogroside V and its metabolite mogroside IIIA1 in T2DM rats and normal rats showed some difference, it might be affected by the metabolic changes in the pathological state of T2DM.

3.
J Ethnopharmacol ; : 114729, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34634365

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: As a commercial Chinese patent medicine, Yanning Syrup (YN) is used to treat acute upper respiratory tract infections and acute enteritis effectively in clinical practice. However, the underlying mechanism remains unclear. AIMS OF THE STUDY: To reveal the effect of YN on gut microbiota dysbiosis, and explore the potential role of the gut microecosystem and CD4+ T cell immune homeostasis in YN-treated respiratory and intestinal diseases in lipopolysaccharide (LPS)-induced inflammatory rats. METHODS: Inflammation in rat models was induced by intraperitoneal injection of LPS (8 mg/kg). Histological changes were observed by H & E staining. Changes in gut microbiota and short-chain fatty acid (SCFA) production were analysed using 16S rRNA gene sequencing and targeted metabolomics. A Luminex cytokine microarray and enzyme-linked immunosorbent assay (ELISA) were conducted to evaluate the serum and colon cytokine profiles. The frequencies of immune cells, including Th1, Th2, Th17 and Treg cells in the mesenteric lymph nodes (MLNs), bronchoalveolar lavage fluid (BALF) and whole blood were phenotyped using flow cytometry. RESULTS: The YN-treated rats showed less colon inflammation, as evidenced by the reduction in mortality rate and histology score. Notably, YN was found to improve the immunosuppressed state induced by LPS in rats, which not only upregulated the levels of the proinflammatory cytokine IL-17A and the immunosuppressive cytokines IL-4 and IL-10 in colon tissue but also increased the levels of IL-1α, IL-5, IL-7, IL-12 (p70), GM-CSF and VEGF in serum. The numbers of Th17 cells and Treg cells in the MLNs, blood, and BALF of model rats were regulated by YN, with the restoration of the Th17/Treg balance. Additionally, the Th1/Th2 balance in MLNs and whole blood of model rats was restored after YN administration. Sequencing of 16S rRNA gene indicated that YN-treated rats exhibited greater gut microbial diversity and flora composition, specifically inhibiting some harmful bacteria such as Enterobacter and Blautia and increasing Firmicutes and Actinobacteria. Targeted metabolomics analysis demonstrated an increase of SCFA (acetic acid, butyric acid, valeric acid, and hexanoic acid) production in YN-treated rats. Most of the dominant bacterial genera regulated by YN administration were correlated with the concentrations of SCFA and inflammatory cytokines. CONCLUSIONS: These results demonstrated that YN could ameliorate LPS-induced inflammation in rats by modifying gut microbiota, increasing microbiota-derived SCFA production and regulating the balance of Th1/Th2 and Treg/Th17 cells.

4.
J Hazard Mater ; 424(Pt B): 127354, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34634699

RESUMO

Due to its wide applications in tire and rubber products, carbon black (CB) implicates concerns on its safety during production, collection, and handling. Here we report that exposure CB, increases coagulation-thrombosis potential in a splenic extramedullary hemopoiesis (EMH)-dependent manner. Adult C57BL/6 mice are kept in whole-body inhalation chambers, and exposed to filtered room air (FRA) or CB for 28 consecutive days. CB exposure resulted in splenic EMH characterized with platelet precursor cells, megakaryocytes (MKs), hyperplasia and enhanced in vivo blood coagulation ability. Metabolomics analysis suggests significant enhance in PGE2 production but reduction in folic acid (FA) levels in murine serum following CB exposure. Mechanistically, activation of COX-dependent PGE2 production promotes IL-6 expression in splenic macrophages, which subsequently results in splenic EMH and increased platelet counts in circulation. Administration of FA protects the mice against CB-induced splenic EMH through inhibiting prostaglandin-endoperoxide synthase 2 (Ptgs2 or Cox2) and prostaglandin E synthase (Ptges) expression in splenic macrophages, eventually recover the coagulation capacity to normal level. The results strongly suggest the involvement of splenic EMH in response to CB exposure and subsequently increased coagulation-thrombosis potential. Supplementation with FA may be a candidate to prevent thrombosis potential attributable to CB exposure.

5.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3846-3852, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34472258

RESUMO

The lignans in Urtica cannabina were isolated by preparative HPLC, silica, and ODS column chromatographies, and identified by NMR and HR-MS. The inhibitory activities on 5α-reductase were evaluated in vitro. As a result, ten secolignans,(2R,4S)-2,4-bis(3-methoxyl-4-hydroxyphenyl)-3-butoxypropanol(1), 3,4-trans-3-hydroxymethyl-4-[bis(3,4-dimethoxyphenyl)methyl] butyrolactone(2), 3,4-trans-3-hydroxymethyl-4-[(3,4-dimethoxyphenyl)(3-methoxyl-4-hydroxyphenyl)methyl] butyrolactone(3), 3,4-trans-3-hydroxymethyl-4-[bis(3-methoxyl-4-hydroxyphenyl)methyl] butyrolactone(trans urticol, 4), 3,4-trans-3-hydroxymethyl-4-[bis(3,4-dimethoxyphenyl)methyl] butyrolactone-3-O-ß-D-glucopyranoside(5), 3,4-trans-3-hydroxymethyl-4-[(3,4-dimethoxyphenyl)(3-methoxyl-4-hydroxyphenyl)methyl]butyrolactone-3-O-ß-D-glucopyranoside(6), 3,4-trans-3-hydroxymethyl-4-[bis(3-methoxyl-4-hydroxyphenyl)methyl]butyrolactone-3-O-ß-D-glucopyranoside(trans-urticol-7-O-ß-D-glucopyranoside, 7), cycloolivil-4-O-ß-D-glucopyranoside(8), isolariciresinol-4'-O-ß-D-glucopyranoside(9), and olivil-4'-O-ß-D-glucopyranoside(10), together with a polyphenol [α-viniferin(11)], were isolated from U. cannabina for the first time. Compound 1 was a new lignan. Compound 7 was potent in inhibiting 5α-reductase.


Assuntos
Colestenona 5 alfa-Redutase/farmacologia , Lignanas , Urticaceae , Inibidores de 5-alfa Redutase , Cromatografia Líquida de Alta Pressão , Lignanas/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Urticaceae/efeitos dos fármacos , Urticaceae/enzimologia
6.
J Hazard Mater ; 416: 125878, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492818

RESUMO

With the increased appreciation for the significance of noncoding RNAs (ncRNAs), the present research aimed to determine the role of competing endogenous RNA (ceRNA) in the process of particulate matter (PM) exposure-induced pulmonary damage. Alterations in messenger RNA (RNA), microRNA and long non-coding RNA (lncRNA) profiles of human bronchial epithelial (HBE) cells treated with PM were analyzed by microarray assays. Next, we identified that lncRNA taurine upregulated gene 1 (TUG1) acted as a competing endogenous RNA for microRNA-222-3p (miR-222-3p) and subsequently attenuated the inhibitory effect of miR-222-3p on CUGBP elav-like family member 1 (CELF1). The binding potency among ceRNAs was verified by RNA immunoprecipitation (RIP) assay and dual-luciferase reporter assay. Knockdown of TUG1 attenuated HBE cell apoptosis and cell cycle arrest by downregulation of CELF1 and protein 53 (p53). Further, we confirmed that Tug1/mir-222-3p/CELF1/p53 network aggravated PM-induced airway hyper-reactivity (AHR) in mice. In summary, our novel findings revealed that TUG1 triggered dysfunction of pulmonary cells followed by PM exposure by serving as a sponge for miR-222-3p and thereby upregulating the expression of CELF1and p53.


Assuntos
MicroRNAs , RNA Longo não Codificante , Animais , Proliferação de Células , Camundongos , MicroRNAs/genética , Material Particulado/toxicidade , RNA Longo não Codificante/genética , Taurina
7.
Acta Trop ; 224: 106145, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34562426

RESUMO

Cerebral malaria (CM) is the most severe neurological complication caused by Plasmodium falciparum infection. The accumulating evidence demonstrated that mast cells (MCs) and its mediators played a critical role in mediating malaria severity. Earlier studies identified that exosomes were emerging as key mediators of intercellular communication and can be released from several kinds of MCs. However, the potential functions and pathological mechanisms of MCs-derived exosomes (MCs-Exo) impacting on CM pathogenesis remain largely unknown. Herein, we utilized an experimental CM (ECM) model (C57BL/6 mice infected with P. berghei ANKA strain), and then intravenously (i.v.) injected MCs-Exo into P. berghei ANKA-infected mice to unfold this mechanism and investigate the effect of MCs-Exo on ECM pathogenies. We also used an in vitro model by investigating the pathogenesis development of brain microvascular endothelial cells line (bEnd.3 cells) co-cultured with P. berghei ANKA blood-stage soluble antigen (PbAg) after MCs-Exo treatment. The higher numbers of MCs and levels of MCs degranulation were observed in skin, cervical lymph node, and brain of ECM mice than those of the uninfected mice. Exosomes were successfully isolated from culture supernatants of mouse MCs line (P815 cells) and characterized by spherical vesicles with the diameter of 30-150 nm, and expression of typical exosomal markers (e.g., CD9, CD63, and CD81). The i.v. injection of MCs-Exo dramatically elevated incidence of ECM in the P. berghei ANKA-infected mice, exacerbated liver and brain histopathological damage, promoted Th1 cytokine response, aggravated brain vascular endothelial activation and blood brain barrier breakdown in ECM mice. In addition, the treatment of MCs-Exo led to the decrease of cells viability and mRNA levels of Ang-1, ZO-1, and Claudin-5, but increase of mRNA levels of Ang-2, CCL2, CXCL1, and CXCL9 in bEnd.3 cells co-cultured with PbAg in vitro. Taken together, our data indicated that MCs-Exo could worsen pathogenesis of ECM in mice.

8.
J Pharm Biomed Anal ; 206: 114347, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34536823

RESUMO

Weikangling capsules (WKLCs), a Chinese patent medicine consisting of 8 Chinese drugs, have been widely used in clinic to treat gastrointestinal diseases for more than 30 years. The current "Chinese Pharmacopoeia" (2020 Edition, ChP2020) uses paeoniflorin content (≥ 1.0 mg per capsule) as the standard of quality control, but it is insufficient to evaluate the overall quality of WKLCs. An efficient and economic method for quality control is urgently needed to ensure the quality consistency and clinical effects of WKLCs. Herein, a systematic and reliable method for the rapid analysis of chemical components in WKLCs was established for the first time based on ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). A total of 115 components covering 7 herbs in WKLCs were preliminarily identified by comparison with standard substances or literature. To evaluate the quality of 26 batches of WKLCs, a new method of fingerprinting combined with quantitative analysis was established, and 16 common peaks were selected to establish the fingerprint similarity model (similarity>0.90). Simultaneously, the contents of albiflorin, paeoniflorin, dactylorhin A, militarine, and glycyrrhizic acid were determined to be 0.82 ± 0.22, 2.09 ± 0.24, 1.15 ± 0.40, 3.73 ± 0.76 and 0.99 ± 0.20 mg/capsule, respectively. The transfer rates and dissolution curves of the five compounds were successfully detected in WKLCs, and the average transfer rates were 67.2%, 33.0%, 68.3%, 54.7%, and 33.7%, respectively. Notably, the dissolution profiles of different manufacturers presented remarkable differences in pH 1.2 hydrochloric acid solution. This method not only qualitatively identified the chemical components of Chinese patent medicines at the microlevel but also evaluated the quality consistency between batches at the macrolevel, which provided a comprehensive reference for the quality consistency of Chinese patent medicines between batches.


Assuntos
Medicamentos de Ervas Chinesas , Espectrometria de Massas em Tandem , Cápsulas , Cromatografia Líquida de Alta Pressão , Solubilidade
9.
Pathol Oncol Res ; 27: 1609789, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408553

RESUMO

Background: Reprogramming of cell metabolism is one of the most important hallmarks of breast cancer. This study aimed to comprehensively analyze metabolic genes in the initiation, progression, and prognosis of breast cancer. Materials and Methods: Data from The Cancer Genome Atlas (TCGA) in breast cancer were downloaded including RNA-seq, copy number variation, mutation, and DNA methylation. A gene co-expression network was constructed by the weighted correlation network analysis (WGCNA) package in R. Association of metabolic genes with tumor-related immune cells and clinical parameters were also investigated. Results: We summarized 3,620 metabolic genes and observed mutations in 2,964 genes, of which the most frequently mutated were PIK3CA (51%), TNN (26%), and KMT2C (15%). Four genes (AKT1, ERBB2, KMT2C, and USP34) were associated with survival of breast cancer. Significant association was detected in the tumor mutation burden (TMB) of metabolic genes with T stage (p = 0.045) and N stage (p = 0.004). Copy number variations were significantly associated with recurrence and prognosis of breast cancer. The co-expression network for differentially expressed metabolic genes by WGCNA suggested that the modules were associated with glycerophospholipid, arachidonic acid, carbon, glycolysis/gluconeogenesis, and pyrimidine/purine metabolism. Glycerophospholipid metabolism correlated with most of the immune cells, while arachidonic acid metabolism demonstrated a significant correlation with endothelial cells. Methylation and miRNA jointly regulated 14 metabolic genes while mutation and methylation jointly regulated PIK3R1. Conclusion: Based on multi-omics data of somatic mutation, copy number variation, mRNA expression, miRNA expression, and DNA methylation, we identified a series of differentially expressed metabolic genes. Metabolic genes are associated with tumor-related immune cells and clinical parameters, which might be therapy targets in future clinical application.

10.
Biomed Pharmacother ; 142: 111971, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34343893

RESUMO

Recent studies report that inhibiting TNF-α might be a novel therapeutic strategy for managing brain ischemia. Our previous study reported that mesenchymal stem cell (MSC) transplantation could suppress TNF-α level in both serum and brain. However, the cell type(s) that contribute to the production of TNF-α during ischemia following MSC transplantation has not been well studied. In the present study, we found by fluorescent immunohistochemistry, that 7.95 ± 6.17% of TNF-α+ cells co-expressed Iba-1 in the infarct area of dMCAO rats, a majority of which were found to be CD68+ (activated microglia), suggesting that resident microglial population were not the major source of TNF-α expression. 68.49 ± 5.12% of the TNF-α+ cells in the infarct area could be labeled by GFAP, a specific marker for astrocytes, indicating that resident GFAP+ astrocytes might be the major source of TNF-α expression in the infarct area. In addition to the infarct area, the GFAP+/TNF-α+ double-positive astrocytes accounted for 73.68 ± 7.48% of the TNF-α+ cells in striatum and corpus callosum. The infiltrating cells, including monocytes and lymphocytes, were not the main source of TNF-α either. In response to MSC transplantation, the total TNF-α+ cells as well as the percentage of TNF-α-expressing astrocytes were significantly reduced in the infarct area, suggesting that MSC transplantation could suppress the expression of TNF-α by astrocytes. Taken together, the results demonstrated that resident astrocytes, but not microglia, were the major source of TNF-α expression and could be suppressed by MSC infusion.

11.
Cell Biol Toxicol ; 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34401974

RESUMO

Acetaminophen (APAP) overdose is a common cause of drug-induced liver injury (DILI). Ferroptosis has been recently implicated in APAP-induced liver injury (AILI). However, the functional role and underlying mechanisms of mitochondria in APAP-induced ferroptosis are unclear. In this study, the voltage-dependent anion channel (VDAC) oligomerization inhibitor VBIT-12 and ferroptosis inhibitors were injected via tail vein in APAP-injured mice. Targeted metabolomics and untargeted lipidomic analyses were utilized to explore underlying mechanisms of APAP-induced mitochondrial dysfunction and subsequent ferroptosis. As a result, APAP overdose led to characteristic changes generally observed in ferroptosis. The use of ferroptosis inhibitor ferrostatin-1 (or UAMC3203) and iron chelator deferoxamine further confirmed that ferroptosis was responsible for AILI. Mitochondrial dysfunction, which is associated with the tricarboxylic acid cycle and fatty acid ß-oxidation suppression, may drive APAP-induced ferroptosis in hepatocytes. APAP overdose induced VDAC1 oligomerization in hepatocytes, and protecting mitochondria via VBIT-12 alleviated APAP-induced ferroptosis. Ceramide and cardiolipin levels were increased via UAMC3203 or VBIT-12 in APAP-induced ferroptosis in hepatocytes. Knockdown of Smpd1 and Taz expression responsible for ceramide and cardiolipin synthesis, respectively, aggravated APAP-induced mitochondrial dysfunction and ferroptosis in hepatocytes, whereas Taz overexpression protected against these processes. By immunohistochemical staining, we found that levels of 4-hydroxynonenal (4-HNE) protein adducts were increased in the liver biopsy samples of patients with DILI compared to that in those of patients with autoimmune liver disease, chronic viral hepatitis B, and non-alcoholic fatty liver disease (NAFLD). In summary, protecting mitochondria via inhibiting VDAC1 oligomerization attenuated hepatocyte ferroptosis by restoring ceramide and cardiolipin content in AILI.

12.
Front Immunol ; 12: 702172, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447373

RESUMO

Containment of the AIDS pandemic requires reducing HIV transmission. HIV infection is initiated by the fusion of the membrane between the virus and the cell membrane of the host. 2P23 is an effective HIV membrane fusion inhibitor that may be a good entry inhibitor microbicide candidate. This study evaluated the potential of using gel-formulated 2P23 as a topical microbicide to prevent sexual transmission of HIV in the rectum and vagina. Our data revealed that 2P23 formulated in gel is effective against HIV. There was no change in antiviral activity at 25°C for 4 months or 60°C for 1 week. In addition, we demonstrated that the 2P23 gel was stable and fully functional at pH 4.0-8.0 and under different concentrations of H2O2. Finally, the 2P23 gel exhibited no cytotoxicity or antimicrobial activity and did not induce inflammatory changes in the rectal or vaginal mucosal epithelium in New Zealand rabbits after 20 mg/day daily rectovaginal application for 14 consecutive days. Despite repeated tissue sampling and 2P23 gel treatment, the inflammatory cytokines and microbiota of the rectum and vagina remained stable. These results add to general knowledge on the in vivo evaluation of anti-HIV microbicide application concerning inflammatory cytokines and microbiota changes in the rectum and vagina. These findings suggest that the 2P23 gel is an excellent candidate for further development as a safe and effective pre-exposure prophylactic microbicide for the prevention of HIV transmission.

13.
Biomaterials ; 277: 121075, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34428734

RESUMO

In somatic cell reprogramming, cells must escape the somatic cell-specific gene expression program to adopt other cell fates. Here, in vitro chemical induction with RepSox generated chemically induced mammary epithelial cells (CiMECs) with milk secreting functions from goat ear fibroblasts (GEFs). Transplanted CiMECs regenerated the normal mammary gland structure with milk-secreting functions in nude mice. Single-cell RNA sequencing revealed that during the reprogramming process, GEFs may sequentially undergo embryonic ectoderm (EE)-like and different MEC developmental states and finally achieve milk secreting functions, bypassing the pluripotent state. Mechanistically, Smad3 upregulation induced by transforming growth factor ß (TGFß) receptor 1 (TGFßR1) downregulation led to GEF reprogramming into CiMECs without other reprogramming factors. The TGFßR1-Smad3 regulatory effects will provide new insight into the TGFß signaling pathway regulation of somatic cell reprogramming. These findings suggest an innovative strategy for autogenous cell therapy for mammary gland defects and the production of transgenic mammary gland bioreactors.

14.
J Phys Chem A ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34235933

RESUMO

Effectively adjusting and controlling the valence state of neptunium from the spent fuel reprocessing process is essential to separating neptunium. Hydrazine and its derivatives as free-salt reductants have been experimentally demonstrated to effectively reduce Np(VI) to Np(V). We have theoretically investigated the reduction mechanisms of Np(VI) with hydrazine and three derivatives (HOC2H4N2H3, CH3N2H3, and CHON2H3) in previous works. Herein, we further explored the reduction reaction of Np(VI) with phenylhydrazine (C6H5N2H3) including the free radical ion mechanism and the free radical mechanism. Potential energy profiles (PEPs) indicate that the rate-determining step of both mechanisms is the first stage. Moreover, for the free radical ion mechanism, phenylhydrazine possesses better reduction ability to Np(VI) compared to HOC2H4N2H3, CH3N2H3, and CHON2H3, which falls completely in line with the experimental results. Additionally, the analyses of the quantum theory of atoms in molecules (QTAIM), natural bond orbitals (NBOs), electron localization function (ELF), and localized molecular orbitals (LMOs) have been put forward to elucidate the bonding evolution for the structures of the reaction pathways. This work offers insights into the reduction mechanism of Np(VI) with phenylhydrazine from the theory point of view and contributes to design more high-efficiency reductants for the separation of U/Np and Np/Pu in spent fuel reprocessing.

15.
BMC Cancer ; 21(1): 771, 2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34217249

RESUMO

BACKGROUND: Due to negative results in clinical trials of postoperative chemoradiation for gastric cancer, at present, there is a tendency to move chemoradiation therapy forward in gastric and gastroesophageal junction (GEJ) adenocarcinoma. Several randomized controlled trials (RCTs) are currently recruiting subjects to investigate the effect of neo-adjuvant radiotherapy (NRT) in gastric and GEJ cancer. Large retrospective studies may be beneficial in clarifying the potential benefit of NRT, providing implications for RCTs. METHODS: We retrieved the clinicopathological and treatment data of gastric and GEJ adenocarcinoma patients who underwent surgical resection and chemotherapy between 2004 and 2015 from Surveillance, Epidemiology, and End Results (SEER) database. We compared survival between NRT and non-NRT patients among four clinical subgroups (T1-2N-, T1-2N+, T3-4N-, and T3-4N+). RESULTS: Overall, 5272 patients were identified, among which 1984 patients received NRT. After adjusting confounding variables, significantly improved survival between patients with and without NRT was only observed in T3-4N+ subgroup [hazard ratio (HR) 0.79, 95% confidence interval (CI): 0.66-0.95; P = 0.01]. Besides, Kaplan-Meier plots showed significant cause-specific survival advantage of NRT in intestinal type (P <  0.001), but not in diffuse type (P = 0.11) for T3-4N+ patients. In the multivariate competing risk model, NRT still showed survival advantage only in T3-4 N+ patients (subdistribution HR: 0.77; 95% CI: 0.64-0.93; P = 0.006), but not in other subgroups. CONCLUSIONS: NRT might benefit resectable gastric and GEJ cancer patients of T3-4 stages with positive lymph nodes, particularly for intestinal-type. Nevertheless, these results should be interpreted with caution, and more data from ongoing RCTs are warranted.

16.
Artigo em Inglês | MEDLINE | ID: mdl-34310301

RESUMO

Separating the dominant person from the complex background is significant to the human-related research and photo-editing based applications. Existing segmentation algorithms are either too general to separate the person region accurately, or not capable of achieving real-time speed. In this paper, we introduce the multi-domain learning framework into a novel baseline model to construct the Multi-domain TriSeNet Networks for the real-time single person image segmentation. We first divide training data into different subdomains based on the characteristics of single person images, then apply a multi-branch Feature Fusion Module (FFM) to decouple the networks into the domain-independent and the domain-specific layers. To further enhance the accuracy, a self-supervised learning strategy is proposed to dig out domain relations during training. It helps transfer domain-specific knowledge by improving predictive consistency among different FFM branches. Moreover, we create a large-scale single person image segmentation dataset named MSSP20k, which consists of 22,100 pixel-level annotated images in the real world. The MSSP20k dataset is more complex and challenging than existing public ones in terms of scalability and variety. Experiments show that our Multi-domain TriSeNet outperforms state-of-the-art approaches on both public and the newly built datasets with real-time speed.

17.
Eur J Neurol ; 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34255403

RESUMO

BACKGROUND AND PURPOSE: The purpose was to provide an overview of genotype and phenotype distribution in a cohort of patients with Charcot-Marie-Tooth disease (CMT) and related disorders from central south China. METHODS: In all, 435 patients were enrolled and detailed clinical data were collected. Multiplex ligation-dependent probe amplification for PMP22 duplication/deletion and CMT multi-gene panel sequencing were performed. Whole exome sequencing was further applied in the remaining patients who failed to achieve molecular diagnosis. RESULTS: Among the 435 patients, 216 had CMT1, 14 had hereditary neuropathy with pressure palsies (HNPP), 178 had CMT2, 24 had distal hereditary motor neuropathy (dHMN) and three had hereditary sensory and autonomic neuropathy (HSAN). The overall molecular diagnosis rate was 70%: 75.7% in CMT1, 100% in HNPP, 64.6% in CMT2, 41.7% in dHMN and 33.3% in HSAN. The most common four genotypes accounted for 68.9% of molecular diagnosed patients. Relatively frequent causes were missense changes in PMP22 (4.6%) and SH3TC2 (2.3%) in CMT1; and GDAP1 (5.1%), IGHMBP2 (4.5%) and MORC2 (3.9%) in CMT2. Twenty of 160 detected pathogenic variants and the associated phenotypes have not been previously reported. Broad phenotype spectra were observed in six genes, amongst which the pathogenic variants in BAG3 and SPTLC1 were detected in two sporadic patients presenting with the CMT2 phenotype. CONCLUSIONS: Our results provided a unique genotypic and phenotypic landscape of patients with CMT and related disorders from central south China, including a relatively high proportion of CMT2 and lower occurrence of PMP22 duplication. The broad phenotype spectra in certain genes have advanced our understanding of CMT.

18.
J Exp Bot ; 72(15): 5751-5765, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34195821

RESUMO

Due to their sessile nature, plants must respond to various environmental assaults in a coordinated manner. The endoplasmic reticulum is a central hub for plant responses to various stresses. We previously showed that Phytophthora utilizes effector PsAvh262-mediated binding immunoglobulin protein (BiP) accumulation for suppressing endoplasmic reticulum stress-triggered cell death. As a BiP binding partner, Bcl-2-associated athanogene 7 (BAG7) plays a crucial role in the maintenance of the unfolded protein response, but little is known about its role in plant immunity. In this work, we reveal a double-faced role of BAG7 in Arabidopsis-Phytophthora interaction in which it regulates endoplasmic reticulum stress-mediated immunity oppositely in different cellular compartments. In detail, it acts as a susceptibility factor in the endoplasmic reticulum, but plays a resistance role in the nucleus against Phytophthora. Phytophthora infection triggers the endoplasmic reticulum-to-nucleus translocation of BAG7, the same as abiotic heat stress; however, this process can be prevented by PsAvh262-mediated BiP accumulation. Moreover, the immunoglobulin/albumin-binding domain in PsAvh262 is essential for both pathogen virulence and BiP accumulation. Taken together, our study uncovers a double-faced role of BAG7; Phytophthora advances its colonization in planta by utilizing an effector to detain BAG7 in the endoplasmic reticulum.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Phytophthora , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Estresse do Retículo Endoplasmático , Doenças das Plantas , Imunidade Vegetal/genética
19.
Oncoimmunology ; 10(1): 1929005, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262796

RESUMO

Interferons (IFNs) are a large family of pleiotropic cytokines that regulate both innate and adaptive immunity and show anti-cancer effects in various cancer types. Moreover, it was revealed that IFN signaling plays critical roles in the success of cancer therapy strategies, thereby enhancing their therapeutic effects. However, IFNs have minimal or even adverse effects on cancer eradication, and mediate cancer immune escape in some instances. Thus, IFNs have a double-edged effect on the cancer immune response. Recent studies suggest that IFNs regulate each step of the cancer immunity-cycle, consisting of cancer antigen release, presentation of antigens and activation of T cells, trafficking and infiltration of effector T cells into the tumor microenvironment, and recognition and killing of cancer cells, which contributes to our understanding of the mechanisms of IFNs in regulating cancer immunity. In this review, we focus on IFNs and cancer immunity and elaborate on the roles of IFNs in regulating the cancer-immunity cycle.


Assuntos
Interferons , Neoplasias , Imunidade Adaptativa , Citocinas , Humanos , Neoplasias/tratamento farmacológico , Linfócitos T , Microambiente Tumoral
20.
Sci Rep ; 11(1): 14636, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282208

RESUMO

Finding effective and objective biomarkers to inform the diagnosis of schizophrenia is of great importance yet remains challenging. Relatively little work has been conducted on multi-biological data for the diagnosis of schizophrenia. In this cross-sectional study, we extracted multiple features from three types of biological data, including gut microbiota data, blood data, and electroencephalogram data. Then, an integrated framework of machine learning consisting of five classifiers, three feature selection algorithms, and four cross validation methods was used to discriminate patients with schizophrenia from healthy controls. Our results show that the support vector machine classifier without feature selection using the input features of multi-biological data achieved the best performance, with an accuracy of 91.7% and an AUC of 96.5% (p < 0.05). These results indicate that multi-biological data showed better discriminative capacity for patients with schizophrenia than single biological data. The top 5% discriminative features selected from the optimal model include the gut microbiota features (Lactobacillus, Haemophilus, and Prevotella), the blood features (superoxide dismutase level, monocyte-lymphocyte ratio, and neutrophil count), and the electroencephalogram features (nodal local efficiency, nodal efficiency, and nodal shortest path length in the temporal and frontal-parietal brain areas). The proposed integrated framework may be helpful for understanding the pathophysiology of schizophrenia and developing biomarkers for schizophrenia using multi-biological data.

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