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1.
Food Chem ; 366: 130712, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34343953

RESUMO

The aim of this study was to investigate the effect of selenium enrichment on the gel properties and gastrointestinal digestive properties of egg white. Results of texture profile analysis, scanning electron microscopy and differential scanning calorimetry showed that the heat-induced gel of selenium-enriched egg white (EW-2) exhibited higher gel strength, smoother microstructure, and higher thermal denaturation temperature than ordinary egg white (EW-1), which might be due to the change of ovomucin and ovotransferrin content. The gastrointestinal digestive products of the EW-2 protein contained a higher proportion of small peptides and more free amino acids than those of EW-1. Results of oxygen radical absorbance capacity and cellular antioxidant activity assays indicated that digestive products of the EW-2 protein exhibited stronger antioxidant activity than those of the EW-1 protein. In summary, Se enrichment improved heat-induced gel properties of egg white, and promoted the gastrointestinal digestion of egg white protein.


Assuntos
Selênio , Animais , Galinhas , Digestão , Feminino , Temperatura Alta , Saccharomyces cerevisiae
2.
Food Chem ; 367: 130749, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34375886

RESUMO

To improve the quality of cultured large yellow croaker (Larimichthys crocea), this study was performed to study the impacts of glycerol monolaurate (GML) on the nutritional value, growth performance, muscle texture, and taste intensity of L. crocea. The results showed that GML as a feed additive significantly increased the crude lipid content and reduced the diameters of muscle fibers, which in turn markedly altered the flesh texture in terms of cohesiveness. Moreover, the taste indicators (umami and richness) and flavor-related amino acid (glutamic acid, glycine, and proline) contents of L. crocea muscle were significantly higher in the GML group. Metabolomic and gene expression analyses showed that GML supplementation could significantly improve amino acid biosynthesis and metabolism, promote protein and lipid synthesis, and activate myogenic-related signaling pathways of L. crocea. Consequently, adding an appropriate amount of GML to fish feed would be conducive to providing healthy, nutrient-rich and acceptably flavored aquatic-products.


Assuntos
Perciformes , Animais , Proteínas de Peixes/genética , Expressão Gênica , Lauratos , Monoglicerídeos , Perciformes/genética
3.
Behav Brain Res ; 417: 113562, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-34499939

RESUMO

BACKGROUND: Our previous works demonstrated that ß2-microglobulin (ß2m), a systemic pro-aging factor, induce depressive-like behaviors. Hydrogen sulfide (H2S) is identified as a potential target for treatment of depression. The aim of the present work is to explore whether H2S antagonizes ß2m-induced depressive-like behaviors and the underlying mechanisms. METHODS: The depressive-like behaviors were detected using the novelty suppressed feeding test (NSFT), tail suspension test (TST), forced swimming test (FST) and open field test (OFT). The expressions of Warburg-related proteins, including hexokinase II (HK II), pyruvate kinase M2 (PKM2), Lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH) and pyruvate dehydrogenase kinase 1(PDK1), and synaptic plasticity-related proteins, including postsynaptic density protein 95 (PSD95) and synaptophysin1 (SYN1), were determined by western blotting. RESULT: we found that NaHS (the donor of H2S) attenuated the depressive-like behaviors in the ß2m-exposed rats, as judged by NSFT, TST, FST, and OFT. We also demonstrated that NaHS enhanced the synaptic plasticity, as evidenced by the upregulations of PSD95 and SYN1 expressions in the hippocampus of ß2m-exposed rats. Furthermore, NaHS improved the Warburg effect in the hippocampus of ß2m-exposed rats, as evidenced by the upregulations of HK II, PKM2, LDHA and PDK1 expressions, and the downregulation of PDH expression. CONCLUSION: H2S prevents ß2m-induced depressive-like behaviors, which is involved in improvement of hippocampal synaptic plasticity as a result of enhancement of hippocampal Warburg effect.

4.
Neural Regen Res ; 17(4): 875-880, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34472488

RESUMO

The neutrophil-to-lymphocyte ratio (NLR) is considered a robust prognostic biomarker for predicting patient survival outcomes in many diseases. However, it remains unclear whether it can be used as a biomarker for amyotrophic lateral sclerosis (ALS). To correlate NLR with disease progression and survival in sporadic ALS, 1030 patients with ALS between January 2012 and December 2018 were included in this study. These patients were assigned into three groups according to their NLR values: Group 1 (NLR < 2, n = 544 [52.8%]), Group 2 (NLR = 2-3, n = 314 [30.5%]), and Group 3 (NLR > 3, n = 172 [16.7%]). All patients were followed up until April 2020. Patients in Group 3 had a significantly older onset age, a lower score on the Revised ALS Functional Rating Scale, and rapidly progressing disease conditions. Furthermore, faster disease progression rates were associated with higher NLR values (odds ratio = 1.211, 95% confidence interval [CI]: 1.090-1.346, P < 0.001) after adjusting for other risk factors. Compared with Groups 1 and 2, the survival time in Group 3 was significantly shorter (log-rank P = 0.002). The NLR value was considered an independent parameter for the prediction of survival in ALS patients after normalizing for all other potential parameters (hazard ratio [HR] = 1.079, 95% CI: 1.016-1.146, P = 0.014). The effects on ALS survival remained significant when adjusted for treatment (HR = 1.074, 95% CI: 1.012-1.141, Ptrend = 0.019) or when considering the stratified NLR value (HR = 1.115, 95% CI: 1.009-1.232, Ptrend = 0.033). Thus, the NLR may help to predict the rate of disease progression and survival in patients with sporadic ALS. The study was approved by the Institutional Ethics Committee of West China Hospital of Sichuan University, China (approval No. 2015 (236)) on December 23, 2015.

5.
Sci Total Environ ; 803: 149929, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34478900

RESUMO

Nitrous acid (HONO) is a major source of hydroxyl radicals in the troposphere through its photolysis, and can significantly influence ozone (O3) levels, thereby causing considerable crop yield losses. Previous studies have assessed relative crop yield losses by using exposure-response equations with observed or simulated O3, however, the contribution of enhanced O3 due to potential HONO sources to the crop yield losses has never been quantified. In this study, for the first time, we evaluated the crop yield losses caused by potential HONO sources in the North China Plain (NCP), which is one of the major grain-producing areas in China suffering from heavy O3 pollution, by using the Weather Research and Forecasting/Chemistry (WRF-Chem) model during the wheat and maize growing seasons of 2016. HONO simulations were significantly improved after including six potential HONO sources in the WRF-Chem model. The potential HONO sources produced a daily maximum 8-h O3 enhancement of 8.1/8.2 ppb during the wheat/maize growing seasons, respectively, and led to ~11.4%/3.3% relative yield losses for wheat/maize, respectively, corresponding to approximately US$3.78/0.66 billion losses, respectively, in NCP in 2016. The above results suggest that potential HONO sources play a significant role in O3 formation and could induce high crop yield losses globally.


Assuntos
Poluentes Atmosféricos , Ozônio , Poluentes Atmosféricos/análise , China , Ácido Nitroso , Ozônio/análise , Estações do Ano
7.
Microbiol Spectr ; : e0114121, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34851156

RESUMO

The emergence of high-level tigecycline resistance mediated by plasmid-borne tet(X) genes greatly threatens the clinical effectiveness of tigecycline. However, the dissemination pattern of plasmid-borne tet(X) genes remains unclear. We here recovered tet(X)-positive Acinetobacter isolates from 684 fecal and environmental samples collected at six livestock farms. Fifteen tet(X)-positive Acinetobacter isolates were identified, mainly including 9 tet(X3)- and 5 tet(X6)-positive Acinetobacter towneri isolates. A clonal dissemination of tet(X3)-positive A. towneri was detected in a swine farm, while the tet(X6)-positive A. towneri isolates mainly disseminated sporadically in the same farm. A tet(X3)-carrying plasmid (pAT181) was self-transmissible from a tigecycline-susceptible A. towneri strain to Acinetobacter baumannii strain ATCC 17978, causing 64- to 512-fold increases in the MIC values of tetracyclines (including tigecycline). Worrisomely, pAT181 was stably maintained and increased the growth rate of strain ATCC 17978. Further identification of tet(X) genes in 10,680 Acinetobacter genomes retrieved from GenBank revealed that tet(X3) (n = 249), tet(X5)-like (n = 61), and tet(X6) (n = 53) were the prevalent alleles mainly carried by four species, and most of them were livestock associated. Phylogenetic analysis showed that most of the tet(X3)- and tet(X6)-positive isolates disseminated sporadically. The structures of the tet(X3), and tet(X6) plasmidomes were highly diverse, and no epidemic plasmids were detected. However, cross-species and cross-region transmissions of tet(X3) might have been mediated by several plasmids in a small proportion of strains. Our study implies that horizontal plasmid transfer may be insignificant for the current dissemination of tet(X3) and tet(X6) in Acinetobacter strains. Continuous surveillance for tet(X) genes in the context of One Health is necessary to prevent them from transmitting to humans. IMPORTANCE Recently identified plasmid-borne tet(X) genes have greatly challenged the efficiency of tigecycline, a last-resort antibiotic for severe infection, while the dissemination pattern of the plasmid-borne tet(X) genes remains unclear. In this study, we identified a clonal dissemination of tet(X3)-positive A. towneri isolates on a swine farm, while the tet(X6)-positive A. towneri strains mainly disseminated sporadically on the same farm. Of more concern, a tet(X3)-carrying plasmid was found to be self-transmissible, resulting in enhanced tigecycline resistance and growth rate of the recipient. Further exploration of a global data set of tet(X)-positive Acinetobacter genomes retrieved from GenBank revealed that most of the tet(X3)- and tet(X6)-positive isolates shared a highly distant relationship, and the structures of tet(X3) and tet(X6) plasmidomes exhibited high mosaicism. Notably, some of the isolates belong to Acinetobacter species that are opportunistic pathogens and have been identified as sources of nosocomial infections, raising concerns about transmission to humans in the future. Our study evidenced the sporadic dissemination of tet(X3) and tet(X6) in Acinetobacter strains and the necessity of continuous surveillance for tet(X) genes in the context of One Health.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34851444

RESUMO

PURPOSE: Fuzuloparib (AiRuiYiTM, formerly fluzoparib, SHR3162) is a new orally active poly adenosine diphosphate ribose polymerase (PARP) inhibitor. It has multiple pharmacological activities in breast, ovarian, and prostatic cancer. Fuzuloparib is mainly metabolized through the enzyme CYP3A4 may slow fuzuloparib metabolism and increase its concentrations in blood. We evaluated the pharmacokinetics and tolerability of fuzuloparib by fluconazole, which is a broad antifungal agent and a moderate inhibitor of CYP3A4. METHODS: In this study, the effects of CYP3A4 inhibition on the pharmacokinetics of fuzuloparib were assessed in a total of 20 healthy Chinese male subjects in an open-label, two-period, single-sequence, crossover study. RESULTS: Pharmacokinetic parameters, including the maximal plasma concentration (Cmax), the plasma concentration-time curve from time 0 to last measurable area under concentration (AUC0-t), and from time 0 to infinity (AUC0-∞), were increased by 32.4%, 104.5%, and 109.6%, with corresponding 90% confidence intervals of (23-43%), (93-116%), and (98-122%), respectively, when fluconazole was combined with fuzuloparib compared to fuzuloparib alone. There was also a slight increase in the incidence of treatment emergent adverse events, including hyperlipidemia and elevated aspartate transaminase. CONCLUSION: The fuzuloparib is 150 mg b.i.d in clinics use. Our results suggest that fuzuloparib could well be tolerated when administered as a single 20 mg oral dose alone or co-administered with 400 mg fluconazole in healthy male subjects. It is recommended to avoid using moderate CYP3A4 inhibitors together with fuzuloparib or instead of 50 mg when necessary.

9.
Invest New Drugs ; 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34731354

RESUMO

BACKGROUND: Mucosal melanoma is rare and has distinct clinical and genetic features. Even with advances in targeted and immune therapies, the survival of patients with advanced or recurrent mucosal melanomas remains poor. The standard treatment remains controversial and we conducted this real-world study aimed to explore continuous intravenous recombinant human endostatin (Rh-endostatin) infusion plus chemotherapy in this population in the first-line setting. METHODS: Overall, 43 patients with advanced or recurrent mucosal melanoma treated at Fudan University Shanghai Cancer Center between April 2017 and August 2020 were retrospectively included. Patients received dacarbazine plus cisplatin or temozolomide plus cisplatin per the investigators' preference. Rh-endostatin (105 mg/m2) was administered with continuous infusion for 168 h (Civ 168 h). RESULTS: Of the 43 patients, 72.1% had metastatic disease, and the most common primary site was the gastrointestinal tract (51.2%). The most commonly observed mutations were NRAS (23.1%), BRAF (7.7%) and CKIT mutations (5.1%). An objective response was observed in 12 (30.0%) of the 40 evaluable patients, and disease control was achieved in 31 (77.5%) patients. With a median follow-up of 17.6 months, the median progression-free survival (PFS) and overall survival (OS) were 4.9 and 15.3 months, respectively. Additionally, high lymphocyte-to-monocyte ratio (LMR) (p = 0.023, HR 0.29, 95% CI: 0.10-0.84) and BRAF/KIT/RAS mutation (p = 0.028, HR 0.24, 95% CI: 0.07-0.86) were independently correlated with prolonged OS. Toxicity was manageable overall. CONCLUSION: Continuous Rh-endostatin infusion plus chemotherapy was effective and safe for the treatment of advanced or recurrent mucosal melanoma. High LMR was correlated with favorable PFS and OS in this patient population.

10.
J Inflamm Res ; 14: 5501-5511, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34737599

RESUMO

Purpose: Inflamm-aging is a novel-concept in rheumatoid arthritis (RA) with accelerating aging process. We try to find a correlation between serum albumin/globulin (A/G) ratio and clinical biochemical parameters, incidence of aging-related diseases (ARDs) as well as inflammaging-related molecules. Patients and Methods: Healthy controls (HC) and RA patients were compared with their clinical biochemical parameters including albumin and globulin levels, A/G ratio, and levels of serum lipids. Incidence of ARDs in RA was compared with A/G ratio, having a cut off value of 1.2. Expression levels of leptin and Trf2 genes in PBMCs, and inflammatory factors like IL-1ß, IL-6, IL-8 and TNF-ɑ between HC and RA patients were compared, and correlated with the A/G ratio. Results: Compared to HC, RA patients had decreased levels of albumin, while globulin levels were found to be increased, which led to a significantly lower A/G ratio in RA patients. A/G ratio rather than ESR and CRP had significant correlation with dyslipidemia in RA patients. Patients with A/G <1.2 had a higher risk of ARDs than patients with A/G >1.2. The RR was 2.48 (95% CI: 1.79 to 3.64, p <0.0001). In addition, A/G ratio has positively correlated to leptin and Trf2 expression, while an inverse correlation was observed with the levels of inflamm-aging related cytokines like IL-6, IL-8 and TNF-ɑ. Conclusion: A decreased A/G ratio in RA patients has significantly correlated with dyslipidemia and ARDs, as well as inflammaging- related adipokine and pro-inflammatory cytokines. Thus, A/G ratio could be a reliable marker for evaluating the inflammaging process during clinical management in ARDs.

11.
J Inflamm Res ; 14: 5527-5540, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34737602

RESUMO

Background: Systemic inflammation and cachexia are associated with adverse clinical outcomes in elderly patients with cancer. The survival outcomes of elderly patients with cancer cachexia (EPCC) with high inflammation and a high risk of mortality are unknown. This study aimed to investigate the impact of high inflammation on the prognosis of EPCC patients with high mortality. Patients and Methods: This multicenter cohort study included 746 EPCC (age >65 years) with a mean age of 72.00 ± 5.24 years, of whom 489 (65.5%) were male. The cut-off value for the inflammation index was obtained using the optimal survival curve. The different inflammatory indicators were assessed using the concordance index (C-index), decision curve analysis (DCA), and prognostic receiver operating characteristic (ROC). The high mortality risk group of EPCC was defined by the 2011 Fearon Cancer Diagnostic Consensus. EPCC were divided into the high-risk group, which satisfies three diagnostic criteria, and a low-risk group, which satisfies only one or two diagnostic criteria. Results: The C-index, DCA, and prognostic ROC indicated the superiority of advanced lung cancer inflammation index (ALI) compared with other indicators, including neutrophil-lymphocyte ratio (NLR), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), and platelet-lymphocyte ratio (PLR). Whether ALI was used as a continuous or a categorical variable, ALI had a better prognostic value in EPCC compared with other inflammatory indicators. In particular, patients with low ALI (<25.03) had a worse overall survival (OS) than patients with high ALI (≥25.03) (P < 0.001, HR [95% CI] = 2.092 [1.590-2.751]). The combination effect analysis showed that the risk of mortality of the patients in the low-ALI and high-risk groups was 3.095-fold higher than that of patients in the high-ALI and low-risk groups. Conclusion: The prognostic and discriminative value of the inflammatory indicator ALI was better than that of NLR, PNI, SII, and PLR in EPCC. The high-risk group of EPCC with a low ALI would increase the death risk of OS.

12.
J Int Med Res ; 49(11): 3000605211055387, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34738481

RESUMO

Pulmonary large cell neuroendocrine carcinoma (LCNEC), which accounts for approximately 1% of all lung cancers, is a rare and highly aggressive malignancy with a poor prognosis. Therefore, it is important to devise an effective treatment strategy. In the treatment of locally advanced complex LCNEC, it is unique to first administer radiotherapy combined with albumin-bound paclitaxel plus carboplatin, followed by durvalumab for immune maintenance treatment after concurrent radiotherapy and chemotherapy to achieve complete remission. We report a 54-year-old man who smoked and who felt chest tightness for 2 weeks and was diagnosed as having combined pulmonary LCNEC. For patients with locally advanced pulmonary LCNEC, chemoradiotherapy increases overall survival. After surgical resection and chemoradiotherapy, our patient achieved complete remission. Durvalumab was then started to consolidate the treatment. After six courses of immune maintenance therapy, the patient developed grade 2 immune-related pneumonitis and took prednisone orally until the symptoms resolved, and then reached complete remission again. The patient achieved complete remission, which was a challenge with this rare carcinoma, through albumin-bound paclitaxel plus platinum-based chemotherapy combined with radiotherapy and durvalumab for immune maintenance therapy. This approach may provide a treatment option for locally advanced combined pulmonary LCNEC.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma Neuroendócrino/tratamento farmacológico , Quimiorradioterapia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade
13.
Front Pharmacol ; 12: 740821, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34744724

RESUMO

Background: Hypertension, a risk factor for cardiovascular events, is often associated with chronic kidney disease. This is called hypertensive nephropathy (HN), which negatively affects physical fitness and body mass, leading to economic burden. Traditional Chinese medicine injections (TCMIs) are common traditional Chinese-patent medicine preparations in China. There was a lack of evidence to prove which TCMIs combine with ADs (TCMIs+ADs) may be a therapeutic option for HN. Thus, we systematically reviewed the efficacy and safety of various TCMIs + ADs in patients with HN. Methods: We conducted a comprehensive search of PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, and VIP information resource integration service platform databases for relevant Chinese- and English-language randomized controlled trials (RCTs) published from database inception until May 2021. Literature screening, data extraction, and quality assessment was performed by two reviewers independently but using the same criteria. We performed the effect modeling to analyze the data for all outcomes and ranked each intervention using the P-score. Furthermore, sensitivity analysis, meta-regression, and funnel plots were used to test the stability, heterogeneity, and publication bias, respectively. Results: We included 69 RCTs with 6373 patients and including six TCMIs + ADs. Network analysis indicated that the ginkgo leaf extract and dipyridamole combined with ADs (GLED + ADs) was the most efficacious in terms of 24-h urinary protein excretion [mean difference (MD) = -0.70, 95% confidence interval (CI): -0.82 to -0.58; P-score = 1] and systolic blood pressure (MD = -12.95, 95% CI: -21.03 to -4.88; P-score = 0.88), whereas the salvianolate combined with ADs (SA + ADs) showed the highest effectiveness for diastolic blood pressure (MD = -6.88, 95% CI: -10.55 to -3.21; P-score = 0.9). Based on the combined P-score of network meta-analysis results (88% and 85.26%) and sensitivity analysis results (72% and 71.54%), the biplots showed that the GLED + ADs was the most efficacious intervention in all TCMIs + ADs for primary outcomes, followed by the SA + ADs and sodium tanshinone IIA sulfonate combined with ADs (STS + ADs). There was no significant difference in terms of safety between TCMIs + ADs and ADs alone. Conclusion: Of all the TCMIs + ADs, GLED + ADs, SA + ADs, and STS + ADs may demonstrate a higher efficacy than ADs alone for HN. Weighing with the potential benefits and limitations in methodology, potential heterogeneity and outcomes, we should use various TCMIs with caution in clinical practice. Nevertheless, additional high-quality RCTs are warranted and future research should focus on the clinical value of core outcomes to confirm the effectiveness and safety of TCMIs for HN. Systematic Review Registration: clinicaltrials.gov, identifier CRD42020205358.

14.
Front Oncol ; 11: 751777, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745980

RESUMO

Introduction: Role of response to antiviral therapies on survival of patients with intermediate-stage hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) undergoing transarterial chemoembolization (TACE) remains unknown. We aimed to determine whether virological response (VR) or prolonged maintained virological response (MVR) to nucelos(t)ide analogues (NA) therapy could result in improved survival in HBV-HCC patients receiving TACE. Methods: Between January 2012 and October 2018, data of patients with intermediate HBV-HCC who underwent TACE and started NA therapy within one week prior to TACE treatment at our institution were reviewed. Overall survival (OS) was compared using the Kaplan-Meier method with log-rank test between different VR status groups. Univariable and multivariable Cox regression analyses were used to determine the association between achievement of VR or MVR and OS. VR was defined as an undetectable HBV DNA level (<100 IU/ml) on two consecutive measurements during NA treatment. MVR was defined as a persistently undetectable HBV DNA level after achieving a VR. Results: A total of 1265 patients undergoing TACE with a median follow-up time of 18 months (range, 2-78 months) were included in the analysis. Of 1265 NA-treated patients [1123 (88.8%) male, median (range) age, 56 (18-75) years], 744 patients (58.8%) achieved VR and the remaining patients (41.2%) did not. Patients with achievement of VR showed a significantly longer OS than those without VR (median OS: 21 vs 16 months; HR, 0.707; 95% CI, 0.622-0.804; P<0.001). Among patients with VR, MVR was present in 542 patients (72.8%), while the other 202 patients (27.2%) in the non-MVR group. The OS for the MVR group was significantly higher than the non-MVR group (median OS: 23.2 vs 18 months; HR, 0.736; 95% CI, 0.612-0.885; P=0.001). Additionally, patients with MVR status more than two years showed a better OS than those with just one-year (HR, 0.719; 95% CI, 0.650-0.797; P<0.001) or one-to-two-year MVR (HR, 0.612; 95% CI, 0.471-0.795; P=0.024). On multivariable analyses, splenomegaly and up-to-seven criteria were independent prognostic factors of OS in both VR and MVR cohorts. Conclusions: In patients with intermediate-stage HBV-HCC, both VR to antiviral therapy and prolonged response are associated with prolonged OS after TACE, especially for those within up-to-seven criteria.

15.
Front Nutr ; 8: 746342, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746210

RESUMO

Mortierella alpina has a strong capacity for lipid accumulation. Isocitrate dehydrogenase (IDH) plays an important role in affecting the flow of intracellular carbon sources and reducing power NADPH for lipid biosynthesis. In this study, the effect of various IDHs (NAD+- and NADP+-specific) in M. alpina on the lipid accumulation was investigated through homologous overexpression. The results showed that the transcription level and enzyme activity of the IDHs from M. alpina (MaIDHs) in homologous overexpressing strains were higher than those of the control strain, but that their biomass was not significantly different. Among the various NAD+-specific MaIDH1/2/3 overexpression, NAD+-MaIDH3 reduced total lipid content by 12.5%, whereas overexpression NAD+-MaIDH1 and NAD+-MaIDH2 had no effect on fatty acid content. Intracellular metabolites analysis indicated that the overexpression NAD+-MaIDH3 strain had reduced the fatty acid accumulation, due to its greater carbon flux with the tricarboxylic acid cycle and less carbon flux with fatty acid biosynthesis. For the NADP+-MaIDH4/5/6 recombinant strains overexpressing only NADP+-MaIDH4 enhanced the total fatty acid content by 8.2%. NADPH analysis suggested that this increase in lipid accumulation may have been due to the great reducing power NADPH is produced in this recombinant strain. This study provides theoretical basis and guidance for the analysis of the mechanism of IDH function and the potential to improve lipid production in M. alpina.

16.
J Clin Pharmacol ; 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34761398

RESUMO

The pharmacokinetics (PK) of teicoplanin differs in children as compared with adults, and especially in renally-impaired pediatric patients. Inappropriate empirical antibacterial therapy may lead to treatment-related antibacterial resistance and increased toxicity, making adjustment of the dosage regimen essential. In the present study, physiologically based pharmacokinetic (PBPK) models were developed to define the appropriate dosage regimen for pediatric patients with differing renal function. Our PBPK models accurately predicted teicoplanin exposures in both adult and pediatric subjects after single and multiple intravenous infusions, with less than a 1.36-fold error between predicted and observed data, and all observed data were within minimal and maximal data of the corresponding population simulation. The area under the plasma concentration-time curve was predicted to increase 1.25-fold, 1.95-fold, and 2.82-fold in pediatric patients with mild, moderate, and severe renal impairment (RI), respectively, relative to that of healthy children. Subsequently, the results of Monte Carlo simulations indicated that the recommended dosing of 12, 9.5, 6, and 4 mg/kg at 12-hour intervals would be appropriate in pediatric patients with normal renal function and in those with mild RI, moderate RI, and severe RI, respectively, at a susceptible MIC <2 mg/L. In conclusion, our PBPK model with an incorporated Monte Carlo simulation can provide improved guidance on dosing in pediatric patients with differing renal function and provide a basis for precision therapy with teicoplanin. This article is protected by copyright. All rights reserved.

17.
Andrology ; 2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34779135

RESUMO

OBJECTIVES: To investigate the effect of icariin on endothelial microparticles, endothelial progenitor cells, platelets, and erectile function in spontaneously hypertensive rats. MATERIALS AND METHODS: Twelve 8-week-old healthy male Wistar-Kyoto rats and 12 spontaneously hypertensive rats were randomly divided into four following groups: Wistar-Kyoto control group (normal saline 1 ml/d given by gavage), Wistar-Kyoto + icariin group (icariin 10 mg/kg × d dissolved in 1 ml normal saline and given by gavage), spontaneously hypertensive rats control group (normal saline 1 ml/d given by gavage), and spontaneously hypertensive rats + icariin group (icariin 10 mg/kg × d dissolved in 1 ml normal saline and given by gavage). Four weeks later, the maximum intracavernous pressure/mean arterial pressure, platelet count, mean platelet volume, platelet distribution width, endothelial microparticles, endothelial progenitor cells, and vitronectin receptor were measured in each group. RESULTS: Under 3 or 5 V electrical stimulation, the maximum intracavernous pressure/mean arterial pressure in the spontaneously hypertensive rats + icariin group (0.23 ± 0.03, 0.38 ± 0.02) was significantly higher compared to the spontaneously hypertensive rats control group (0.12 ± 0.02, 0.20 ± 0.02) (p<0.05). Platelet count, mean platelet volume, and platelet distribution width in the spontaneously hypertensive rats + icariin group (1103.67 ± 107.70 × 109 /L, 9.08 ± 0.50 fl, 11.87 ± 0.45%) were significantly lower than those in the spontaneously hypertensive rats control group (1298.00 ± 89.54 × 109 /L, 9.72 ± 0.44 fl, 13.03 ± 0.59%) (all p < 0.05). Endothelial microparticles, endothelial progenitor cells, and vitronectin receptor in the spontaneously hypertensive rats + icariin group (1.01 ± 0.28%, 1.53 ± 0.65%, 2.13 ± 0.53%) were significantly lower than those in the spontaneously hypertensive rats control group (1.58 ± 0.19%, 2.71 ± 0.64%, 3.76 ± 0.52%) (all p < 0.05). Moreover, maximum intracavernous pressure/mean arterial pressure was strongly negatively correlated with platelet distribution width and vitronectin receptor (r > 0.7), and maximum intracavernous pressure/mean arterial pressure was moderately negatively correlated with mean platelet volume, endothelial microparticles, and endothelial progenitor cells (0.5 < r<0.7). CONCLUSION: Icariin may improve erectile function in spontaneously hypertensive rats by reducing the content of endothelial microparticles in blood and inhibiting the activation of the platelets. Endothelial microparticles, endothelial progenitor cells, and platelet activation-related (mean platelet volume, platelet distribution width, and vitronectin receptor) can be used as indicators for icariin to improve erectile function in spontaneously hypertensive rats.

18.
J Med Chem ; 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34779204

RESUMO

VPS34 is a class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation. Inhibitors of VPS34 were believed to have value as anticancer agents, but genetic and pharmacological data suggest that sustained inhibition of VPS34 kinase activity may not be well tolerated. Here we disclose the identification of a novel series of dihydropyrazolopyrazinone compounds represented by compound 5 as potent, selective, and orally bioavailable VPS34 inhibitors through a structure-based design strategy. A water-interacting hydrogen bond acceptor within an appropriate distance to a hinge-binding element was found to afford significant VPS34 potency across chemical scaffolds. The selectivity of compound 5 over PIK family kinases arises from interactions between the hinge-binding element and the pseudo-gatekeeper residue Met682. As recent in vivo pharmacology data suggests that sustained inhibition of VPS34 kinase activity may not be tolerated, structure-activity relationships leading to VPS34 inhibition may be helpful for avoiding this target in other ATP-competitive kinase programs.

19.
J Chem Theory Comput ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34788039

RESUMO

Interferences emerge when multiple pathways coexist together, leading toward the same result. Here, we report a theoretical study for a reaction scheme that leads to constructive quantum interference in a photoassociation (PA) reaction of a 87Rb Bose-Einstein condensate where the reactant spin state is prepared in a coherent superposition of multiple bare spin states. This is achieved by changing the reactive scattering channel in the PA reaction. As the origin of coherent control comes from the spin part of the wavefunction, we show that it is sufficient to use radio frequency (RF) coupling to achieve the superposition state. We simulate the RF coupling on a quantum processor (IBMQ Lima), and our results show that interferences can be used as a resource for the coherent control of photochemical reactions. The approach is general and can be employed to study a wide spectrum of chemical reactions in the ultracold regime.

20.
Dis Markers ; 2021: 2409820, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34795805

RESUMO

Enhancer RNAs (eRNAs), a subclass of noncoding RNAs from enhancers, have been demonstrated to exhibit important regulatory effects on the expressions of various genes. However, the role of eRNAs in skin cutaneous melanoma (SKCM) remained largely unclear. In this study, we aimed to explore the expression and prognostic value of an enhancer RNA TEX41 in SKCM as well as the associations between TEX41 and tumor-infiltrating immune cells (TICs). We observed that TEX41 expression was distinctly increased in SKCM specimens compared with normal skin specimens using GEPIA. Survival assays based on TGCA datasets revealed that patients with low TEX41 expressions displayed a longer overall survival than those with high TEX41 expression. CIBERSORT datasets revealed that TEX41 was related to 8 types of TICs (macrophages M1, T cells regulatory, plasma cells, mast cells resting, T cells CD8, dendritic cells resting, and T cells follicular helper). Three kinds of TICs were negatively related to TEX41 expressions, including macrophages M2, NK cells resting, and macrophages M0. The expressions of TEX41 were involved in five KEGG pathways, including transcriptional misregulation in cancer, SNARE interactions in vesicular transport, mitophagy-animal, melanoma, melanogenesis, and progesterone-mediated oocyte maturation. Overall, TEX41 can be used as a novel biomarker for the prognosis of SKCM patients and is associated with TICs, indicating it as a therapeutic target for SKCM.

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