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1.
J Psychopharmacol ; : 2698811221122008, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36069168

RESUMO

BACKGROUND: Intracerebral translocator protein 18 kDa (TSPO) mediates the transport of cholesterol from cytoplasm to mitochondria and activation of microglia. The change of TSPO and the dysfunction of microglia are closely related to the pathogenesis of Alzheimer's disease (AD). AIMS: This study aimed to investigate the effects of microglial TSPO and its selective ligand YL-IPA08 on the cognitive function of transgenic mice in 5 × familial Alzheimer's disease (FAD) mouse model of AD. METHODS: The TSPO knockout 5 × FAD transgenic mice were bred, and tested by Morris water maze. The effects of YL-IPA08 on cognitive abilities and expression of Aß in 5 × FAD mice were also explored into. RESULTS: The latency of escape by TSPO knockout 5 × FAD mice was significantly prolonged compared with the 5 × FAD group, indicating that the cognitive impairment of mice aggravated. With the attenuated phagocytic ability of microglia, the deposition of Aß in prefrontal cortex of TSPO knockout 5 × FAD mice increased, and the expression of proinflammatory factors (IL-1ß, TNF-α, IL-6) were upregulated. In addition, YL-IPA08 significantly reduced the latency of escape by 5 × FAD mice, increased the number of times of crossing over the platform by mice, and inhibited the deposition of Aß in the prefrontal cortex of 5 × FAD mice without affecting the cleavage of APP. CONCLUSION: Our findings suggested that TSPO knockout in 5 × FAD mice inhibited microglial phagocytosis, promoted Aß deposition and neuroinflammation, and aggravated cognitive dysfunction in AD mice. YL-IPA08 had a significant cognition-enhancing effect in 5 × FAD transgenic mice, which might provide a new basis for potential drug candidates in AD treatment.

2.
Artigo em Inglês | MEDLINE | ID: mdl-36115062

RESUMO

SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80% of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome.

3.
Front Microbiol ; 13: 1001540, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36110302

RESUMO

Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) is an important soilborne fungal pathogen that causes the most devastating banana disease. Effectors secreted by microbes contribute to pathogen virulence on host plants in plant-microbe interactions. However, functions of Foc TR4 effectors remain largely unexplored. In this study, we characterized a novel cupin_1 domain-containing protein (FoCupin1) from Foc TR4. Sequence analysis indicated that the homologous proteins of FoCupin1 in phytopathogenic fungi were evolutionarily conserved. Furthermore, FoCupin1 could suppress BAX-mediated cell death and significantly downregulate the expression of defense-related genes in tobacco by using the Agrobacterium-mediated transient expression system. FoCupin1 was highly induced in the early stage of Foc TR4 infection. The deletion of FoCupin1 gene did not affect Foc TR4 growth and conidiation. However, FoCupin1 deletion significantly reduced Foc TR4 virulence on banana plants, which was further confirmed by biomass assay. The expression of the defense-related genes in banana was significantly induced after inoculation with FoCupin1 mutants. These results collectively indicate FoCupin1 is a putative effector protein that plays an essential role in Foc TR4 pathogenicity. These findings suggest a novel role for cupin_1 domain-containing proteins and deepen our understanding of effector-mediated Foc TR4 pathogenesis.

4.
BMC Genomics ; 23(1): 580, 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35953780

RESUMO

BACKGROUND: High temperature induces early bolting in lettuce (Lactuca sativa L.), which affects both quality and production. However, the molecular mechanism underlying high temperature-induced bolting is still limited. RESULTS: We performed systematical analysis of morphology, transcriptome, miRNAs and methylome in lettuce under high temperature treatment. Through a comparison of RNA-Seq data between the control and the high temperature treated lettuces at different time points totally identified 2944 up-regulated genes and 2203 down-regulated genes, which cover three floral pathways including photoperiod, age and gibberellin (GA) pathways. Genome wide analysis of miRNAs and methylome during high temperature treatment indicated miRNAs and DNA methylation might play a role controlling gene expression during high temperature-induced bolting. miRNA targets included some protein kinase family proteins, which potentially play crucial roles in this process. CONCLUSIONS: Together, our results propose a possible regulation network involved in high temperature-induced bolting.


Assuntos
Alface , MicroRNAs , Flores/genética , Regulação da Expressão Gênica de Plantas , Alface/genética , Alface/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Temperatura
5.
Nature ; 608(7922): 413-420, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35922515

RESUMO

High cholesterol is a major risk factor for cardiovascular disease1. Currently, no drug lowers cholesterol through directly promoting cholesterol excretion. Human genetic studies have identified that the loss-of-function Asialoglycoprotein receptor 1 (ASGR1) variants associate with low cholesterol and a reduced risk of cardiovascular disease2. ASGR1 is exclusively expressed in liver and mediates internalization and lysosomal degradation of blood asialoglycoproteins3. The mechanism by which ASGR1 affects cholesterol metabolism is unknown. Here, we find that Asgr1 deficiency decreases lipid levels in serum and liver by stabilizing LXRα. LXRα upregulates ABCA1 and ABCG5/G8, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and faeces4, respectively. ASGR1 deficiency blocks endocytosis and lysosomal degradation of glycoproteins, reduces amino-acid levels in lysosomes, and thereby inhibits mTORC1 and activates AMPK. On one hand, AMPK increases LXRα by decreasing its ubiquitin ligases BRCA1/BARD1. On the other hand, AMPK suppresses SREBP1 that controls lipogenesis. Anti-ASGR1 neutralizing antibody lowers lipid levels by increasing cholesterol excretion, and shows synergistic beneficial effects with atorvastatin or ezetimibe, two widely used hypocholesterolaemic drugs. In summary, this study demonstrates that targeting ASGR1 upregulates LXRα, ABCA1 and ABCG5/G8, inhibits SREBP1 and lipogenesis, and therefore promotes cholesterol excretion and decreases lipid levels.


Assuntos
Receptor de Asialoglicoproteína , Colesterol , Metabolismo dos Lipídeos , Proteínas Quinases Ativadas por AMP/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Receptor de Asialoglicoproteína/antagonistas & inibidores , Receptor de Asialoglicoproteína/deficiência , Receptor de Asialoglicoproteína/genética , Receptor de Asialoglicoproteína/metabolismo , Assialoglicoproteínas/metabolismo , Atorvastatina/farmacologia , Proteína BRCA1 , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Colesterol/metabolismo , Sinergismo Farmacológico , Endocitose , Ezetimiba/farmacologia , Humanos , Lipídeos/análise , Lipídeos/sangue , Fígado/metabolismo , Receptores X do Fígado/metabolismo , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 1 , Ubiquitina-Proteína Ligases/metabolismo
6.
Int Wound J ; 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36008920

RESUMO

Radiodermatitis is an inevitable side effect of radiotherapy in cancer treatment and there is currently no consensus on effective drugs for treating the condition. Vitamin B12 is known to be effective for repairing and regenerating damaged skin. However, there are few studies on the use of Vitamin B12 for treating radiodermatitis. This study explored the therapeutic efficacy and mechanism of action of Vitamin B12 ointment on radiodermatitis. A porcine model of grade IV radiodermatitis was established. The ointment was applied for 12 weeks after which histological staining, transmission electron microscopy, RT-qPCR, western blotting, and gene sequencing were performed for the evaluation of specific indicators in skin samples. After 12 weeks of observation, the Vitamin B12 treatment was found to have significantly alleviated radiodermatitis. The treatment also significantly reduced the expression levels of NF-κB, COX-2, IL-6, and TGF-ß in the skin samples. The pathways involved in the effects of the treatment were identified by analysing gene expression. In conclusion, Vitamin B12 ointment was found to be highly effective for treating radiodermatitis, with strong anti-radiation, anti-inflammatory, and anti-fibrosis effects. It is thus a promising drug candidate for the treatment of severe radiodermatitis.

7.
8.
Front Immunol ; 13: 913483, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35958603

RESUMO

Objective: To explore the efficacy and safety of single-agent programmed cell death protein-1 (PD-1) inhibitor in the neoadjuvant treatment of patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) locally advanced colorectal cancer (LACRC) through single-center large⁃sample analysis based on real⁃world data in China. Methods: This study was a retrospective, single-center, case series study. 33 colorectal cancer (CRC) patients with clinical stage of T3~4N0~2M0 treated in Yunnan Cancer Hospital from June 2019 to June 2021 were analyzed retrospectively. Among them, 32 patients were dMMR or MSI-H or both dMMR and MSI-H, and one patient was both dMMR and microsatellite stability (MSS) (excluded in the final analysis). All 32 patients received neoadjuvant immunotherapy (nIT) with single-agent PD⁃1 inhibitor. Results: Among the 32 patients, 8 (25%) were locally advanced rectal cancer (LARC) and 24 (75%) were locally advanced colon cancer (LACC); 4 (12.55%) were stage II and 28 (87.5%) were stage III. The median number of cycles of 32 patients with dMMR/MSI-H LACRC receiving nIT with single-agent PD-1 blockade was 6 (4~10), and the median number of cycles to achieve partial response (PR) was 3 (2~4). Among them, three LARC patients achieved clinical complete response (cCR) and adopted the watch-and-wait (W&W) strategy. The objective response rate (ORR) of the other 29 patients with radical surgery was 100% (29/29), the pathological response rate was 100% (29/29), the rate of major pathological response (MPR) was 86.2% (25/29), and the rate of pathological complete response (pCR) was 75.9% (22/29). The incidence of immune-related adverse events (irAEs) in 32 patients during nIT was 37.5% (12/32), while the incidence of irAEs in 22 patients with operation during adjuvant immunotherapy was 27.3% (6/22), all of which were grade 1~2. No grade 3 or above irAEs were occured. The median time from the last nIT to surgery was 27 (16~42) days. There were no delayed radical resection due to irAEs in these patients. All 29 patients achieved R0 resection. The incidence of surgical-related adverse events (srAEs) in perioperative period was 10.3% (3/29). Conclusions: Neoadjuvant monoimmunotherapy with PD-1 inhibitor has favorable ORR and pCR rate, and relatively low incidences of irAEs and srAEs for patients with dMMR/MSI-H LACRC, suggesting that this nIT regimen of single-agent PD-1 inhibitor is significantly effective and sufficiently safe.


Assuntos
Neoplasias do Colo , Terapia Neoadjuvante , China , Reparo de Erro de Pareamento de DNA , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos
9.
Metab Brain Dis ; 2022 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-35779149

RESUMO

TSPO, an 18 kDa translocator protein, has received increased attention due to its antidepressant-anxiolytic effects. The balance between glutamatergic and GABAergic (E: I) in the medial prefrontal cortex (mPFC) is crucial for antidepressant-anxiolytic effects. However, no evidence is available to clarify the relationship between TSPO and E:I balance. In the present study, we used the TSPO global-knockout (KO) and TSPO wild-type (WT) mice to assess the effects of TSPO on antidepressant-anxiolytic effects of YL-IPA08 (a novel TSPO ligand) and the underlying neurobiological mechanism. Additionally, a multichannel electrophysiological technique was used to explore the effects of YL-IPA08 on pyramidal neurons and interneurons in mPFC. Open field test (OFT) and elevated plus maze (EPM) test revealed that a single dose of YL-IPA08 (0.3 mg/kg, i.p.) exhibited significant anxiolytic actions in WT mice except in KO mice. In only WT mice, significant antidepressant effects were observed in tail suspension test (TST) and forced swim test (FST). The multichannel electrophysiological technique demonstrated that YL-IPA08 significantly increased the firing rates of pyramidal neurons and decreased those of interneurons. Further studies illustrated that the firing rates of glutamatergic might be antagonized by PK11195 (a classic TSPO antagonist). Our results suggest that YL-IPA08 might regulate the E:I balance in mPFC, mediated by TSPO. In summary, TSPO regulates E:I functional balance in mPFC, play a critical role in antidepressant-anxiolytic effects of YL-IPA08, and provide a potential target site for the development of antidepressant and anxiolytic drugs.

10.
Hepatology ; 2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-35908246

RESUMO

BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations (EpCAM+ CD63+ , CD147+ CD63+ , and GPC3+ CD63+ HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort (n = 106) and an independent validation cohort (n = 72). Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

11.
Org Lett ; 24(31): 5736-5740, 2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-35904329

RESUMO

Differentiation between similarly reactive sites in molecules represents an ongoing challenge of organic synthesis. Herein we described one kind of versatile reagents, N-thiohydroxy succinimide esters (NTSEs), serving as both acyl and acylthio surrogates for the diverse synthesis of ketones, thioesters, amides, and acyl disulfides by selective cleavage of similarly reactive C-S and N-S bonds.


Assuntos
Ésteres , Succinimidas , Amidas , Ésteres/química , Indicadores e Reagentes , Cetonas/química
12.
Front Psychol ; 13: 906153, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35795410

RESUMO

Financial literacy is essential for every individual concerned with public welfare and household portfolio choices. In this study, we investigate the impact of household financial literacy on individuals' financial behavior using the China Household Financial Survey Data (CHFS) of 2015 and 2017. The results show that financial knowledge has significant current, long-term, and dynamic effects on financial behavior. This finding suggests that financial literacy is an important factor in shaping and improving financial behavior. Second, financial literacy can improve residents' limited attention, and residents with high attention tend to have formal bank accounts, participate in the stock market, and engage in financial behaviors in situations such as risky financial markets. High attention also helps to improve residents' financial behavior. This relationship suggests that financial literacy positively impacts formal bank account holding, participation in financial markets, participation in commercial insurance, participation in pension plans, and credit card holdings through limited attention channels that facilitate access to specific financial information. In addition, heterogeneity analysis showed that the impact of financial literacy on financial behavior differs significantly between urban and rural households, between men and women, and between high and low education levels. The study provides valuable insights for policy implications to enhance financial literacy, such as carrying out financial training to improve residents' knowledge about financial aspects, which further helps to optimize household financial decision-making.

13.
PLoS One ; 17(7): e0271783, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35834533

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0001397.].

14.
J Clin Med ; 11(14)2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35887748

RESUMO

BACKGROUND: Aging and physical inactivity are associated with declines in physical fitness and cognitive function. Active video games have proven to be beneficial for the physical health of older adults, but the exact effect of active video games on physical fitness and cognitive function was still unclear. Based on self-determination theory (SDT), which is a widely used theory of healthy behavior change, this study aimed to explore the effects of an active video game intervention on fitness and cognitive function in older adults. METHODS: A total of 38 participants (mean age = 65.68 ± 3.78 years, 24 female) were randomly assigned to either an intervention group (active video game training) or a control group (no additional intervention). The participants in the intervention group trained for a total of 36 sessions (3 times per week for 50-55 min each) for 12 weeks. The control group continued with their normal daily living. The pre- and posttest measurements included: IPAQ-C score and physical fitness (BMI, body fat percent, blood pressure, reaction time, sit and reach, vital capacity, grip strength, static balance, blood biochemical tests for liver function, kidney function, blood lipids, glucose and insulin levels) and cognitive functions (processing speed, spatial ability, working memory, language ability, associative memory). RESULT: The intervention group showed a significantly smaller decrease in total average physical activity relative to the control group. BMI, vital capacity, systolic blood pressure, diastolic blood pressure, and spatial cognition significantly improved after training in the intervention group (BMI: F = 9.814, p = 0.004, d = -0.93, vital capacity: F = 4.708, p = 0.038, d = 0.67, systolic blood pressure: F = 5.28, p = 0.028, d = -0.68, diastolic blood pressure: F = 6.418, p = 0.016, d = -0.86, spatial cognition: F = 8.261, p = 0.007, d = 0.72). Three measures of static balance (closed eyes) also showed improvements after training (total length of swing: F = 3.728, d = -0.62, total velocity of swing: F = 3.740, d = -0.62, total area of swing: F = 2.920, d = -0.70). No significant training effects were evident in the results from the blood biochemical tests. CONCLUSION: This study indicates a positive influence of active video game training on physical fitness and cognitive function. The use of SDT-based active video game exercise as a feasible, safe, and effective training method for improving community older adults' healthy, promoting group cohesion, and increasing motivation to exercise.

15.
Plant Cell ; 2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35904763

RESUMO

Leaf morphology is one of the most important features of the ideal plant architecture. However, the genetic and molecular mechanisms controlling this feature in crops remain largely unknown. Here, we characterized the rice (Oryza sativa) wide leaf 1 (wl1) mutant, which has wider leaves than the wild type (WT) due to more vascular bundles and greater distance between small vascular bundles. WL1 encodes a Cys-2/His-2-type (C2H2) zinc finger protein that interacts with Tillering and Dwarf 1 (TAD1), a co-activator of the anaphase-promoting complex/cyclosome (APC/C) (a multi-subunit E3 ligase). The APC/CTAD1 complex degrades WL1 via the ubiquitin-26S proteasome degradation pathway. Loss-of-function of TAD1 resulted in plants with narrow leaves due to reduced vascular bundle numbers and distance between the small vascular bundles. Interestingly, we found that WL1 negatively regulated the expression of a narrow leaf gene, NARROW LEAF 1 (NAL1), by recruiting the co-repressor TOPLESS-RELATED PROTEIN and directly binding to the NAL1 regulatory region to inhibit its expression by reducing the chromatin histone acetylation. Furthermore, biochemical and genetic analyses revealed that TAD1, WL1, and NAL1 operated in a common pathway to control the leaf width. Our study establishes an important framework for understanding the APC/CTAD1-WL1-NAL1 pathway-mediated control of leaf width in rice, and provides insights for improving crop plant architecture.

16.
Front Pharmacol ; 13: 925879, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35784746

RESUMO

Depression is the most common type of neuropsychiatric illness and has increasingly become a major cause of disability. Unfortunately, the recent global pandemic of COVID-19 has dramatically increased the incidence of depression and has significantly increased the burden of mental health care worldwide. Since full remission of the clinical symptoms of depression has not been achieved with current treatments, there is a constant need to discover new compounds that meet the major clinical needs. Recently, the roles of sigma receptors, especially the sigma-1 receptor subtype, have attracted increasing attention as potential new targets and target-specific drugs due to their translocation property that produces a broad spectrum of biological functions. Even clinical first-line antidepressants with or without affinity for sigma-1 receptors have different pharmacological profiles. Thus, the regulatory role of sigma-1 receptors might be useful in treating these central nervous system (CNS) diseases. In addition, long-term mental stress disrupts the homeostasis in the CNS. In this review, we discuss the topical literature concerning sigma-1 receptor antidepressant mechanism of action in the regulation of intracellular proteostasis, calcium homeostasis and especially the dynamic Excitatory/Inhibitory (E/I) balance in the brain. Furthermore, based on these discoveries, we discuss sigma-1 receptor ligands with respect to their promise as targets for fast-onset action drugs in treating depression.

17.
Exp Dermatol ; 2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35737869

RESUMO

SHJHhr mice line is rhino-like mice with a nonsense Hairless (Hr) mutant, which shows the characteristic of shedding hair and wrinkled skin with increasing age. Through histological analysis and aging indexes detection, SHJHhr mice show an increased thickness skin with degraded hair follicle and dermal cysts and disorganized collagen fibres, as well as decreased level of Hyp. Meanwhile, the aging markers p16 and p21 are significantly higher in SHJHhr mouse skin than ICR mouse skin at same age. Moreover, the data of MDA and SOD show a higher oxidative stress in SHJHhr mouse skin, and the levels of Nrf2 and its targets are significantly downregulated, which suggests SHJHhr mice have a faster aging skin and its reason maybe poor antioxidative protection. Overall, this study shows SHJHhr mice with an accelerated aging skin, which suggests the role of Hr gene in skin aging.

18.
J Clin Endocrinol Metab ; 107(9): 2606-2615, 2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-35704027

RESUMO

CONTEXT: Conjugated linoleic acid (CLA) may optimize body composition, yet mechanisms underlining its benefits are not clear in humans. OBJECTIVE: We aimed to reveal the CLA-induced changes in the plasma metabolome associated with body composition improvement and the predictive performance of baseline metabolome on intervention responsiveness. METHODS: Plasma metabolome from overnight fasted samples at pre- and post-intervention of 65 participants in a 12-week randomized, placebo-controlled trial (3.2 g/day CLA vs 3.2 g/day sunflower oil) were analyzed using untargeted LC-MS metabolomics. Mixed linear model and machine learning were applied to assess differential metabolites between treatments, and to identify optimal panel (based on baseline conventional variables vs metabolites) predicting responders of CLA-derived body composition improvement (increased muscle variables or decreased adiposity variables) based on dual-energy x-ray absorptiometry. RESULTS: Compared with placebo, CLA altered 57 metabolites (P < 0.10) enriched in lipids/lipid-like molecules including glycerophospholipids (n = 7), fatty acyls (n = 6), and sphingolipids (n = 3). CLA-upregulated cholic acid (or downregulated aminopyrrolnitrin) was inversely correlated with changes in muscle and adiposity variables. Inter-individual variability in response to CLA-derived body composition change. The areas under the curves of optimal metabolite panels were higher than those of optimal conventional panels in predicting favorable response of waist circumference (0.93 [0.82-1.00] vs 0.64 [0.43-0.85]), visceral adiposity index (0.95 [0.88-1.00] vs 0.58 [0.35-0.80]), total fat mass (0.94 [0.86-1.00] vs 0.69 [0.51-0.88]) and appendicular fat mass (0.97 [0.92-1.00] vs 0.73 [0.55-0.91]) upon CLA supplementation (all FDR P < 0.05). CONCLUSION: Post-intervention metabolite alterations were identified, involving in lipid/energy metabolism, associated with body composition changes. Baseline metabolite profiling enhanced the prediction accuracy for responsiveness of CLA-induced body composition benefits.


Assuntos
Ácidos Linoleicos Conjugados , Adiposidade , Composição Corporal , Suplementos Nutricionais , Humanos , Ácidos Linoleicos Conjugados/uso terapêutico , Obesidade/metabolismo
19.
Dis Markers ; 2022: 5883101, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35677634

RESUMO

The value of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an N6-methyladenosine (m6A) RNA methylation regulatory factor, in the prognosis of colon cancer was still unclear. High levels of IGF2BP3 were expressed in colon adenocarcinoma (COAD) samples and in human colon cancer tissues, which was associated with poorer overall survival (OS). We validated IGF2BP3 as an independent prognostic risk biomarker in COAD patients. Moreover, functional enrichment analysis suggested that differentially expressed genes (DEGs) of groups with high versus low IGF2BP3 expression were related to immune- and cancer-related pathways. Furthermore, the tumor microenvironments of high- versus low-IGF2BP3 expression groups showed significant differences and IGF2BP3 predicted the efficiency of immunotherapy. Finally, protein-protein interaction network analysis suggested that there was a direct or indirect interaction among IGF2BP3, WNT7B, VANGL2, NKD1, AXIN2, RNF43, and CDKN2A. In brief, IGF2BP3 was confirmed as an independent prognostic signature in COAD patients and might be a therapeutic target in this study. Moreover, IGF2BP3 could be used in personalized immunotherapy for COAD.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Adenocarcinoma/patologia , Adenosina/análogos & derivados , Neoplasias do Colo/genética , Humanos , Metilação , Prognóstico , RNA , Microambiente Tumoral
20.
Nat Commun ; 13(1): 3264, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35672320

RESUMO

Confinement of fibrous hydrogels in narrow capillaries is of great importance in biological and biomedical systems. Stretching and uniaxial compression of fibrous hydrogels have been extensively studied; however, their response to biaxial confinement in capillaries remains unexplored. Here, we show experimentally and theoretically that due to the asymmetry in the mechanical properties of the constituent filaments that are soft upon compression and stiff upon extension, filamentous gels respond to confinement in a qualitatively different manner than flexible-strand gels. Under strong confinement, fibrous gels exhibit a weak elongation and an asymptotic decrease to zero of their biaxial Poisson's ratio, which results in strong gel densification and a weak flux of liquid through the gel. These results shed light on the resistance of strained occlusive clots to lysis with therapeutic agents and stimulate the development of effective endovascular plugs from gels with fibrous structures for stopping vascular bleeding or suppressing blood supply to tumors.


Assuntos
Hidrogéis , Hidrogéis/química , Pressão
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