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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120230, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34358784

RESUMO

Luminescent metal-organic frameworks (LMOFs) and their functional materials with unique characteristics can provide the basis for the construction of new analytical techniques, which can meet the continuous demand for various fields. In this work, guanosine monophosphate (GMP), terbium ion (Tb3+) and zeolitic imidazolate framework-8 (ZIF-8) are self-assembled to form a ZIF-8@GMP-Tb nanocomplex, which can be utilized as a ratiometric fluorescent probe to monitor alkaline phosphatase (ALP) activity. Specifically, with adding ALP, the fluorescence intensity at 547 nm (one of the characteristic emission peaks of Tb3+) obviously decreased. Meanwhile, the conjugated structure of GMP increased the fluorescence of ZIF-8 (located at 330 nm). The possible mechanism was proposed through the characterization of the materials. Based on the variation of the emission peaks at 330 and 547 nm, the ratiometric fluorescent sensor of ALP has a linear range of 0.25-20 U/L. Moreover, applying this sensing system to the detection of ALP in the human serum sample and ALP inhibitor investigation possesses satisfactory results. This work provides a new perspective for the utilization of ZIF-8 and lanthanide ions in manufacturing simple and sensitive sensors.


Assuntos
Guanosina Monofosfato , Zeolitas , Fosfatase Alcalina , Corantes Fluorescentes , Humanos , Térbio
2.
Spectrochim Acta A Mol Biomol Spectrosc ; 265: 120325, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34520895

RESUMO

This paper mainly focuses on the feasibility of rapidly identifying Fritillariae cirrhosae varieties, distinguishing its authenticity and detecting its components by using a portable near infrared (NIR) spectrometer. Five different varieties of Fritillariae cirrhosae, five common counterfeits and two main components (ethanol-soluble extractives and total alkaloids) were studied. The reference values of ethanol-soluble extractives were determined by hot dip method and the reference value of total alkaloid was determined by ultraviolet-visible spectrophotometry (UV-Vis). Linear discriminant analysis (LDA) algorithm was used to identify the sources of different varieties of Fritillariae cirrhosae and the common counterfeits of Fritillariae cirrhosae, respectively. As a result, the best models seemed to be effective, with accuracy of the two models' prediction sets reaches 83.33% and 90.91%, respectively. The partial least squares regression (PLSR) algorithm was used to relate the sample spectra with the reference values of ethanol-soluble extractives and total alkaloid content. Coefficient of determination of prediction (R2p) and root mean square errors of prediction (RMSEP) obtained were 0.8562 and 0.3911; 0.6917 and 0.0117, for ethanol-soluble extractives and total alkaloid content, respectively. The results showed that the portable NIR spectrometer could evaluate the quality of Fritillariae cirrhosae with high efficiency and practicability.


Assuntos
Alcaloides , Medicamentos de Ervas Chinesas , Análise dos Mínimos Quadrados , Refratometria
3.
Signal Transduct Target Ther ; 6(1): 375, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34728602

RESUMO

The scope and variety of the metabolic intermediates from the mitochondrial tricarboxylic acid (TCA) cycle that are engaged in epigenetic regulation of the chromatin function in the nucleus raise an outstanding question about how timely and precise supply/consumption of these metabolites is achieved in the nucleus. We report here the identification of a nonclassical TCA cycle in the nucleus (nTCA cycle). We found that all the TCA cycle-associated enzymes including citrate synthase (CS), aconitase 2 (ACO2), isocitrate dehydrogenase 3 (IDH3), oxoglutarate dehydrogenase (OGDH), succinyl-CoA synthetase (SCS), fumarate hydratase (FH), and malate dehydrogenase 2 (MDH2), except for succinate dehydrogenase (SDH), a component of electron transport chain for generating ATP, exist in the nucleus. We showed that these nuclear enzymes catalyze an incomplete TCA cycle similar to that found in cyanobacteria. We propose that the nTCA cycle is implemented mainly to generate/consume metabolic intermediates, not for energy production. We demonstrated that the nTCA cycle is intrinsically linked to chromatin dynamics and transcription regulation. Together, our study uncovers the existence of a nonclassical TCA cycle in the nucleus that links the metabolic pathway to epigenetic regulation.

4.
Pestic Biochem Physiol ; 179: 104966, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34802516

RESUMO

Pesticide resistance in spider mites drives the development of acaricides with novel mode of action, which could benefit from RNAi as a screening tool in search of new molecular targets. RNAi via oral delivery of dsRNA has been frequently reported in spider mites, but injection of dsRNA is rarely reported. We compare here the efficiency of oral delivery versus injection of dsRNA in female adult mites. When comparing silencing efficiency, oral delivery of dsRNAs silenced 40.6 ± 8.9% of CPR, 63.8 ± 6.9% of CHMP2A, and 37.7 ± 5.7% of CHMP3 genes. Similar silencing efficiencies were found for injection (48.6 ± 3.7% of CPR, 70.2 ± 4.1% of CHMP2A, 59.8 ± 2.2% of CHMP3), but with much lower quantities of dsRNAs. Oral delivery of dsRNA failed to silence the expression of the CHMP4B gene, but this could be accomplished by injection of dsRNA (23.1 ± 1.0%). When scoring the phenotypic effects of silencing, both oral delivery and injection of CHMP2A- and CHMP3-dsRNA influenced the locomotion speed of mites significantly. For CPR, silencing could only be accomplished by dsRNA injection, not by feeding. CPR silencing significantly impacted the toxicity of a typical acaricide, pyridaben, as the susceptibility of mites raised 2.75-fold. Last, injection of Eya-dsRNA in adults produced transgenerational phenotypic effects on 3.59% of offspring, as quantified by an observed deviation in eye development, while oral delivery of Eya-dsRNA did not. In conclusion, injection of dsRNA is superior to oral delivery in silencing the expression of the selected genes in this study and could be considered the method of choice to study gene function in reverse genetic approaches.


Assuntos
Acaricidas , Ácaros , Tetranychidae , Animais , Ácaros/genética , Interferência de RNA , RNA de Cadeia Dupla/genética
5.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(5): 727-735, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34728033

RESUMO

Objective To evaluate the influence of temperature on the outpatient visits for urticaria in Lanzhou City and its hysteresis and to find out the sensitive populations by sex and age stratification.Methods We collected the urticaria outpatient data in three grade A class three hospitals as well as the meteorological data and air pollutant data in Lanzhou from January 2011 to December 2017.The distributed lag non-linear model(DLNM)was employed to analyze the influence of daily mean temperature on the outpatient visits for urticaria.Stratification analysis was performed for different age groups(0-14,15-59,≥60 years)and different sex populations.Results Temperature had a non-linear relationship with the outpatient visits for urticaria,and there existed hysteresis.During the research period,the average daily outpatient visits for urticaria at the three hospitals in Lanzhou was 25,ranging from 1 to 76.With the rise in the daily mean temperature within 0-10 ℃,the risk of outpatient visits for urticaria first increased and then decreased.When the daily mean temperature was 2 ℃,hysteresis occurred on the 18th day,and the relative risk(RR)reached the maximum(1.12,95% CI:1.04-1.20)at the lag of 21 days.The risk of urticaria increased with the rise in temperature at high temperature.In addition,the effect of high temperature on the outpatient visits for urticaria in Lanzhou presented hysteresis,and the hysteresis was more obvious at higher temperatures.At the lag of 21 days,when the temperatures were 19.9 ℃ and 25.5 ℃,the RR values were 1.20(95% CI:1.12-1.27)and 1.39(95% CI:1.31-1.48),respectively.The results of stratified analysis showed that the effect of high temperature was more sensitive for those of 0-14 years and 15-59 years as well as the female population,and the RR values at a lag of 21 days were 1.60(95% CI:1.45-1.71),1.34(95% CI:1.25-1.43),and 1.43(95% CI:1.33-1.53)for the population of 0-14 years,the population of 15-59 years,and female population,respectively.Low temperature mainly affected the people aged ≥60 years,with a maximum RR of 1.38(95% CI:1.03-1.85)when the daily mean temperature was -4.8 ℃ at a lag of 12 days.It did not affect other populations.Conclusions The daily mean temperature in Lanzhou share a close relationship with the outpatient visits for urticaria.High temperature will increase the risk of urticaria for people at the age of 0-14 years and 15-59 years,while low temperature will increase the risk of urticaria for people above 60 years.


Assuntos
Poluentes Atmosféricos , Urticária , Adolescente , Poluentes Atmosféricos/análise , Criança , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Dinâmica não Linear , Pacientes Ambulatoriais , Temperatura , Urticária/epidemiologia
6.
Ann N Y Acad Sci ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34791665

RESUMO

The human transcriptome contains many types of noncoding RNAs, which rival the number of protein-coding species. From long noncoding RNAs (lncRNAs) that are over 200 nucleotides long to piwi-interacting RNAs (piRNAs) of only 20 nucleotides, noncoding RNAs play important roles in regulating transcription, epigenetic modifications, translation, and cell signaling. Roles for noncoding RNAs in disease mechanisms are also being uncovered, and several species have been identified as potential drug targets. On May 11-14, 2021, the Keystone eSymposium "Noncoding RNAs: Biology and Applications" brought together researchers working in RNA biology, structure, and technologies to accelerate both the understanding of RNA basic biology and the translation of those findings into clinical applications.

7.
Cell Rep ; 37(6): 109982, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34758315

RESUMO

Early blastomeres of mouse preimplantation embryos exhibit bi-potential cell fate, capable of generating both embryonic and extra-embryonic lineages in blastocysts. Here we identify three major two-cell-stage (2C)-specific endogenous retroviruses (ERVs) as the molecular hallmark of this bi-potential plasticity. Using the long terminal repeats (LTRs) of all three 2C-specific ERVs, we identify Krüppel-like factor 5 (Klf5) as their major upstream regulator. Klf5 is essential for bi-potential cell fate; a single Klf5-overexpressing embryonic stem cell (ESC) generates terminally differentiated embryonic and extra-embryonic lineages in chimeric embryos, and Klf5 directly induces inner cell mass (ICM) and trophectoderm (TE) specification genes. Intriguingly, Klf5 and Klf4 act redundantly during ICM specification, whereas Klf5 deficiency alone impairs TE specification. Klf5 is regulated by multiple 2C-specific transcription factors, particularly Dux, and the Dux/Klf5 axis is evolutionarily conserved. The 2C-specific transcription program converges on Klf5 to establish bi-potential cell fate, enabling a cell state with dual activation of ICM and TE genes.

8.
Nurs Open ; 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34761532

RESUMO

OBJECTIVES: This study aimed to evaluate the comorbidities among severe and non-severe COVID-19 patients in Asian versus non-Asian populations. DESIGN: Systemic review and Meta-analysis. METHODS: A systematic literature search was conducted using PubMed, Embase, Scopus and the web of science Database up to 24 March 2021. Odds ratios were calculated using a random-effects model. RESULTS: We identified 66 studies including 39 Asian and 27 non-Asian studies. This study demonstrated that the proportion of hypertension was significantly higher in severe group than in non-severe group for Asian (OR = 2.46) and non-Asian (OR = 1.60, 95% CI: 1.37-1.86, I2  = 84%; p < .00001) patients. Similarly, the proportion of diabetes, cardiovascular disease and chronic kidney disease was significantly higher in severe group than in non-severe group for both Asian and non-Asian studies. We found no statistically significant difference between the severe versus non-severe group for cancer (OR = 1.26) and chronic obstructive pulmonary disease (OR = 1.32) among non-Asian patients.

9.
EBioMedicine ; 72: 103609, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34628353

RESUMO

BACKGROUND: Schizophrenia (SCZ) is a severe psychiatric disorder that affects approximately 0.75% of the global population. Both genetic and environmental factors contribute to development of SCZ. SCZ tends to run in family while both genetic and environmental factor contribute to its etiology. Much evidence suggested that alterations in DNA methylations occurred in SCZ patients. METHODS: To investigate potential inheritable pattern of DNA methylation in SCZ family, we performed a genome-wide analysis of DNA methylation of peripheral blood samples from 106 Chinese SCZ family trios. Genome-wide DNA methylations were quantified by Agilent 1 × 244 k Human Methylation Microarray. FINDINGS: In this study, we proposed a loci inheritance frequency model that allows characterization of differential methylated regions as SCZ biomarkers. Based on this model, 112 hypermethylated and 125 hypomethylated regions were identified. Additionally, 121 hypermethylated and 139 hypomethylated genes were annotated. The results of functional enrichment analysis indicated that multiple differentially methylated genes (DMGs) involved in Notch/HH/Wnt signaling, MAPK signaling, GPCR signaling, immune response signaling. Notably, a number of hypomethylated genes were significantly enriched in cerebral cortex and functionally enriched in nervous system development. INTERPRETATION: Our findings not only validated previously discovered risk genes of SCZ but also identified novel candidate DMGs in SCZ. These results may further the understanding of altered DNA methylations in SCZ. FUNDING: None.

10.
Cell ; 184(22): 5541-5558.e22, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34644528

RESUMO

Retrotransposons mediate gene regulation in important developmental and pathological processes. Here, we characterized the transient retrotransposon induction during preimplantation development of eight mammals. Induced retrotransposons exhibit similar preimplantation profiles across species, conferring gene regulatory activities, particularly through long terminal repeat (LTR) retrotransposon promoters. A mouse-specific MT2B2 retrotransposon promoter generates an N-terminally truncated Cdk2ap1ΔN that peaks in preimplantation embryos and promotes proliferation. In contrast, the canonical Cdk2ap1 peaks in mid-gestation and represses cell proliferation. This MT2B2 promoter, whose deletion abolishes Cdk2ap1ΔN production, reduces cell proliferation and impairs embryo implantation, is developmentally essential. Intriguingly, Cdk2ap1ΔN is evolutionarily conserved in sequence and function yet is driven by different promoters across mammals. The distinct preimplantation Cdk2ap1ΔN expression in each mammalian species correlates with the duration of its preimplantation development. Hence, species-specific transposon promoters can yield evolutionarily conserved, alternative protein isoforms, bestowing them with new functions and species-specific expression to govern essential biological divergence.

11.
NPJ Schizophr ; 7(1): 51, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34711862

RESUMO

Schizophrenia is a debilitating mental disorder and often has a prodromal period, referred to as clinical high risk (CHR) for psychosis, prior to the first episode. The etiology and pathogenesis of schizophrenia remain unclear. Despite the human gut microbiome being associated with schizophrenia, the role of the oral microbiome, which is a vital player in the mouth-body connection, is not well understood. To address this, we performed 16S rRNA gene sequencing to investigate the salivary microbiome in 85 patients with drug-naïve first-episode schizophrenia (FES), 43 individuals at CHR, and 80 healthy controls (HCs). The salivary microbiome of FES patients was characterized by higher α-diversity and lower ß-diversity heterogeneity than those of CHR subjects and HCs. Proteobacteria, the predominant phylum, was depleted, while Firmicutes and the Firmicutes/Proteobacteria ratio was enriched, in a stepwise manner from HC to CHR to FES. H2S-producing bacteria exhibited disease-stage-specific enrichment and could be potential diagnostic biomarkers for FES and CHR. Certain salivary microbiota exhibited disease-specific correlation patterns with symptomatic severities, peripheral pro-inflammatory cytokines, thioredoxin, and S100B in FES. Furthermore, the metabolic functions from inferred metagenomes of the salivary microbiome were disrupted in FES, especially amino acid metabolism, carbohydrate metabolism, and xenobiotic degradation. This study has established a link between salivary microbiome alterations and disease initiation and provided the hypothesis of how the oral microbiota could influence schizophrenia.

12.
Org Biomol Chem ; 19(42): 9237-9241, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34647948

RESUMO

The organic superbase t-Bu-P4-catalyzed direct thiolation of trimethyl(perfluorophenyl)silanes and thiosulfonates was developed. Yields of perfluorophenylsulfides of up to 97% under catalysis of 5 mol% t-Bu-P4 were achieved. This method was shown to provide an efficient way to construct the perfluorophenyl-sulfur bond under mild metal-free reaction conditions.

13.
Drug Des Devel Ther ; 15: 4125-4140, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616145

RESUMO

Introduction: Huangtu decoction (HTD) has been widely used in the treatment of gastrointestinal bleeding, ulcerative colitis (UC) and gastrointestinal tumors in China, but its active compounds and mechanism are still not clear yet. The present research aimed to identify the active compounds and mechanism of HTD for the treatment of UC. Methods: Firstly, the chemical compounds of HTD were qualitatively identified based on Q Exactive Orbitrap LC-MS/MS, and their potential targets were predicted through SwissTargetPrediction. Secondly, the differential expressed genes (DEGs) in colon tissues of UC patients and normal controls were retrieved from the GEO database. Thirdly, the overlapping targets of DEGs and the predicted targets were obtained and subjected to GO and KEGG analysis. Finally, the key targets in the most significantly enriched pathway were verified by in vivo experiment, and the protein and mRNA expressions of matrix metalloproteinase-1 (MMP1), MMP3, MMP7, MMP9 and MMP12 were determined by immunohistochemistry (IHC), Western blotting (WB) and quantitative real-time-PCR (qRT-PCR). Results: A total of 47 compounds were identified and 29 overlapping targets were obtained from HTD extract. The most significantly enriched pathway of overlapping targets involved was MMP. HTD improved the pathological damage in colon tissues of DSS-induced UC model and significantly decreased the serum levels of IL-1ß and IL-6. The protein and mRNA expressions of MMP1, MMP3 and MMP9 in colon tissues were significantly decreased after HTD treatment. Conclusion: HTD treatment can alleviate the colonic inflammation via inhibiting MMPs including MMP1, MMP3 and MMP9.

14.
Int J Cardiol ; 345: 98-104, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34710491

RESUMO

Programmed cell death 5 (PDCD5) is a tumor suppressor gene that regulates the cell cycle, apoptosis and immune responses. However, the physiological function of Pdcd5 in cardiac aging remains unknown. We find that Pdcd5 mRNA and protein levels were significantly increased in the heart of mice with age. Therefore, we hypothesize that Pdcd5 regulates cardiac aging. To test the hypothesis, we generated muscle-specific Pdcd5-deficient mice. Mature adult Pdcd5-deficient mice had normal cardiac morphology and function. In naturally aged mice, Pdcd5 deficiency alleviated age-related cardiac phenotypes including reduced fibrosis and suppressed cardiomyocyte hypertrophy. Moreover, muscle-specific Pdcd5 deficiency attenuated cellular senescence in the heart as demonstrated by decreased number of senescence-associated ß-galactosidase-positive cells, diminished p53, p21 and p16 expression, and reduced the senescence-associated secretory phenotype. Apoptotic cell death was reduced by Pdcd5 deficiency in the heart as revealed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay, which was coincident with diminished Bcl-2-associated X protein, and enhanced B-cell lymphoma 2 and X-linked inhibitor of apoptosis protein expression. Mitochondrial quality in cardiomyocytes was improved by Pdcd5 deficiency through increased Parkin-mediated mitophagy. In addition, Pdcd5 deficiency alleviated doxorubicin-induced premature cellular senescence and cardiac aging. Furthermore, Pdcd5 protein abundance was significantly correlated with p53 protein abundance, and Pdcd5 interacted with p53 in the heart. Taken together, our results reveal that Pdcd5 deficiency attenuates cardiac aging by reducing cellular senescence and apoptosis, and increasing Parkin-mediated mitophagy, likely through p53. Pdcd5 is a novel regulator of cardiac aging and a potential therapeutic target.

15.
J Contam Hydrol ; 243: 103908, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34717180

RESUMO

The efficiencies of thermal desorption and oxidation process in engineering soil remediation are to some extent limited due to the huge loss of heat to the soil or underground water or mass transfer resistance in the soil. To enhance the oxidation and improve the energy utilization. Herein, the thermal desorption process and the oxidation process (by ozone) are combined together to remediate the organic contaminated model soil (take the 2,4-dimethylaniline (2,4-DMA) as pollutant). Results show that this hybrid process could not only reduce the thermal desorption temperature (as low as 50-90 °C), but also improve the oxidation efficiency significantly, even achieving 100% degradation of 2,4-DMA in less than 10 min in the soil. It is found that the remediation efficiency by the hybrid process is also highly dependent on different operational parameters, including the heating temperature, ozone concentration, especially the moisture content in the soil. The results suggest that a proper content of water in the soil is beneficial for the degradation of pollutants by the hybrid process. Finally, the degradation kinetics and mechanisms of 2,4-DMA in the soil by the hybrid process has been primarily discussed. These findings suggest that the low temperature enhanced chemical oxidation process would be a promising method for future remediation of organic contaminated soil due to its relatively low energy consuming and high removal efficiency in shorter time.

16.
Chin J Nat Med ; 19(9): 656-665, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34561076

RESUMO

The first-generation taxanes (including paclitaxel and docetaxel) are widely used for the treatment of various cancers in clinical settings. In the past decade, a series of new-generation taxanes have been developed which are effective in the inhibition of tumor resistance. However, intravenous (i.v.) infusion is still the only route of administration, and may result in serious adverse reactions with respect to the utilization of Cremophor EL or Tween-80 as solvent. Besides, the dosing schedule is also limited. Therefore, oral administration of taxanes is urgently needed to avoid the adverse reactionss and increase dosing frequency. In this review, we first outlined the discovery and development of taxane-based anticancer agents. Furthermore, we summarized the research progress on the oral formulations of taxanes and proposed some thoughts on the future development of oral taxane formulations.

17.
Front Cell Dev Biol ; 9: 710864, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34568325

RESUMO

Mammalian female fertility is defined by a successful and strictly periodic ovarian cycle, which is under the control of gonadotropins and steroid hormones, particularly progesterone and estrogen. The latter two are produced by the ovaries that are engaged in controlled follicular growth, maturation, and release of the eggs, i.e., ovulation. The steroid hormones regulate ovarian cycles via genomic signaling, by altering gene transcription and protein synthesis. However, despite this well-studied mechanism, steroid hormones can also signal via direct, non-genomic action, by binding to their membrane receptors. Here we show, that the recently discovered membrane progesterone receptor α/ß hydrolase domain-containing protein 2 (ABHD2) is highly expressed in mammalian ovaries where the protein plays a novel regulatory role in follicle maturation and the sexual cycle of females. Ablation of Abhd2 caused a dysregulation of the estrous cycle rhythm with females showing shortened luteal stages while remaining in the estrus stage for a longer time. Interestingly, the ovaries of Abhd2 knockout (KO) females resemble polycystic ovary morphology (PCOM) with a high number of atretic antral follicles that could be rescued with injection of gonadotropins. Such a procedure also allowed Abhd2 KO females to ovulate a significantly increased number of mature and fertile eggs in comparison with their wild-type littermates. These results suggest a novel regulatory role of ABHD2 as an important factor in non-genomic steroid regulation of the female reproductive cycle.

18.
iScience ; 24(9): 103063, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34568788

RESUMO

TENM4, encoding a member of the teneurin protein family, is a risk gene shared by many types of mental diseases and is implicated in neuronal plasticity and signaling. However, the role and the mechanisms of TENM4 in schizophrenia (SCZ) remain unclear. We identified possible pathogenic mutations in the TENM4 gene through target sequencing of TENM4 in 68 SCZ families. We further demonstrated that aberrant expression of Ten-m leads to lower learning ability, sleep reduction, and increased aggressiveness in animal models. RNA sequencing showed that aberrant expression of Ten-m was related to stimulus perception and metabolic process, and Gene Ontology enrichment terms were neurogenesis and ATPase activity. This study provides strong evidence that TENM4 contributes to SCZ, and its functional mutations might be responsible for the impaired neural circuits and behaviors observed in SCZ.

19.
ACS Cent Sci ; 7(9): 1524-1534, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34584954

RESUMO

Most known probes for activity-based protein profiling (ABPP) use electrophilic groups that tag a single type of nucleophilic amino acid to identify cases in which its hyper-reactivity underpins function. Much important biochemistry derives from electrophilic enzyme cofactors, transient intermediates, and labile regulatory modifications, but ABPP probes for such species are underdeveloped. Here, we describe a versatile class of probes for this less charted hemisphere of the proteome. The use of an electron-rich hydrazine as the common chemical modifier enables covalent targeting of multiple, pharmacologically important classes of enzymes bearing diverse organic and inorganic cofactors. Probe attachment occurs by both polar and radicaloid mechanisms, can be blocked by molecules that occupy the active sites, and depends on the proper poise of the active site for turnover. These traits will enable the probes to be used to identify specific inhibitors of individual members of these multiple enzyme classes, making them uniquely versatile among known ABPP probes.

20.
ACS Biomater Sci Eng ; 7(10): 4859-4869, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34547895

RESUMO

KPV (Lys-Pro-Val), which is a tripeptide derived from α-MSH (α-melanocyte-stimulating hormone), has an anti-inflammatory effect on colitis. However, KPV solution is very unstable when rectally administered, compromising its therapeutic efficacy. Herein, cysteamine-grafted γ-polyglutamic acid (SH-PGA) was synthesized by conjugating cysteamine with the carboxyl groups of γ-PGA. The synthesized SH-PGA has the thiol grafting amount of 4.5 ± 0.3 mmol/g. Without the use of the cross-linker, the SH-PGA hydrogel with 4% of the polymer was formed by self-cross-linking of thiol groups. Moreover, the formation of the SH-PGA hydrogel was not affected by KPV. The KPV/SH-PGA hydrogel presented higher elastic modulus (G') than the corresponding viscous modulus (G″) at 0.01-10 Hz, exhibiting good mechanical stability. The KPV/SH-PGA hydrogel presented a shear-thinning behavior, which was helpful for rectal administration. Only 30% of KPV was released from the KPV/SH-PGA hydrogel within 20 min, followed by a sustained-release behavior. Importantly, the stability of KPV in the SH-PGA hydrogel was obviously enhanced, which was presented by detecting its anti-inflammatory activity and promoting cell migration potential after 2 h of exposure to 37 °C. The enhanced therapeutic effect of the KPV/SH-PGA hydrogel on colitis was confirmed on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced ulcerative colitis rats. The colitis symptoms including body weight loss and the disease activity index score were obviously attenuated by rectally administering the KPV/SH-PGA hydrogel. Besides, the KPV/SH-PGA hydrogel treatment prevented the colon shortening of TNBS-infused rats and decreased the colonic myeloperoxidase level. The morphology of the colon including the epithelial barrier, crypt, and intact goblet cells was recovered after KPV/SH-PGA hydrogel treatment. Besides, the KPV/SH-PGA hydrogel decreased the expression of proinflammatory cytokines such as tumor necrosis factor α and interleukin 6. Collectively, the KPV/SH-PGA hydrogel may provide a promising strategy for the treatment of ulcerative colitis.


Assuntos
Colite Ulcerativa , Animais , Colite Ulcerativa/induzido quimicamente , Cisteamina , Hidrogéis , Ácido Poliglutâmico/análogos & derivados , Ratos , Ácido Trinitrobenzenossulfônico/toxicidade
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