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1.
Zhongguo Zhong Yao Za Zhi ; 47(9): 2449-2456, 2022 May.
Artigo em Chinês | MEDLINE | ID: mdl-35531692

RESUMO

The optimal prescription of tanshinone Ⅱ_A(TSN)-glycyrrhetinic acid(GA) solid lipid nanoparticles(GT-SLNs) was explored and evaluated in vivo and in vitro, and its effect on acne after oral administration was investigated. The preparation processing and prescription were optimized and verified by single factor and response surface methodology. The in vitro release of GA and TSN in GT-SLNs was determined by ultra-performance liquid chromatography(UPLC). The effect of GT-SLNs on acne was investigated by the levels of sex hormones in mice, ear swelling model, and tissue changes in sebaceous glands, and the pharmacokinetics was evaluated. The 24-hour cumulative release rates of GA and TSN in SLNs were 65.87%±5.63% and 36.13%±2.31% respectively. After oral administration of GT-SLNs and the mixture of GA and TSN(GT-Mix), the AUC_(0-t) and AUC_(0-∞) of TSN in GT-SLNs were 1.98 times and 4.77 times those in the GT-Mix group, respectively, and the peak concentration of TSN in the GT-SLNs group was 17.2 times that in the GT-Mix group. After intragastric administration of GT-SLNs, the serum levels of testosterone(T) and the ratio of testosterone to estradiol(T/E2) in the GT-SLNs group significantly declined, and the sebaceous glands of mice were atrophied to a certain extent. The results demonstrated that obtained GT-SLNs with good encapsulation efficiency and uniform particle size could promote the release of GA and TSN. GT-SLNs displayed therapeutic efficacy on acne manifested by androgen increase, abnormal sebaceous gland secretion, and inflammatory damage.


Assuntos
Acne Vulgar , Ácido Glicirretínico , Nanopartículas , Abietanos , Acne Vulgar/tratamento farmacológico , Animais , Portadores de Fármacos , Lipossomos , Camundongos , Tamanho da Partícula , Testosterona
2.
Anal Chem ; 2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35578920

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease with insidious onset, and the deposition of amyloid-ß (Aß) is believed to be one of the main cause. Fluorescence imaging is a promising technique for this task, but the Aß gold standard probe ThT developed based on this still has shortcomings. The development of a new fluorescent probe to detect Aß plaques is thought to be essential. Herein, a series of red to near-infrared emitting fluorescent probes QNO-ADs with newly quinoxalinone skeleton are designed to detect Aß plaques. They all demonstrate excellent optical properties and high binding affinity (∼Kd = 20 nM) to Aß aggregates. As the most outstanding candidate, QNO-AD-3 shows significant signal-to-noise (S/N) ratio at the level of in vitro binding studies, and the brilliant fluorescence staining results in favor of grasping the approximate distribution of Aß plaques in the brain slice. In vivo Aß plaques imaging suggests that QNO-AD-3 can cross the BBB and have a long retention time in the brain with low biological toxicity. In addition, the results of docking theoretical calculation also provide some references for the design of Aß probe. Overall, given the high affinity of QNO-AD-3 and the ability to monitor Aß plaques for a long time that is not common now, we believe QNO-AD-3 will be an effective tool for an Aß-related matrix and AD disease research in the future.

3.
Chemosphere ; 301: 134773, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35500626

RESUMO

BACKGROUND: Genetic variants and modifiable risk factors (including environmental exposure and lifestyle) greatly contribute to the development of lung cancer. The population attributable fraction (PAF) of these risk factors, especially their interactive effects, has not been well quantified. METHODS: A total of 398,577 participants were included in this analysis. There were 2504 incident lung cancer cases identified over an average 10.4-year follow-up. We applied Cox proportional hazards models to examine the associations between risk factors and incident lung cancer. We further developed a polygenic risk score and evaluated whether environmental factors modified the effect of genetic risk on incident lung cancer. Furthermore, we calculated the PAF for each risk factor, as well as their gene-environment additive interaction, and then combined them to create a weighted PAF that takes into consideration participants with overlapping risk factors. RESULTS: Our analysis showed that smoking was the leading risk factor for lung cancer with a PAF of 63.73%. We observed additive interactions between smoking, PM2.5, NOx, and genetic risk, with PAFs of 17.85% (smoking-high genetic risk interaction), 10.79% (smoking-intermediate genetic risk interaction), 5.30% (NOx-high genetic risk interaction), 6.55% (PM2.5-high genetic risk interaction), and 4.99% (PM2.5-intermediate genetic risk interaction). We estimated that 73.46% of lung cancer cases could be attributable to potentially modifiable risk factors after adjusting for the correlation between them. CONCLUSION: High genetic risk and several modifiable factors may increase the risk of incident lung cancer. Participants with a high genetic risk may be more vulnerable to developing lung cancer if exposed to smoking and/or high air pollution. Our findings provide evidence that the majority of incident lung cancer cases could be prevented by eliminating modifiable risk factors.

4.
Neuropharmacology ; 213: 109076, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35500677

RESUMO

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are key regulators during the process of synaptic plasticity in major depression disorder (MDD). Synapse differentiation-induced gene 1 (SynDIG1) functions as an atypical AMPAR auxiliary subunit and regulates synaptic AMPAR content; however, the role of SynDIG1 in MDD remains elusive. In this study, we found that the SynDIG1 expression was significantly increased in the neurons of the nucleus accumbens (NAc) of male mice after chronic social defeat stress (CSDS). CSDS enhanced SynDIG1-GluA2 binding and promoted the surface expression of AMPAR subunit GluA2 in the NAc. Knockdown of SynDIG1 decreased the surface expression of GluA2 and reversed the alteration of dendrite spines in the neurons, eventually alleviating the depressive-like behaviors of the stressed mice. Moreover, intra-NAc injection of IP12, a specific peptide to disrupt the interaction of SynDIG1 with GluA2, rescued depressive-like behaviors. Collectively, SynDIG1 regulates the surface expression of GluA2 and dendritic remodeling in the NAc of male mice under CSDS, thus mediating the depressive-like behaviors.

5.
Mol Ther ; 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35514086

RESUMO

Although tissue-resident-memory T (TRM) cells, a recently identified non-circulating memory T cell population, play a crucial role in mediating local immune responses and protect against pathogens upon local reinfection, the composition, effector function, and specificity of TRM cells in the kidney and their relevance for chronic kidney disease remain unknown. In this study, we found that renal tissue displayed high abundance of tissue-resident lymphocytes, and the proportion of CD8+ TRM cells was significantly increased in the kidney from patients and mice with focal segmental glomerulosclerosis (FSGS), diabetic kidney disease (DKD), and lupus nephritis (LN). Mechanistically, IL-15 significantly promoted CD8+ TRM cell formation and activation, thereby promoting podocyte injury and glomerulosclerosis. Interestingly, Sparsentan, the dual angiotensin II (Ang II) receptor and endothelin type A receptor antagonist, can also reduce TRM cell responses by intervening IL-15 signaling, exploring its new pharmacological functions. Mechanistically, Sparsentan inhibited Ang II or endothelin-1 (ET-1)-mediated IL-15 signaling, thereby further regulating renal CD8+ TRM cell fates. Collectively, our studies provide direct evidence for the pivotal role of renal CD8+ TRM cells in podocyte injury and further strengthen that targeting TRM cells represents a novel therapeutic strategy for patients with glomerular diseases.

6.
Front Plant Sci ; 13: 872781, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35432423

RESUMO

Biofortification of wheat with mineral through crop breeding is a sustainable and cost-effective approach to address human mineral malnutrition. A better understanding of the trends of grain concentrations of mineral nutrients in wheat over the breeding period may help to assess the breeding progress to date. A 2-year field experiment using 138 Chinese wheat landraces and 154 cultivars was conducted. Grain concentrations of micronutrients (Cu and Mn) and macronutrients (N, P, and K) were measured and corrected for a yield level to elucidate the trends of these mineral nutrients over the 80 years of cultivar releasing and identify genetic variation for these mineral nutrients in cultivars and landraces. Large genetic variation exists for grain mineral nutrients concentrations among tested genotypes, indicating that selection for enhancing mineral nutrient concentrations in wheat is possible. Landraces showed a slightly wide genetic variation of grain Cu concentration and a much narrow variation of Mn concentration when compared to modern cultivars. Grain concentrations of Cu and Mn decreased slightly with increasing grain yield with a weak correlation, while N, P, and K concentrations declined obviously with increasing yield with a strong correlation, revealing that increased grain yield had a strong negative effect on grain concentration of macronutrients, but a relative weak negative effect on micronutrients concentrations. When considering the impact of the variation in yield on mineral concentrations, grain concentrations of Cu, Mn, N, P, and K in wheat cultivars released from 1933 to 2017 exhibited different trends with a year of variety release. Grain Cu, N, and P concentrations showed significant decreasing trends over a breeding period, while grain Mn and K concentrations showed no clear trend, suggesting wheat breeding in China over the past 80 years has decreased grain concentrations of Cu, N, and P, and did not alter Mn and K concentrations. Finally, a total of 14 outstanding accessions with high grain mineral nutrients concentrations/contents were identified, and these genotypes can be considered as promising donors for developing mineral-dense wheat cultivars.

7.
Langmuir ; 38(18): 5381-5391, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35467866

RESUMO

Tumor acidic environment-activated combination therapy holds great promise to significantly decrease side effects, circumvent multiple drug resistance, and improve therapeutic outcomes for cancer treatment. Herein, Sorafenib/ZnPc(PS)4@FeIII-TA nanoparticles (SPFT) are designed with acid-environment turned-on fluorescence to report the activation of triple therapy including photodynamic, chemodynamic, and chemotherapy on hepatocellular carcinoma. The SPFT are composed of SP cores formulated via self-assembly of sorafenib and ZnPc(PS)4, with high drug loading efficiency, and FeIII-TA shells containing FeCl3 and tannic acid. Importantly, the nanoparticles suppress reactive oxygen species (ROS) generation of ZnPc(PS)4 due to their formation in nanoparticles, while assisting simultaneous uptake of the uploaded drugs in cancer cells. The tumor acidic environment initiates FeIII-TA decomposition and accelerates a chemodynamic reaction between FeII and H2O2 to generate toxic •OH. Then, the SP core is decomposed to separate ZnPc(PS)4 and sorafenib, which leads to fluorescence turning-on of ZnPc(PS)4, expedited photodynamic reactions, and burst release of sorafenib. Notably, SPFT shows low dark cytotoxicity to normal cells but exerts high potency on hepatocellular carcinoma cells under near-infrared light irradiation, which is much more potent than either sorafenib or ZnPc(PS)4 alone. This research offers a facile nanomedicine design strategy for cancer therapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Fotoquimioterapia , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Compostos Férricos , Fluorescência , Humanos , Peróxido de Hidrogênio , Neoplasias Hepáticas/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Sorafenibe/farmacologia
8.
Biochem Biophys Res Commun ; 611: 126-131, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35487062

RESUMO

Sustained inflammatory responses delay wound repair in diabetic skin. The stimulator of interferon genes (STING) plays a vital role in the innate immune responses. However, its function in diabetic skin wound repair, and the underlying mechanism remains unclear. Here, we reported that STING activation is a pathogenic marker that correlates with delayed wound repair in diabetic skin. Firstly, we found that STING expression is enhanced in the epidermis of STZ induced diabetes mouse model and db/db mouse model. Consistently, we also found that STING expression was upregulated in keratinocytes with the high-glucose (HG) treatment. Moreover, silencing of STING accelerated wound healing in vitro. In vivo, inhibition of STING by c176 inhibited inflammatory response in the epidermis and accelerated wound healing in diabetic skin. In addition, we found that autophagy dysfunction is correlated with the expression of STING in epidermis of diabetic mice. Induction of autophagy by rapamycin significantly reduced STING expression in keratinocytes. Collectively, these results indicated that defects of autophagy might lead to the activation of STING and finally delay the diabetic wound healing.

9.
EBioMedicine ; 78: 103980, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35367771

RESUMO

BACKGROUND: Previous research has revealed that KIBRA controls secretion of extracellular vesicles (EVs) by inhibiting the proteasomal degradation of Rab27a and EVs play an important role in amyloid ß (Aß) metabolism and transmission during Alzheimer's disease (AD) pathogenesis. Here, we further test the hypothesis that KIBRA regulates Aß metabolism via the endosomal-lysosomal system. METHODS: We generated KIBRA knockout mice on a 5XFAD background and KIBRA knockdown cells in murine HT22 cells with stably overexpressing APP. Various forms of Aß and quantification of EVs were analyzed by biochemical methods and nanoparticle tracking analysis, respectively. Multivesicular bodies (MVBs) were visualized by electron microscopy and confocal fluorescent microscopy. In a population-based cohort (n = 1419), KIBRA genotypes and plasma Aß levels were analyzed using multiple-PCR amplification and Simoa, respectively. FINDINGS: Multiple forms of Aß were dramatically attenuated in KIBRA knockout mouse brain, including monomers, oligomers, and extracellular deposition, but KIBRA knockout had no effect on intraneuronal APP C-terminal fragment ß (APP-CTFß)/Aß levels. KIBRA depletion also decreased APP-CTFß/Aß-associated EVs secretion and subsequently enhanced MVBs number. Furthermore, we found that excessive accumulation of MVBs harboring APP-CTFß/Aß promoted the MVBs-lysosome fusion for degradation and inhibition of lysosomal function rescued secretion of APP-CTFß/Aß-associated EVs. More importantly, whole exon sequencing of KIBRA in a large population-based cohort identified the association of KIBRA rs28421695 polymorphism with plasma Aß levels. INTERPRETATION: These results demonstrate that KIBRA regulates Aß metabolism via controlling the secretion of APP-CTFß/Aß-associated EVs. FUNDING: National Key R&D Program of China, and National Natural Science Foundation of China.


Assuntos
Doença de Alzheimer , Vesículas Extracelulares , Peptídeos e Proteínas de Sinalização Intracelular , Fosfoproteínas , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Endossomos/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Knockout , Fosfoproteínas/metabolismo
10.
Micromachines (Basel) ; 13(4)2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35457843

RESUMO

Acute kidney injury (AKI) is a common and severe problem associated with high morbidity, mortality, and healthcare costs. There are no reliable therapeutic interventions except dialysis that could improve survival, limit injury, or speed up recovery. Thus, it is essential to develop new therapies to treat AKI. Previous studies revealed that histone deacetylase inhibitor (HDACi) could attenuate renal injury and enhance kidney recovery in AKI. However, the hydrophobic nature of HDACi, such as vorinostat (SAHA), requires organic solvents to promote its dissolution, leading to inevitable detrimental effects. Herein, calcium alginate microspheres (CAM) were prepared by the microfluidic method as HDACi carriers to treat AKI by intravenous injection. First, we designed the structure of the microfluidic channel for the fabrication of the PDMS microfluidic chip in which the emulsion state of droplets was analyzed. As the flow rate increases, the continuous phase changed from laminar flow to the dripping pattern in the microfluidic device. Then, the CAM was fabricated by a W/O microfluidic emulsion template and the size of the microspheres was adjusted from 3 to 7 µm by the concentration of alginate and the flow rate of the continuous phase and dispersal phase. The higher degree of cross-linking of sodium alginate with calcium ions would lead to longer drug release time but lower swelling rates. Furthermore, we selected CAM with suitable sizes as the HDACi carrier and delivered the HDACi-loaded CAM to the AKI mice by intravenous tail injection. The in vivo results showed that the HDACi-loaded CAM could effectively reduce the renal regional inflammatory response and attenuate renal injury.

11.
Sci Total Environ ; 832: 154987, 2022 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-35378175

RESUMO

As an important member of transition-metal dichalcogenides family, tungsten disulfides nanomaterials (WS2 NMs) have a wide range of applications. To date, their environmental risks remain largely unknown. In this study, rice plants were grown in soil amended with different concentrations (0, 10, and 100 mg/kg) of WS2 NMs for 4 weeks. WS2 NMs at 100 mg/kg significantly increased MDA (malondialdehyde) content and decreased total antioxidant capacities of leaves, indicating the oxidative response induced by WS2 NMs. Meanwhile, WS2 NMs at 100 mg/kg significantly decreased root biomass compared to control, indicating the negative impacts of WS2 NMs on plant growth. While exposure to 100 mg/kg WS2 NMs significantly increased soil bioavailable Cu, Fe, Zn, and Olsen-P, and increased the content of Cu, Fe, Zn, and P in rice leaves. Inductively coupled plasma-optical emission spectroscopy (ICP-OES) analysis showed that W was taken up by rice roots and translocated into leaves. The impact of WS2 on soil microbial communities was evaluated by 16S rRNA gene sequencing. WS2 NMs at 100 mg/kg significantly decreased soil microbial diversity, as indicated by decreased Shannon index. In addition, 100 mg/kg WS2 shifted the soil microbial profile, the relative abundance of the phylum Acidobacteriota decreased, and Actinobacteriota increased. Taken together, the soil microbial community's diversity and composition have been altered upon exposure to 100 mg/kg WS2 NMs. The results of this study provide some basic information regarding the environmental behavior and phytotoxicity of WS2 NMs, which is valuable for safe use of WS2 NMs.

12.
BMJ Open ; 12(4): e055355, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35470189

RESUMO

INTRODUCTION: Total mesorectal excision (TME) has been the gold standard for the surgical treatment of mid-low rectal cancer, but traditional TME removal of Denonvilliers' fascia (DVF) is too low and is prone to damage the connecting branches of the bilateral neurovascular bundles, which can lead to posturogenital dysfunction. A recently published multicenter randomised controlled trial revealed that TME with complete preservation of DVF (CP-DVF) has protective effects on postoperative urogenital function for male patients with rectal cancer with specific staging and location (preoperative staging T1-4N0-2M0, but T1-2 for anterior rectal wall). Our previous studies have confirmed that TME with partial preservation of DVF (PP-DVF) could also achieve satisfactory results regardless of the circumferential location of the tumour. However, there is a lack of randomised controlled trials to prove that the efficacy of TME with PP-DVF is equivalent to that with CP-DVF with respect to postoperative urogenital function. METHODS AND ANALYSIS: This study is a prospective, multicentre, equivalent design, open-label randomised clinical trial in which 278 male patients with low rectal cancer will be recruited from 11 large-scale gastrointestinal medical centres in China. Patients will be randomly assigned to undergo PP-DVF or CP-DVF. We will test the hypothesis that PP-DVF is similar to CP-DVF with respect to sexual function at postoperative month 12 (5-item version of the International Erectile Function Index Questionnaire and ejaculation function classification). The secondary outcomes include the assessment of urinary function, surgical safety and oncological outcomes. ETHICS AND DISSEMINATION: This trial has been approved by the Institutional Review Board of Fujian Medical University Union Hospital (2020YF016-01) and is filed on record by all other centres. Written informed consent will be obtained from all eligible participants before enrolment. The trial's results will be disseminated via peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: ChiCTR2000034892.


Assuntos
Neoplasias Retais , Fáscia , Feminino , Humanos , Masculino , Margens de Excisão , Estudos Multicêntricos como Assunto , Período Pós-Operatório , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Retais/cirurgia
13.
J Affect Disord ; 309: 229-235, 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35489555

RESUMO

BACKGROUND: Depressive symptoms (DS) can increase the risk of stroke, but it is unclear whether long-term DS trajectories are associated with incident stroke. This study aimed to explore the association of long-term DS trajectories with incident stroke. METHODS: This prospective cohort study included 11,002 adults aged 50 and older from the Health and Retirement Study during 1994-2018. DS was assessed using the 8-item version of the Center for Epidemiologic Studies Depression Scale. Stroke was obtained through self-report of doctors' diagnosis. The group-based trajectory model was used to determine DS trajectories from 1994 to 2000. Cox proportional hazard model was applied to explore the correlation of DS trajectories with incident stroke from 2000 to 2018. RESULTS: We identified five distinct 6-year DS trajectories. Compared with the persistent no DS trajectory, the full-adjusted HRs (95% CIs) for the persistent mild, improving, worsening, and persistent high DS trajectories were 1.15 (1.01, 1.30), 1.27 (0.88, 1.84), 1.41 (1.17, 1.71), and 1.61 (1.21, 2.16), respectively. In addition, the persistent mild DS trajectories had the largest population attributable risk percent (PAR%). LIMITATIONS: There was a lack of information on stroke subtypes. CONCLUSIONS: This study suggests that compared with persistent no DS, persistent mild, worsening, and persistent high DS trajectories increase the risk of stroke in the elderly. Considering that the PAR% of stroke events in the persistent mild DS trajectory is the largest, we should pay attention not only to individuals with DS, but also to those being chronically close to the cut-off value of DS.

14.
J Nanobiotechnology ; 20(1): 146, 2022 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-35305659

RESUMO

BACKGROUND: Silica nanoparticles (SiO2 NPs) are extensively applied in the biomedical field. The increasing medical application of SiO2 NPs has raised concerns about their safety. However, studies on SiO2 NP-induced retinal toxicity are lacking. METHODS: We investigated the retinal toxicity of SiO2 NPs with different sizes (15 and 50 nm) in vitro and in vivo along with the underlying mechanisms. The cytotoxicity of SiO2 NPs with different sizes was assessed in R28 human retinal precursor cells by determining the ATP content and LDH release. The cell morphologies and nanoparticle distributions in the cells were analyzed by phase-contrast microscopy and transmission electron microscopy, respectively. The mitochondrial membrane potential was examined by confocal laser scanning microscopy. The retinal toxicity induced by SiO2 NPs in vivo was examined by immunohistochemical analysis. To further investigate the mechanism of retinal toxicity induced by SiO2 NPs, reactive oxygen species (ROS) generation, glial cell activation and inflammation were monitored. RESULTS: The 15-nm SiO2 NPs were found to have higher cytotoxicity than the larger NPs. Notably, the 15-nm SiO2 NPs induced retinal toxicity in vivo, as demonstrated by increased cell death in the retina, TUNEL-stained retinal cells, retinal ganglion cell degeneration, glial cell activation, and inflammation. In addition, The SiO2 NPs caused oxidative stress, as demonstrated by the increase in the ROS indicator H2DCF-DA. Furthermore, the pretreatment of R28 cells with N-acetylcysteine, an ROS scavenger, attenuated the ROS production and cytotoxicity induced by SiO2 NPs. CONCLUSIONS: These results provide evidence that SiO2 NPs induce size-dependent retinal toxicity and suggest that glial cell activation and ROS generation contribute to this toxicity.


Assuntos
Nanopartículas , Dióxido de Silício , Sobrevivência Celular , Humanos , Nanopartículas/química , Nanopartículas/toxicidade , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/química
15.
Angew Chem Int Ed Engl ; 61(21): e202200303, 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35302274

RESUMO

Lysine acylation plays pivotal roles in cell physiology, including DNA transcription and repair, signal transduction, immune defense, metabolism, and many other key cellular processes. Molecular mechanisms of dysregulated lysine acylation are closely involved in the pathophysiological progress of many human diseases, most notably cancers. In recent years, chemical biology tools have become instrumental in studying the function of post-translational modifications (PTMs), identifying new "writers", "erasers" and "readers", and in targeted therapies. Here, we describe key developments in chemical biology approaches that have advanced the study of lysine acylation and its regulatory proteins (2016-2021). We further discuss the discovery of ligands (inhibitors and PROTACs) that are capable of targeting regulators of lysine acylation. Next, we discuss some current challenges of these chemical biology probes and suggest how chemists and biologists can utilize chemical probes with more discriminating capacity. Finally, we suggest some critical considerations in future studies of PTMs from our perspective.


Assuntos
Lisina Acetiltransferases , Lisina , Acilação , Biologia , Humanos , Lisina/metabolismo , Lisina Acetiltransferases/metabolismo , Processamento de Proteína Pós-Traducional
16.
Obesity (Silver Spring) ; 30(4): 931-942, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35275605

RESUMO

OBJECTIVE: This study aimed to examine the association of socioeconomic status with obesity. METHODS: A total of 39,262 twin individuals were included from the Chinese National Twin Registry (CNTR). Generalized estimating equation models for unmatched twin individual analyses and conditional logistic regression for the co-twin matched design were used. Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) was used to explore the evidence of a causal relationship. RESULTS: In general estimating equation models, high education level and income were associated with lower risk of obesity (odds ratio [OR] = 0.74 [95% CI: 0.65 to 0.84] and 0.86 [95% CI: 0.77 to 0.96]). In conditional logistic regression analysis, the association with education was significant (OR = 0.50 [95% CI: 0.34 to 0.74]) but the association with income was insignificant (OR = 0.74 [95% CI: 0.48 to 1.15]). From the ICE FALCON analysis, a twin's obesity was associated with the co-twin's education and income. After adjusting for the twin's own education, the association disappeared ( ß co - twin '  = -0.10 [95% CI: -0.26 to 0.07]), whereas the twin's obesity was still associated with the co-twin's income but attenuated toward the null ( ß co - twin '  = -0.21 [95% CI: -0.36 to -0.06]). CONCLUSIONS: Socioeconomic status is negatively associated with obesity. Education may have a causal effect on obesity, whereas the association between income and obesity is confounded by familial factors.


Assuntos
Obesidade , Gêmeos , China/epidemiologia , Humanos , Obesidade/epidemiologia , Razão de Chances
17.
Front Oncol ; 12: 856021, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35311081

RESUMO

Background: Use of the novel transoral endoscopic thyroidectomy vestibular approach (TOETVA) is increasing worldwide. Although several studies have compared safety and efficacy of TOETVA and other approaches, most focused on comparisons in the context of unilateral thyroidectomy. Therefore, the present study aimed to compare the safety and surgical completeness of TOETVA with conventional open thyroidectomy (COT) in patients with papillary thyroid carcinoma (PTC) undergoing total thyroidectomy and central neck dissection. Methods: The medical records of patients who underwent TOETVA or COT by a single surgeon between June 2017 and October 2021 were retrospectively reviewed. All patients were diagnosed with PTC and underwent total thyroidectomy with central neck dissection. Propensity score-matching (PSM) was used to reduce potential selection bias and to adjust for differences in baseline clinicopathological characteristics. Results: After PSM, 84 (TOETVA: 28; COT: 56) patients remained in the study population. There were no significant differences in sex, mean age, combined thyroiditis, tumor size, capsule invasion, tumor multifocality in the same lobe, or tumor location between the groups. Operative time was longer (190.54 ± 28.26 vs. 123.93 ± 29.78 min, P<0.001), while postoperative drainage volume (161.07 ± 225.30 vs. 71.16 ± 28.56 ml, P=0.045) was greater, in the TOETVA group than in the COT group. The groups exhibited no significant differences in the mean number of central lymph nodes retrieved (9.39 ± 4.01 vs. 10.71 ± 5.17, P=0.202), mean number of metastatic central lymph nodes (1.36 ± 1.93 vs. 1.77 ± 2.31, P=0.421), postoperative mean thyroglobulin levels (0.08 ± 0.24 vs. 0.10 ± 0.27, P=0.686), rate of transient hypoparathyroidism (TOETVA: 67.9% vs. COT: 66.1%, P=0.870), rate of transient vocal cord palsy (TOETVA: 0% vs. COT: 1.8%, P=1.000), or other complications (TOETVA: 3.6% vs. COT: 0%, P=0.333). Conclusions: TOETVA is a safe approach in select patients with PTC and exhibits similar efficacy to COT in terms of surgical completeness.

18.
Bioengineered ; 13(4): 9106-9116, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35354355

RESUMO

Although major advances were achieved in colorectal cancer (CRC) therapy, major concerns still remain on proper control of cancer metastasis and chemo-resistance in order to achieve satisfactory general treatment response. Previous studies suggested that OTUB1 (OTU domain-containing ubiquitin aldehyde-binding protein 1) serves as regulator of gene ubiquitination and participates in the pathogenesis of multiple malignancies. Therefore, to discover its molecular mechanism in CRC tumor growth and metastasis will contribute in CRC treatment strategy development. Clinical tissues and CRC cancer cell lines were utilized to evaluate OTUB1 expression pattern. Functional tests including cellular proliferation, migration and invasion, as well as chemo-resistance, etc., were evaluated to investigate the role of OTUB1/ß-catenin regulatory pathway on CRC malignant biological behaviors. Both CRC tumor tissues and CRC cell lines exhibited promoted OTUB1 expression level. Subsequent experiments further suggested that OTUB1 promoted CRC malignancy by enhancing protein stability of ß-catenin, via inhibition of its protein degradation by UPP pathway, which indicated its crucial role in enhancement of CRC tumor cellular proliferative and chemo-resistant capabilities. This study reported that OTUB1 exhibited novel pro-survival and pro-metastatic function by interaction of ß-Catenin via Ubiquitin-proteasome pathway. Our research indicated that OTUB1/ß-Catenin regulatory axis might be potential druggable target for CRC cancer patients' treatment.


Assuntos
Neoplasias Colorretais , Complexo de Endopeptidases do Proteassoma , Aldeídos , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-35349062

RESUMO

Endocrine disrupting compounds (EDCs), such as bisphenol A (BPA) and 17α-ethynylestradiol (EE2), have increasingly negative effects on human and wildlife health. In this study, the biogenic Mn oxides (BMOs) generated by Bacillus sp. WH4 were characterized, and the removal effects and reaction kinetics of BPA and EE2 by BMOs under different pH values, initial organic concentrations, and dosages of BMOs were discussed. The results showed that the formation of BMOs was extracellular process, and Mn(II) was oxidized to Mn(III) and Mn(IV) with 23.56% and 76.44%, respectively. The degradation processes of BPA and EE2 by BMOs followed first-order reaction kinetics, and the removal effect decreased with increasing initial BPA/EE2 concentrations and increased with increasing dosages of BMOs. However, the removal effect of BPA by BMOs decreased and then increased with increasing pH, while the removal effect of EE2 by BMOs decreased with increasing pH. Under optimal conditions, the removal efficiency of BPA and EE2 exceeded 98.2% and 94.3%, respectively. Additionally, this study showed that BMOs degraded BPA by coupling, oxidative condensation, substitution, and elimination reactions to obtain sixteen intermediate products and EE2 by substitution and elimination reactions to obtain seven intermediate products.

20.
Artigo em Inglês | MEDLINE | ID: mdl-35280509

RESUMO

Methods: This was a retrospective analysis in a general hospital emergency department in Beijing, China. 212 adult AIS patients treated with thrombolysis who failed to use EMSs were included. In addition to DNT, door-to-vein open time (DVT), door-to-blood sample deliver time (DBT), and 7-day NIHSS scores were evaluated. Results: 137 (64.6%) patients were in the triage nurse-activated group and 75 (35.4%) patients were in the doctor-activated group. The DNT of the triage nurse-activated group was significantly reduced compared with the doctor-activated group (28 (26, 32.5) min vs. 30 (28, 40) min, p=0.001). DNT less than 45 min was seen in 95.6% of patients in the triage nurse-activated group and 84% of patients in the doctor-activated group (p=0.011, OR 3.972, 95% CI 1.375-11.477). In addition, DVT (7 (4, 10) min vs. 8 (5, 12) min, P=0.025) and DBT (15 (13, 21) min vs. 19 (15, 26) min, p=0.001) of the triage nurse-activated group were also shorter than those of the doctor-activated group (p < 0.05). The 7-day NIHSS scores were not statistically different between the two groups. Conclusions: Triage nurse-activated urgent emergency evaluation could reduce the door-to-needle time, which provides a feasible opportunity to optimize the emergency department service for AIS patients who failed to use emergency medical services.

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