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1.
Neurotox Res ; 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34982356

RESUMO

Circular RNA (circRNA) plays a crucial part in glioma progression. However, the function of circ_0001588 in glioma development is still unknown. The study aims to reveal the role of circ_0001588 in glioma malignant progression and the inner molecular mechanism. The RNA expressions of circ_0001588, microRNA-1281 (miR-1281), and erb-b2 receptor tyrosine kinase 4 (ERBB4) were detected by qRT-PCR. Protein expression was checked by western blot analysis or immunohistochemistry assay. Cell proliferation was investigated by cell counting kit-8 and colony formation assays. Flow cytometry, transwell, and tube formation assays were used to detect cell apoptosis, cell migration, and invasion as well as angiogenesis, respectively. The binding relationship between miR-1281 and circ_0001588 or ERBB4 was identified by dual-luciferase reporter and RNA immunoprecipitation assays. Mouse model assay was performed to confirm the effect of circ_0001588 knockdown on tumor formation in vivo. Circ_0001588 and ERBB4 expressions were significantly upregulated, while miR-1281 was downregulated in glioma tissues and cells compared with control groups. Circ_0001588 expression was closely related to tumor size and WHO grade of glioma. Decreased expression of circ_0001588 in glioma cells led to significant decreases of cell proliferation, migration, invasion, and tube formation and an increase of cell apoptosis. Additionally, downregulation of miR-1281, a target miRNA of circ_0001588, rescued circ_0001588 knockdown-mediated effects. MiR-1281 also inhibited glioma malignant progression by targeting ERBB4. Importantly, circ_0001588 regulated ERBB4 expression by interacting with miR-1281. Furthermore, circ_0001588 depletion suppressed tumor formation in vivo. Circ_0001588 acted as an oncogene in glioma malignant progression by miR-1281/ERBB4 pathway, suggesting the potential of circ_0001588 as a therapeutic target for glioma.

2.
Eur J Med Chem ; 227: 113888, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34628244

RESUMO

Although gastric cancer has become a major public health problem, oral agents applied in clinics for gastric cancer therapy are scarce. Therefore, to explore new oral chemical entities with high efficiency and low toxicity, 41 o-aminobenzamide derivatives based on the scaffolds of MS-275 and SAHA were designed, synthesized, and evaluated for their anti-gastric cancer abilities in vitro and in vivo. Structure-activity relationships were discussed, leading to the identification of compounds F8 (IC50 = 0.28 µM against HGC-27 cell) and T9 (IC50 = 1.84 µM against HGC-27 cell) with improved cytotoxicity, anti-gastric cancer proliferation potency, induction of cell apoptosis and cell cycle arrest ability, inhibition of cell migration and invasion. What is worth mentioning is that compound F8 was more efficient and less toxic than the positive drug capecitabine in vivo on the HGC-27-xenograft model. Meanwhile, compound F8 exhibited suitable pharmacokinetic properties and less acute toxicity (LD50 > 1000 mg/kg). Besides, western blotting analysis, IHC analysis, differentially expressed proteins analysis and ABPP experiment indicated that compound F8 could modulate molecular pathways involved in apoptosis and cell cycle progression. Consequently, compound F8 is a strong candidate for the development of human gastric cancer therapy.

3.
Eur J Med Chem ; 227: 113908, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34656900

RESUMO

Highly efficacious and tolerable agents for the treatment of glioblastoma (GBM), the most common and aggressive primary brain tumor, are urgently needed. Herein, we reveal the design, synthesis and biological evaluation of several piperazine based benzamide derivatives, which are based on the non-classical isostere principle and combination principle for GBM therapy. After structure-activity relationship (SAR) study, compound L19 was demonstrated as the most promising compound with IC50 values of 0.15 µM, 0.29 µM, 1.25 µM against GBM C6, U87-MG, U251 cells, respectively. Moreover, compound L19 could inhibit the proliferation, migration and invasion, as well as induce apoptosis and cell cycle arrest of GBM cell lines in vitro. From mechanism perspective, compound L19 could regulate the cell cycle-related proteins and influence the p16INK4a-CDK4/6-pRb pathway by western blotting experiment. What is worth mentioning is that compound L19 could penetrate the blood-brain barrier (BBB) with an exceptional brain-to-plasma ratio of 1.07 in vivo. Besides, the superior anti-glioblastoma potency in vivo of compound L19 was identified on U87-MG-xenograft model without any apparent host toxicity. Overall, the potential of compound L19 warrants further pre-clinical investigation for GBM therapy.

4.
Kidney Blood Press Res ; : 1-9, 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34856559

RESUMO

OBJECTIVES: Klotho (KL) plays pivotal roles in the progression of salt-sensitive hypertension. Salt-sensitive hypertension was associated with KL genotypes. We aimed to explore the association of common genetic variants of KL with individual blood pressure (BP) responses to sodium and potassium through a dietary intervention study as well as long-term BP progression. METHODS: We conducted family-based dietary interventions among 344 participants from 126 families in rural villages of northern China in 2004. Subjects sequentially underwent a baseline diet, a low-salt diet (51.3 mmol/day Na), a high-salt diet (307.8 mmol/day Na), and a high-salt + potassium supplementation diet (307.8 mmol/day Na + 60 mmol/day K). After dietary intervention, we followed up with these participants in 2009 and 2012. The associations between 6 single-nucleotide polymorphisms (SNPs) of KL and phenotypes were analyzed through a linear mixed-effects model. RESULTS: SNPs rs211247 and rs1207568 were positively correlated with the BP response to high-salt diet in the dominant model after adjusting for confounders (ß = 1.670 and 2.163, p = 0.032 and 0.005, respectively). BPs rs526906 and rs525014 were in a haplotype block. Block rs526906-rs525014 was positively correlated with diastolic BP response to potassium and potassium sensitivity in the additive model (ß = 0.845, p = 0.032). In addition, regression analysis indicated that rs211247 was associated with long-term systolic BP alterations after 8 years of follow-up in the recessive model (ß = 20.47, p = 0.032). CONCLUSIONS: Common variants of the KL gene might modify individual BP sensitivity to sodium or potassium and influence the long-term progression of BP, suggesting a potential role in the development of salt-sensitive hypertension. Thus, KL may be a new early intervention target for salt-sensitive hypertension.

5.
Cardiovasc Ther ; 2021: 4971300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858521

RESUMO

The present study is aimed at investigating the molecular mechanism of C1q/TNF-related protein 9 (CTRP9) and providing a new perspective in arteriovenous shunt-induced pulmonary arterial hypertension (PAH). PAH was established by an arteriovenous shunt placement performed in rats. Adenovirus(Ad)-CTRP9 and Ad-green fluorescent protein viral particles were injected into the rats through the tail vein. Following 12 weeks, the mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured and morphological analysis was conducted to confirm the establishment of the PAH model. The systemic elevation of CTRP9 maintained pulmonary vascular homeostasis and protected the rats from dysfunctional and abnormal remodeling. CTRP9 attenuated the pulmonary vascular remodeling in the shunt group by decreasing the mPAP and RVSP, which was associated with suppressed inflammation, apoptosis, and extracellular matrix injury. In addition, CTRP9 dramatically increased the phosphorylation of AKT and p38-MAPK in the lung tissues of shunt-operated animals. These findings suggest a previously unrecognized effect of CTRP9 in pulmonary vascular homeostasis during PAH pathogenesis.

6.
Int J Mol Sci ; 22(24)2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34948169

RESUMO

Rooting is a key innovation during plant terrestrialization. RGFs/GLVs/CLELs are a family of secreted peptides, playing key roles in root stem cell niche maintenance and pattern formation. The origin of this peptide family is not well characterized. RGFs and their receptor genes, RGIs, were investigated comprehensively using phylogenetic and genetic analyses. We identified 203 RGF genes from 24 plant species, representing a variety of land plant lineages. We found that the RGF genes originate from land plants and expand via multiple duplication events. The lineage-specific RGF duplicates are retained due to their regulatory divergence, while a majority of RGFs experienced strong purifying selection in most land plants. Functional analysis indicated that RGFs and their receptor genes, RGIs, isolated from liverwort, tomato, and maize possess similar biological functions with their counterparts from Arabidopsis in root development. RGFs and RGIs are likely coevolved in land plants. Our studies shed light on the origin and functional conservation of this important peptide family in plant root development.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34948762

RESUMO

The Guangdong-Hong Kong-Macao Greater Bay Area (GBA) is one of the significant regions with the strongest economic vitality in China. This study focuses on environmental regulation in the eleven Greater Bay Area cities to explore the relationship between it and economic performance for the period 2000-2016. In doing so, we employ spatial panel models (including the spatial instrumental variable method) to investigate the nonlinear relationship between economic growth and environmental regulation. We confirm the existence of a U-shaped relationship between economic growth and environmental regulation in the Greater Bay Area. In the first half of the inverted U shape, the higher the economic development level, the stronger the environmental regulation strength; however, the latter begins to decrease after the peak point. The doubled-edged sword does not cut both ways. This paper verifies that technology innovation and resource consumption are two important mechanisms. Further, we find that both economic growth and environmental regulation have negative spatial externalities; innovation has a positive impact on the environmental regulation of the local city as well as surrounding cities, while resource consumption is on the contrary. In conclusion, this paper provides policy recommendations to further promote economic growth and environmental technologies, and to enhance energy efficiency in GBA.


Assuntos
Desenvolvimento Econômico , Tecnologia , China , Cidades , Hong Kong
8.
Eur J Med Chem ; 229: 114044, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34923430

RESUMO

In this study, we designed, synthesized, and evaluated a series of carbamate derivatives of N-salicyloyl tryptamine as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). After screening the acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitory activities, target compound 1g stood out as a mixed type reversible dual inhibitor of AChE and BChE. In addition, molecular docking studies were conducted to explore the actions on AChE and BChE. The results showed that 1g could decrease the level of pro-inflammatory cytokines NO, iNOS, IL-6, TNF-α, and ROS, increase the level of anti-inflammatory cytokines IL-4, and inhibit the aggregation of Aß1-42. Moreover, the administration of 1g suppressed the activity of AChE in the brain. In a word, the compound 1g is effective for improving learning and memory behavior, blood-brain barrier permeation, pharmacokinetics, ChE inhibition, and anti-neuroinflammation. It may be considered as a promising multi-functional therapeutic agent for further investigation for the treatment of AD.

9.
Nanomaterials (Basel) ; 11(11)2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34835800

RESUMO

Electromagnetic (EM) and infrared (IR) stealth play an important role in the development of military technology and the defense industry. This study focused on developing a new type of multifunctional composite film based on polyimide (PI)/graphene/Fe3O4 hybrid aerogel and polyethylene glycol (PEG) as a phase change material (PCM) for EM and IR bi-stealth applications. The composite films were successfully fabricated by constructing a series of PI-based hybrid aerogels containing different contents of graphene nanosheets and Fe3O4 nanoparticles through prepolymerizaton, film casting, freeze-drying, and thermal imidization, followed by loading molten PEG through vacuum impregnation. The construction of PI/graphene/Fe3O4 hybrid aerogel films provides a robust, flexible, and microwave-absorption-functionalized support material for PEG. The resultant multifunctional composite films not only exhibit high microwave absorption effectiveness across a broad frequency range, but also show a good ability to implement thermal management and temperature regulation under a high latent-heat capacity of over 158 J/g. Most of all, the multifunctional composite films present a wideband absorption capability at 7.0-16.5 GHz and a minimum reflection loss of -38.5 dB. This results in excellent EM and IR bi-stealth performance through the effective wideband microwave absorption of graphene/Fe3O4 component and the thermal buffer of PEG. This study offers a new strategy for the design and development of high-performance and lightweight EM-IR bi-stealth materials to meet the requirement of stealth and camouflage applications in military equipment and defense engineering.

10.
Opt Express ; 29(21): 34510-34521, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34809239

RESUMO

Terahertz (THz) frequency modulated continuous wave (FMCW) technology is a means of nondestructive testing. The signal's nonlinearity is an unavoidable problem in the daily application of THz FMCW technology. The signal's nonlinearity will lead to the spectrum broadening of the FMCW's beat frequency (BF) signal, which degrades the range resolution and result in distance-measuring error. Traditional methods require additional hardware or require a lot of computation, which are not conducive to the miniaturization of the system and real-time measurement. A novel method for correcting the nonlinear error of THz FMCW technology has been proposed and demonstrated in this article. In the proposed method, the windowed Fourier transform (WFT) is introduced to estimate the BF corresponding to the measured target, according to the linearity distribution of voltage-controlled oscillator (VCO). In this way, the measured target's BF can be accurately estimated from the unprocessed BF signal with a poor linearity. From the estimated BF of the reference target, the non-linear compensation coefficients are calculated. With the non-linear compensation coefficients, the non-linearity of the output BF signal can be calibrated. The results of simulations and experiments show that the proposed method allows the range resolution of an FMCW system to reach the theoretical limit.

11.
Front Pharmacol ; 12: 767982, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34764876

RESUMO

Background: Patients with chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSAS) overlap syndrome (OS) are thought to be at increased risk for cardiovascular diseases. Objective: To evaluate the burden of cardiovascular diseases and long-term outcomes in patients with OS. Methods: This was a retrospective cohort study. The prevalence of cardiovascular diseases and 1-year mortality were compared among patients diagnosed with OS (OS group), COPD alone (COPD group) and OSAS alone (OSAS group), and Cox proportional hazards models were used to assess independent risk factors for all-cause mortality. Results: Overall, patients with OS were at higher risk for pulmonary hypertension (PH), heart failure and all-cause mortality than patients with COPD or OSAS (all p < 0.05). In multivariate Cox regression analysis, the Charlson comorbidity index (CCI) score [adjusted hazard ratio (aHR): 1.273 (1.050-1.543); p = 0.014], hypertension [aHR: 2.006 (1.005-4.004); p = 0.048], pulmonary thromboembolism (PTE) [aHR: 4.774 (1.335-17.079); p = 0.016] and heart failure [aHR: 3.067 (1.521-6.185); p = 0.002] were found to be independent risk factors for 1-year all-cause mortality. Conclusion: Patients with OS had an increased risk for cardiovascular diseases and 1-year mortality. More efforts are needed to identify the causal relationship between OS and cardiovascular diseases, promoting risk stratification and the management of these patients.

12.
Eur J Med Chem ; : 113985, 2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34802836

RESUMO

This article describes the syntheses and biological activity of five 3-arylisoquinoline natural products corydamine (1), N-formyl Corydamine (2), hypecumine (3), Decumbenine B (XW) and 2-(1,3-dioxolo [4,5-h]isoquinolin-7-yl)-4,5-dimethoxy-N-methyl-Benzeneethanamine (A), and twelve analogues. Among them, 1, 2, and A were synthesized for the first time. In vitro screening for anti-proliferative activity showed that derivative 1a could significantly inhibit the proliferation of HCC cells (IC50 = 9.82 µM on Huh7 cells and 6.83 µM on LM9 cells), and arrest cell cycle at G2/M phase. The mechanistic studies further suggested compound 1a was a dual inhibitor of Topo I and Topo II, and Topo II inhibitory activity was superior to etoposide. In addition, 1a could significantly inhibit the invasion and migration of cancer cells by inhibiting the expression of MMP-9, and induce apoptosis through inhibiting the activation of the PI3K/Akt/mTOR signaling pathway. Moreover, in vivo studies demonstrated 1a could obviously reduce the growth of xenograft tumor and possessed good pharmacokinetic parameters, which indicated the potential value of 1a in treating liver cancer.

13.
Phys Rev Lett ; 127(19): 197003, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34797146

RESUMO

Establishing a minimal microscopic model for cuprates is a key step towards the elucidation of a high-T_{c} mechanism. By a quantitative comparison with a recent in situ angle-resolved photoemission spectroscopy measurement in doped 1D cuprate chains, our simulation identifies a crucial contribution from long-range electron-phonon coupling beyond standard Hubbard models. Using reasonable ranges of coupling strengths and phonon energies, we obtain a strong attractive interaction between neighboring electrons, whose strength is comparable to experimental observations. Nonlocal couplings play a significant role in the mediation of neighboring interactions. Considering the structural and chemical similarity between 1D and 2D cuprate materials, this minimal model with long-range electron-phonon coupling will provide important new insights on cuprate high-T_{c} superconductivity and related quantum phases.

14.
Eur J Med Chem ; : 113960, 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34774339

RESUMO

Gastric cancer represents a significant health burden worldwide. Previously, inspired by the traditional Chinese medicine Wu-Chu-Yu to treat the spleen and stomach system for thousands of years, we identified N14-phenyl substituted evodiamine derivatives as potential antitumor agents with favorable inhibition on Top1. Herein, structural optimization and structure-activity relationship studies (SARs) led us to discovering a highly active evodiamine derivative compound 6t against gastric cancer. Further anti-tumor mechanism studies revealed that compound 6t played as the inhibition of topoisomerase 1 (Top1), effectively induced apoptosis, obviously arrested the cell cycle at the G2/M phase, and significantly inhibited the migration and invasion of SGC-7901 and MGC-803 cell lines in a dose-dependent manner. Moreover, the compound 6t was low toxicity in vivo and exhibited excellent anti-tumor activity (TGI = 70.12%) in the MGC-803 xenograft models. In summary, compound 6t represents a promising candidate as a potential chemotherapeutic agent against gastric cancer.

15.
Biomed Environ Sci ; 34(10): 803-813, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34782046

RESUMO

Objective: The study aims to predict 10-year cardiovascular disease (CVD) risk and explore its association with sleep duration among Chinese urban adults. Methods: We analyzed part of the baseline data of a cohort that recruited adults for health screening by cluster sampling. The simplified Pittsburgh Sleep Quality Index (PSQI) and Framingham 10-year risk score (FRS) were used to measure sleep duration and CVD risk. Demographic characteristics, personal history of chronic diseases, lifestyle factors were collected using a questionnaire. Height, weight, total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C) were also measured. Multiple logistic regression models were performed to explore the association of sleep duration with the predicted CVD risk. Results: We included 31, 135 participants (median age 44 years, 53.02% males) free of CVD, cerebral stroke, and not taking lipid-lowering agents. Overall, 14.05%, and 25.55% of participants were at medium and high predicted CVD risk, respectively. Short sleep was independently associated with increased odds of medium to high risk of predicted 10-year CVD among males ( OR = 1.10; 95% CI: 1.01-1.19) and increased odds of medium to high and high risk of predicted 10-year CVD among females ( OR = 1.23; 95% CI: 1.08-1.40; OR = 1.27; 95% CI: 1.11-1.44). In contrast, long sleep had no association with cardiovascular risk. Conclusion: A substantial number of adults free of CVD were at high 10-year CVD risk. Short sleep was associated with increased odds of predicted CVD risk.

16.
Front Cell Dev Biol ; 9: 710479, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34604215

RESUMO

Dysregulation of protein posttranslational modification (PTM) can lead to a variety of pathological processes, such as abnormal sperm development, malignant tumorigenesis, depression, and aging process. SIRT7 is a NAD+-dependent protein deacetylase. Besides known deacetylation, SIRT7 may also have the capacity to remove other acylation. However, the roles of SIRT7-induced other deacylation in aging are still largely unknown. Here, we found that the expression of SIRT7 was significantly increased in senescent fibroblasts and aged tissues. Knockdown or overexpression of SIRT7 can inhibit or promote fibroblast senescence. Knockdown of SIRT7 led to increased pan-lysine crotonylation (Kcr) levels in senescent fibroblasts. Using modern mass spectrometry (MS) technology, we identified 5,149 Kcr sites across 1,541 proteins in senescent fibroblasts, and providing the largest crotonylome dataset to date in senescent cells. Specifically, among the identified proteins, we found SIRT7 decrotonylated PHF5A, an alternative splicing (AS) factor, at K25. Decrotonylation of PHF5A K25 contributed to decreased CDK2 expression by retained intron (RI)-induced abnormal AS, thereby accelerating fibroblast senescence, and supporting a key role of PHF5A K25 decrotonylation in aging. Collectively, our data revealed the molecular mechanism of SIRT7-induced k25 decrotonylation of PHF5A regulating aging and provide new ideas and molecular targets for drug intervention in cellular aging and the treatment of aging-related diseases, and indicating that protein crotonylation has important implications in the regulation of aging progress.

17.
J Invest Surg ; : 1-9, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34670452

RESUMO

OBJECTIVE: We previously showed that HSP90 is involved in postconditioning cardioprotection by inhibiting complement C5a. Here, we investigated whether HSP90-mediated C5a/NF-κB inhibition is responsible for the cardioprotection conferred by liraglutide. METHODS: Rat hearts underwent a 30 min occlusion of the anterior descending coronary artery, after which reperfusion was performed for 2 h. A total of 100 rats were randomly assigned to the following groups: ischemia/reperfusion (I/R), sham, liraglutide preconditioning (LP, liraglutide, 0.18 mg/kg, intravenously, 12 h before ischemia), HSP90 inhibitor geldanamycin (GA, 1 mg/kg, intraperitoneally, 30 min before ischemia) plus LP, and C5a receptor antagonist PMX53 (1 mg/kg, intravenously, 30 min before ischemia) plus LP. Cardiac injury, C5a/NF-κB activation, and inflammation were investigated. RESULTS: LP significantly attenuated I/R-induced cardiomyocyte apoptosis, infarct size, and secretion of creatine kinase-MB, lactate dehydrogenase and cardiac troponin I. These effects were complemented by decreased C5a levels, nuclear factor (NF)-κB signaling, inflammatory cytokine expression, and increased HSP90 levels. GA, an HSP90 inhibitor, promotes C5a activation, NF-κB signaling, and inflammation and suppresses cardioprotection by LP. By contrast, PMX53, a C5a inhibitor, suppressed C5a activation, NF-κB signaling, and inflammation, and enhanced cardioprotection by LP. CONCLUSION: HSP90 markedly contributes to LP cardioprotection by inhibiting inflammatory responsesand C5a/NF-κB signaling , ultimately attenuating I/R-induced cardiomyocyte apoptosis by suppressing the proapoptotic factor Bax, and inducing the anti-apoptotic factor Bcl2.

18.
Antioxidants (Basel) ; 10(10)2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34679713

RESUMO

Reversible cysteine oxidation plays an essential role in redox signaling by reversibly altering protein structure and function. Cysteine oxidation may lead to intra- and intermolecular disulfide formation, and the latter can drastically stabilize protein-protein interactions in a more oxidizing milieu. The activity of the tumor suppressor p53 is regulated at multiple levels, including various post-translational modification (PTM) and protein-protein interactions. In the past few decades, p53 has been shown to be a redox-sensitive protein, and undergoes reversible cysteine oxidation both in vitro and in vivo. It is not clear, however, whether p53 also forms intermolecular disulfides with interacting proteins and whether these redox-dependent interactions contribute to the regulation of p53. In the present study, by combining (co-)immunoprecipitation, quantitative mass spectrometry and Western blot we found that p53 forms disulfide-dependent interactions with several proteins under oxidizing conditions. Cysteine 277 is required for most of the disulfide-dependent interactions of p53, including those with 14-3-3θ and 53BP1. These interaction partners may play a role in fine-tuning p53 activity under oxidizing conditions.

19.
Chem Asian J ; 16(23): 3886-3889, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34591366

RESUMO

A photo-switchable hetero-complementary quadruple H-bonding array, which consists of an azobenzene-derived ureidopyrimidinone (UPy) module (Azo-UPy) and a nonphotoactive diamidonaphthyridine (DAN) derivative (Napy-1), is constructed based on a reversible photo-locking approach. Upon UV (390 nm)/Vis (460 nm) light irradiations, photo-switchable quadruple H-bonded dimerization between Azo-UPy and Napy-1 can be achieved with exhibiting 4.8×104 -fold differences in binding strength (ON/OFF ratios). Furthermore, smart polymeric gels with unique photo-controlled macroscopic self-assembly behavior can be fabricated by introducing such quadruple H-bonding array as photo-regulable noncovalent interfacial connections.

20.
J Transl Med ; 19(1): 401, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34551773

RESUMO

BACKGROUND: Poorly cohesive (PC) is a unique histologic subtype of gastric cancer (GC), with an increasing incidence in recent years. However, the molecular characteristics and therapeutic targets of PC GC are not yet well studied and there are no effective therapies for these patients. METHODS: Formalin fixed paraffin embedded (FFPE) samples of 556 GC patients, including 64 PC GC, were collected for next-generation sequencing (NGS). Clinical characteristics and genomic profiling were analyzed. FGFR2 expression was detected by quantitative real time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). FGFR2 inhibitors response was studied in vitro. RESULTS: Among 556 GC patients, PC GC patients were younger (P = 0.004), had lower tumor mutation burden (TMB-L) (P = 0.001) than non-PC GC. The top 10 most frequently mutated genes in PC GC were TP53 (48%), CDH1 (31%), ARID1A (14%), FGFR2 (14%), ERBB2 (9%), CDKN2A (9%), FGF3 (8%), LRP1B (9%), FGF19 (8%) and FGF4 (8%). Noticeably, FGFR2 is more frequently mutated than non-PC GC (14% vs. 6%, P = 0.037), including copy number variants (CNVs, 12.5%) and gene rearrangements (3.1%, FGFR2/VTI1A and FGFR2/TACC2). Former studies have confirmed that gain of copy number could increase FGFR2 expression and sensitivity to FGFR2 inhibitors in GC. However, no research has verified the function of FGFR2 rearrangements in GC. Our results showed that cell lines of GC transfected with TACC2-FGFR2 fusion had increased mRNA and protein expression of FGFR2, and were more sensitive to FGFR2 inhibitors. FGFR2 inhibitors might be a new therapeutic target for PC GC. In addition, we found patients of PC GC harboring gene rearrangements (n = 9) had poorer overall survival (OS) in comparison with patients without any gene rearrangement (n = 19) (16.0 months vs 21.0 months, P = 0.043). Gene rearrangement might be an adverse prognostic factor for PC GC patients. CONCLUSIONS: FGFR2 alterations were recurrent in PC GC and FGFR2 inhibitors might be a new therapeutic target for PC GC.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Adenocarcinoma/genética , Biomarcadores Tumorais , Proteínas de Transporte , Genes Supressores de Tumor , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Proteínas Supressoras de Tumor
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