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1.
Mol Neurobiol ; 2022 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-35000152

RESUMO

Itching is a common clinical symptom in diabetic patients. This research is to carry out experiments on the pathological changes in the P2Y12 receptor in type 2 diabetes mellitus complicated with chronic itching. Changes in body weight, fasting blood glucose (FBG), thermal hyperalgesia, cold hyperalgesia, spontaneous itching, and sciatic nerve conduction velocity were detected. The content of reactive oxygen species (ROS) in the dorsal root ganglion was detected by chemical fluorescence. The expression of the P2Y12 receptor, NLRP3, ASC, interleukin-1ß (IL-1ß), and IL-18 was detected by Western blotting, real-time quantitative PCR, immunofluorescence double labelling, and enzyme-linked immunosorbent assay. Itching and pain behaviours of the mice in the type 2 diabetes mellitus + itch group were significantly increased, and the expression of P2Y12 and NLRP3 as well as the content of ROS increased, and these changes were significantly reversed by treatment with P2Y12 short hairpin RNA (shRNA) or P2Y12 antagonist ticagrelor. Upregulated P2Y12 receptor expression after the activation of satellite glial cells contributes to the increase in ROS content in vivo, followed by NLRP3 inflammasome activation, increased inflammatory cytokine release, and damage to peripheral nerves, which leads to chronic itching. Treatment with P2Y12 shRNA or ticagrelor can inhibit these pathological changes, thus improving itching behaviour. Development mechanism of diabetes mellitus complicated with chronic itching. Notes: The upregulation of P2Y12 receptor expression and the activation of SGCs lead to the increase of ROS content in vivo, followed by the activation of NLRP3 inflammasome, the increase of inflammatory cytokine release, the abnormal excitation of DRG neurons, and the damage of peripheral nerves, resulting in chronic itching. P2Y12 receptor-related inflammatory injury involves chronic itching in type 2 diabetes mellitus. Treatment with P2Y12 receptor shRNA or P2Y12 antagonist ticagrelor can inhibit these pathological changes and improve itching behaviour.

2.
J Immunol ; 208(2): 501-513, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34911774

RESUMO

Protein arginine methyltransferase 5 (PRMT5) participates in the symmetric dimethylation of arginine residues of proteins and contributes to a wide range of biological processes. However, how PRMT5 affects the transcriptional and epigenetic programs involved in the establishment and maintenance of T cell subset differentiation and roles in antitumor immunity is still incompletely understood. In this study, using single-cell RNA and chromatin immunoprecipitation sequencing, we found that mouse T cell-specific deletion of PRMT5 had greater effects on CD8+ than CD4+ T cell development, enforcing CD8+ T cell differentiation into Klrg1+ terminal effector cells. Mechanistically, T cell deficiency of PRMT5 activated Prdm1 by decreasing H4R3me2s and H3R8me2s deposition on its loci, which promoted the differentiation of Klrg1+CD8+ T cells. Furthermore, effector CD8+ T cells that transited to memory precursor cells were decreased in PRMT5-deficient T cells, thus causing dramatic CD8+ T cell death. In addition, in a mouse lung cancer cell line-transplanted tumor mouse model, the percentage of CD8+ T cells from T cell-specific deletion of PRMT5 mice was dramatically lost, but CD8+Foxp3+ and CD8+PDL1+ regulatory T cells were increased compared with the control group, thus accelerating tumor progression. We further verified these results in a mouse colon cancer cell line-transplanted tumor mouse model. Our study validated the importance of targeting PRMT5 in tumor treatment, because PRMT5 deficiency enforced Klrg1+ terminal CD8+ T cell development and eliminated antitumor activity.

3.
Eur J Pharmacol ; 917: 174728, 2021 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-34965390

RESUMO

Galacto-oligosaccharides (GOS) are commonly used as prebiotic with a variety of known metabolic benefits; however, whether GOS plays a protective role in obesity remains unknown. Here, we demonstrate that GOS prevented obesity in a rat model of obesity induced by a high-fat diet. Our results showed that GOS effectively slowed weight gain in diet-induced obese rats without affecting energy intake. GOS significantly suppressed the hypertrophy and hyperplasia of white adipose tissue and markedly reduced the ratio of the fat/body. Consistently, GOS significantly improved serum total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels, indicating the weight loss activity of GOS. Interestingly, GOS also significantly increased the expression levels of browning proteins, including uncoupling protein 1, peroxisome proliferator-activated receptor-γ, peroxisome proliferator-activated receptor-γ coactivator 1α, and PR domain 16, in both white and brown adipose tissue. Furthermore, we found that GOS markedly increased the expression levels of liver X receptor α, peroxisome proliferation-activated receptor-α, low-density lipoprotein receptor, and cholesterol 7α-hydroxylase proteins in the liver of obese rats. Taken together, we concluded that GOS inhibits obesity by accelerating the browning of white fat cells and the thermogenesis of brown fat cells and that GOS improves host lipid homeostasis by promoting cholesterol catabolism.

4.
Front Genet ; 12: 747274, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777472

RESUMO

Genome-wide association studies have identified >100 genetic risk factors for rheumatoid arthritis. However, the reported genetic variants could only explain less than 40% heritability of rheumatoid arthritis. The majority of the heritability is still missing and needs to be identified with more studies with different approaches and populations. In order to identify novel function SNPs to explain missing heritability and reveal novel mechanism pathogenesis of rheumatoid arthritis, 4 HLA SNPs (HLA-DRB1, HLA-DRB9, HLA-DQB1, and TNFAIP3) and 225 common SNPs located in miRNA, which might influence the miRNA target binding or pre-miRNA stability, were genotyped in 1,607 rheumatoid arthritis and 1,580 matched normal individuals. We identified 2 novel SNPs as significantly associated with rheumatoid arthritis including rs1414273 (miR-548ac, OR = 0.84, p = 8.26 × 10-4) and rs2620381 (miR-627, OR = 0.77, p = 2.55 × 10-3). We also identified that rs5997893 (miR-3928) showed significant epistasis effect with rs4947332 (HLA-DRB1, OR = 4.23, p = 0.04) and rs2967897 (miR-5695) with rs7752903 (TNFAIP3, OR = 4.43, p = 0.03). In addition, we found that individuals who carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, p < 1.0 × 10-6) times more risk of being affected by RA. Finally, we demonstrated that the targets of the significant miRNAs showed enrichment in immune related genes (p = 2.0 × 10-5) and FDA approved drug target genes (p = 0.014). Overall, 6 novel miRNA SNPs including rs1414273 (miR-548ac, p = 8.26 × 10-4), rs2620381 (miR-627, p = 2.55 × 10-3), rs4285314 (miR-3135b, p = 1.10 × 10-13), rs28477407 (miR-4308, p = 3.44 × 10-5), rs5997893 (miR-3928, p = 5.9 × 10-3) and rs45596840 (miR-4482, p = 6.6 × 10-3) were confirmed to be significantly associated with RA in a Chinese population. Our study suggests that miRNAs might be interesting targets to accelerate understanding of the pathogenesis and drug development for rheumatoid arthritis.

5.
Eur J Med Chem ; 226: 113878, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34634742

RESUMO

Cannabinoids are widely studied as therapeutic agents for the treatment of various diseases. Among them, THC and CBD are two important phytocannabinoids which have served as structural templates for the design of synthetic analogs. In this study, we designed and synthesized a variety of novel cannabinoids based on the structural backbones of THC and CBD using the carbon-silicon switch strategy. A dimethyl silyl group was introduced as the tail group and two series of novel compounds were designed and synthesized, which showed a wide range of binding affinity for CB1 and CB2 receptors. Among them, compound 15b was identified as a non-selective CB1 and CB2 agonist and 38b as a selective agonist for the CB2 receptor. Preliminary screening showed that both compounds have improved metabolic stability than their carbon analogs and good in vivo pharmacokinetic profiles. Furthermore, both 15b and 38b significantly alleviated the phenotype of experimental autoimmune encephalomyelitis (EAE) in mice.

6.
J Med Chem ; 64(21): 15949-15972, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34705450

RESUMO

The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein-protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.

7.
J Pharm Pharmacol ; 73(12): 1617-1629, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34718677

RESUMO

OBJECTIVES: This study aimed to discover the active compounds of Sophora flavescens Ait. (SF), the anti-itch effects and underlying mechanisms of oxymatrine (OMT), one of the bioactive compounds from SF. METHODS: Dorsal root ganglion cell membrane immobilized chromatography was used to screen potential anti-pruritic active compounds from SF. The scratching behaviour was analysed to systematically study the anti-pruritic effects of OMT in chloroquine- (CQ), peptide Ser-Leu-Ile-Gly-Arg-Leu- (SLIGRL), histamine- (HIS) and allyl-isothiocyanate-(AITC)-induced itch mice models. Real-time quantitative PCR, in-vivo study and molecular docking were employed to explore the underlying mechanisms. KEY FINDINGS: All in all, 21 compounds of SF were identified and 5 potential bioactive compounds were discovered. OMT significantly reduced scratching bouts in two HIS-independent itch models induced by CQ and SLIGRL but was not effective in the HIS-induced itch model. OMT reduced scratching bouts in a dose-dependent manner and decreased the messenger RNA (mRNA) expression of transient receptor potential ankyrin 1 (TRPA1) channel in two HIS-independent itch models; in addition, OMT reduced the wipes and scratching bouts induced by AITC. CONCLUSIONS: This study discovered five potential anti-pruritic compounds including OMT in the SF extract, and OMT has strong anti-pruritic effects in HIS-independent itch via TRPA1 channel.

8.
Materials (Basel) ; 14(20)2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34683796

RESUMO

With the rapid development of the aerospace field, traditional energy absorption materials are becoming more and more inadequate and cannot meet the requirements of having a light weight, high energy absorption efficiency, and high energy absorption density. Since existing studies have shown that carbon nanotube (CNT) buckypaper is a promising candidate for energy absorption, owing to its extremely high energy absorption efficiency and remarkable mass density of energy absorption, this study explores the application of buckypaper as the landing buffer material in a manned lunar lander. Firstly, coarse-grained molecular dynamics simulations were implemented to investigate the compression stress-strain relationships of buckypapers with different densities and the effect of the compression rate within the range of the landing velocity. Then, based on a self-designed manned lunar lander, buckypapers of appropriate densities were selected to be the energy absorption materials within the landing mechanisms of the lander. For comparison, suitable aluminum honeycomb materials, the most common energy absorption materials in lunar landers, were determined for the same landing mechanisms. Afterwards, the two soft-landing multibody dynamic models are established, respectively, and their soft-landing performances under three severe landing cases are analyzed, respectively. The results depicted that the landers, respectively, adopting the two energy absorption materials well, satisfy the soft-landing performance requirements in all the cases. It is worth mentioning that the lander employing the buckypaper is proved to demonstrate a better soft-landing performance, mainly reflected in reducing the mass of the energy absorption element by 8.14 kg and lowing the maximum center-of-mass overload of the lander by 0.54 g.

9.
Front Pharmacol ; 12: 680139, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512324

RESUMO

Neuropathic pain is a complex disease with high incidence. Adenosine triphosphate (ATP) and its activated P2X7 receptor are involved in the signal transmission of neuropathic pain. Gallic acid (3,4,5-trihydroxybenzoic acid) is a traditional Chinese medicine obtained from natural plants that exhibit anti-inflammatory, analgesic, and antitumor effects. However, the underlying mechanism for gallic acid in analgesia remains unknown. This study aims to reveal how gallic acid alleviates neuropathic pain behaviors in a rat model with chronic constriction injury (CCI). Real-time PCR, western blotting, double-label immunofluorescence, molecular docking, and whole-cell patch clamp technology were used to explore the therapeutic action of gallic acid on neuropathic pain. The results showed that after CCI rats were treated with gallic acid for 1 week, the mechanical withdrawal threshold and thermal withdrawal latency were increased, accompanied by inhibition of the upregulated expression of P2X7 and TNF-α at both mRNA and protein levels, and reduced NF-κB and phosphorylated-STAT3 in the dorsal root ganglia. At the same time, gallic acid significantly decreased the coexpression of P2X7 and glial fibrillary acidic protein in the dorsal root ganglia. In addition, gallic acid could suppress ATP-activated current in human embryonic kidney 293 (HEK293) cells transfected with the plasmid expressing P2X7 but had no effect on ATP activation current of P2X7-mutant plasmid (with the point mutation sequence of the key site where gallic acid binds to the P2X7 receptor). Therefore, our work suggests that gallic acid may alleviate neuropathic pain in CCI rats by inhibiting the P2X7 receptor and subsequent activation of the TNF-α/STAT3 signaling pathway.

10.
Theranostics ; 11(18): 9162-9176, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522232

RESUMO

Rationale: Protein arginine methyltransferase 5 (PRMT5) is an oncogene that promotes tumor cell proliferation, invasion and metastasis. However, the underlying mechanisms by which PRMT5 contributes to the progression of cervical cancer and especially the tumor microenvironment remain poorly understood. Methods: PRMT5 expression level was analyzed by Q-PCR, western blot, immunohistochemistry, and TCGA database. The role of PRMT5 in tumor growth was observed by transplanted tumor models, and the function of T cells in tumor microenvironment and in vitro co-culture system was investigated through flow cytometry. The transcriptional regulation of PRMT5 was analyzed using luciferase reporter and chromatin immunoprecipitation (ChIP) assay. The therapeutic effect of PRMT5 inhibitor was evaluated in a cervical cancer cell line transplanted tumor model. Results: We observed that the mRNA and protein expression levels of PRMT5 were increased in cervical cancer tissues, and the high expression of PRMT5 was associated with poor outcomes in cervical cancer patients. The absence of PRMT5 significantly inhibited tumor growth in a cervical cancer transplanted tumor model, and importantly, PRMT5 absence in tumors led to increase the number and enhance the function of tumor infiltrating T cells. Mechanistically, PRMT5 enhanced the transcription of STAT1 through symmetric dimethylation of histone H3R2 and thus promoted PD-L1 expression in cervical cancer cells. Moreover, in an in vitro co-culture system, knockdown of PRMT5 in tumor cells could directly enhance the expression of IFN-γ, TNF-α and granzyme B in T cells. These results suggested that PRMT5 promoted the development of cervical cancer by the crosstalk between tumor cells and T cells. Furthermore, the PRMT5 inhibitor EPZ015666 treatment could suppress tumor growth in a cervical cancer transplanted tumor model. Conclusion: Our results clarify a new mechanism which PRMT5 knockdown in cervical cancer cells drives an antitumor function via reprogramming T cell-mediated response and regulating PD-L1 expression. Thus, our study highlights that PRMT5 may be a potential target for cervical cancer therapy.

11.
J Insect Physiol ; 132: 104264, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34081960

RESUMO

Visible genetic markers are critical to gene function studies using genome editing technology in insects. However, there is no report about visible phenotypic markers in Apis mellifera, which extremely influences the application of genomic editing in honey bees. Here, we cloned and characterized the Amyellow-y gene in A. mellifera. Stage expression profiles showed that Amyellow-y gene was highly expressed in 2-, 4-day-old pupae, and newly emerged bees, and a high expression level was detected in the leg, thorax, wing and sting. To understand its functional role in pigmentation, Amyellow-y edited honeybees were created using CRISPR/Cas9, and it was found that the black pigment was decreased in the cuticle of mosaic workers and mutant drones. In particular, mutant drones manifested an overall appearance of yellowish cuticle in the body and appendages, including antennae, wings and legs, indicating that mutagenesis induced by disruption of Amyellow-y with CRISPR/Cas9 are heritable. Furthermore, the expression levels of genes associated with melanin pigmentation was investigated in mutant and wild-type drones using quantitative reverse transcription PCR. Transcription levels of Amyellow-y and aaNAT decreased markedly in mutant drones than that in wild-type ones, whereas laccase 2 was significantly up-regulated. Our results provide the first evidence, to our knowledge, that CRISPR/Cas9 edited G1 mutant drones of A. mellifera have a dramatic body pigmentation defect that can be visualized in adults, suggesting that Amyellow-y may serve as a promising visible phenotypic marker for genome editing in honey bees.


Assuntos
Abelhas/genética , Sistemas CRISPR-Cas , Edição de Genes/métodos , Marcadores Genéticos , Animais , Abelhas/metabolismo , Genes de Insetos , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Melaninas , Pigmentação/genética , Fatores de Transcrição/genética
12.
Neurol Sci ; 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34052937

RESUMO

OBJECTIVE: Bipolar disorder (BD) may be associated with an increased risk of stroke, but to date, the results of the studies are still controversial. This study aimed to assess the association of BD with stroke incidence and mortality by a meta-analysis. METHOD: PubMed, EMBASE, the Cochrane library databases, and Web of Science databases were searched from inception to July 2020. We regarded stroke as a composite endpoint. The pooled hazard ratio (HRs) of 95% confidence interval (Cls) was calculated. Subgroup and sensitivity analyses were performed to assess the potential sources of heterogeneity of the pooled estimation. RESULTS: A total of 7 studies involving a total of 13,305,007 participants were included in this meta-analysis. Pooled analysis showed participants with BD experienced a significantly increased risk of both stroke incidence (combined HR, 1.43; 95% CI, 1.24-1.66; p = 0.000) and stroke mortality (combined HR, 1.54; 95% CI, 1.09-2.18; p = 0.013) compared to participants without BD. In addition, the pooled estimate of multivariate HRs of stroke incidence and mortality were 1.35 (95% CI: 1.26-1.45); 2.30 ( 95% CI: 1.37-3.85) among men and 1.43 (95% CI:1.27-1.60); 2.08 (95% CI:1.60-2.71) among women respectively. CONCLUSIONS: This meta-analysis suggests that BD may modestly increase the risk of both stroke incidence and mortality. Extensive clinical observational studies should be conducted in the future to explore whether BD is a potentially modifiable risk factor for stroke.

13.
Immunology ; 164(1): 161-172, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33934341

RESUMO

The IL-7/IL-7R pathway plays a vital role in the immune system, especially in the inflammatory response. Monocytes/macrophages (osteoclast precursors) have been recently recognized as important participants in the osteoclastogenesis of rheumatoid arthritis (RA) patients. Here, we aimed to investigate the therapeutic potential of IL-7/IL-7R pathway in RA and to determine whether it could restrain osteoclastogenic functions and therefore ameliorate RA. Firstly, collagen-induced arthritis (CIA) mice were administered with IL-7Rα-target antibodies to assess their therapeutic effect on arthritis. We found that blockade of the IL-7/IL-7R pathway protected CIA mice from bone destruction in addition to inducing inflammatory remission, by altering the RANKL/RANK/OPG ratio and consequently decreasing osteoclast formation. To explore the effect and mechanism of this pathway, bone marrow cells were induced to osteoclasts and treated with IL-7, a STAT5 inhibitor or supernatants from T cells. The results showed that the IL-7/IL-7R pathway played a direct inhibitory role in osteoclast differentiation via STAT5 signalling pathway in a RANKL-induced manner. We applied flow cytometry to analyse the effect of IL-7 on T-cell RANKL expression and found that IL-7/IL-7R pathway had an indirect role in the osteoclast differentiation process by enhancing the RANKL expression on T cells. In conclusion, the IL-7/IL-7R pathway exhibited a dual effect on osteoclastogenesis of CIA mice by interacting with osteoimmunology processes and could be a novel therapeutic target for autoimmune diseases such as RA.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Interleucina-7/metabolismo , Macrófagos/fisiologia , Osteoclastos/fisiologia , Receptores de Interleucina-7/metabolismo , Linfócitos T/metabolismo , Animais , Anticorpos Bloqueadores/metabolismo , Diferenciação Celular , Modelos Animais de Doenças , Humanos , Interleucina-7/genética , Camundongos , Terapia de Alvo Molecular , Osteogênese , Ligante RANK/metabolismo , Receptores de Interleucina-7/imunologia , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais
14.
J Geriatr Cardiol ; 18(4): 261-270, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33995505

RESUMO

BACKGROUND: The efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors were confirmed by several clinical trials, but its effectiveness in routine clinical practice in China has not been evaluated. This study aims to describe the real world effectiveness of PCSK-9 inhibitors combined with statins compared with statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease (ASCVD). METHODS: This is a multi-center observational study, enrolled patients from 32 hospitals who underwent percutaneous coronary intervention (PCI) from January to June in 2019. There are 453 patients treated with PCSK-9 inhibitors combined with statins in PCSK-9 inhibitor group and 2,610 patients treated with statins-based lipid lowering therapies in statins-based group. The lipid control rate and incidence of major adverse cardiovascular events (MACE) over six months were compared between two groups. A propensity score-matched (PSM) analysis was used to balance two groups on confounding factors. Survival analysis using Kaplan-Meier methods was applied for MACE. RESULTS: In a total of 3,063 patients, 89.91% of patients had received moderate or high-intensity statins-based therapy before PCI, but only 9.47% of patients had low-density lipoprotein cholesterol (LDL-C) levels below 1.4 mmol/L at baseline. In the PSM selected patients, LDL-C level was reduced by 42.57% in PCSK-9 inhibitor group and 30.81% (P < 0.001) in statins-based group after six months. The proportion of LDL-C ≤ 1.0 mmol/L increased from 5.29% to 29.26% in PCSK-9 inhibitor group and 0.23% to 6.11% in statins-based group, and the proportion of LDL-C ≤ 1.4 mmol/L increased from 10.36% to 47.69% in PCSK-9 inhibitor group and 2.99% to 18.43% in statins-based group ( P < 0.001 for both). There was no significant difference between PCSK-9 inhibitor and statins-based treatment in reducing the risk of MACE (hazard ratio = 2.52, 95% CI: 0.49-12.97, P = 0.250). CONCLUSIONS: In the real world, PCSK-9 inhibitors combined with statins could significantly reduce LDL-C levels among patients with very high risk of ASCVD in China. The long-term clinical benefits for patients received PCSK-9 inhibitor to reduce the risk of MACE is still unclear and requires further study.

15.
Dalton Trans ; 50(15): 5244-5250, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33881082

RESUMO

By regulating the solvent used for synthesis, two porous Ni-MOFs, namely {[Ni3(BTC)2(TPT)2/3(H2O)4.08(MeOH)0.92]·2DMF·0.5H2O·0.5MeOH}n (1) and {[Ni3(BTC)2(TPT)2(H2O)6]·6DMF}n (2) (H3BTC = 1,3,5-benzenetricarboxylic acid, TPT = 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine, DMF = N,N-dimethylformamide, and MeOH = methanol) were obtained. Compound 1 reveals a rigid 3D framework, while compound 2 shows a flexible 3-fold interpenetrated framework. Compound 1 exhibits a selective adsorption of CO2 due to the sieving effect of the rigid framework containing two types of cages with small apertures. Noteworthily, the flexible compound 2 displays an obviously guest-induced structural transformation. The desolvated compound 2 reveals a much higher capacity toward CO2 and n-C4H10 than those of N2 CH4, C2H6 and C3H8.

16.
Int J Mol Sci ; 22(7)2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800699

RESUMO

Rheumatoid arthritis (RA) is a complex systemic autoimmune disorder that primarily involves joints, further affects the life quality of patients, and has increased mortality. The pathogenesis of RA involves multiple pathways, resulting in some patients showing resistance to the existing drugs. Salubrinal is a small molecule compound that has recently been shown to exert multiple beneficial effects on bone tissue. However, the effect of Salubrinal in RA has not been clearly confirmed. Hence, we induced collagen-induced arthritis (CIA) in DBA/1J mice and found that Salubrinal treatment decreased the clinical score of CIA mice, inhibiting joint damage and bone destruction. Furthermore, Salubrinal treatment downregulated osteoclast number in knee joint of CIA in mice, and suppressed bone marrow-derived osteoclast formation and function, downregulated osteoclast-related gene expression. Moreover, Salubrinal treatment inhibited RANKL-induced NF-κB signaling pathway, and promoted P65 degradation through the ubiquitin-proteasome system, further restrained RANKL-induced osteoclastogenesis. This study explains the mechanism by which Salubrinal ameliorates arthritis of CIA in mice, indicating that Salubrinal may be a potential drug for RA, and expands the potential uses of Salubrinal in the treatment of bone destruction-related diseases.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Cinamatos/farmacologia , Osteoclastos/metabolismo , Osteogênese , Tioureia/análogos & derivados , Fator de Transcrição RelA/metabolismo , Animais , Células da Medula Óssea/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Complexo de Endopeptidases do Proteassoma/química , Ligante RANK/metabolismo , Células RAW 264.7 , Transdução de Sinais , Frações Subcelulares/metabolismo , Tioureia/farmacologia , Ubiquitina/química
17.
Food Chem Toxicol ; 153: 112244, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33930484

RESUMO

Methylglyoxal (MGO), a cytotoxic byproduct of glycolysis in biological systems, can induce endothelial cells dysfunction, implicated in diabetic vascular complications. Pterostilbene (PTS), a naturally occurring resveratrol derivative, is involved in various pharmacological activities. This study aimed to explore the effects of PTS on MGO induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) and the underlying mechanisms for the first time. In the current study, it has been demonstrated that PTS could enhance the level of glyoxalase 1 (GLO-1) and elevate glutathione (GSH) content to active the glyoxalase system, resulting in elimination of the toxic MGO as well as advanced glycation end products (AGEs) in HUVECs. Meanwhile, PTS could also suppress oxidative stress and thus exert cytoprotective effects by elevating Nrf2 nuclear translocation and the corresponding down-stream antioxidant enzymes in MGO induced HUVECs. In addition, PTS could alleviate MGO induced apoptosis in HUVECs via inhibition of oxidative stress and associated downstream mitochondria-dependent signaling apoptotic cascades, as characterized by preventing caspases family activation. Taken together, these findings suggest that PTS could protect against MGO induced endothelial cell cytotoxicity by regulating glyoxalase, oxidative stress and apoptosis, suggesting that PTS could be beneficial in the treatment of diabetic vascular complications.


Assuntos
Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Lactoilglutationa Liase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Aldeído Pirúvico/toxicidade , Estilbenos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Lactoilglutationa Liase/genética , Espécies Reativas de Oxigênio
18.
ACS Chem Neurosci ; 12(7): 1210-1218, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33733741

RESUMO

Diabetic cardiac autonomic neuropathy (DCAN) is a complication that affects more than 60% of diabetic patients. There is evidence for the involvement of P2X4 receptor in DCAN. This study showed that the expression of the long noncoding RNA (lncRNA) UC.360+ was increased in the stellate ganglion (SG) of type 2 diabetes mellitus (DM) rats, and in situ hybridization revealed a clear presence of UC.360+ in SG neurons. The potential roles of UC.360+ in DCAN and its relationship with P2X4 receptor in SG were further explored via application of the short hairpin RNA (shRNA) against lncRNA UC.360+ in DM rats. The abnormal cardiac sympathetic changes in diabetic rats were improved after treatment with lncRNA UC.360+ shRNA. In the SG of these shRNA-treated DM rats, the upregulation of P2X4, tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß), and phosphorylated ERK1/2 was inhibited. Thus, lncRNA UC.360+ shRNA treatment may improve DCAN mediated by the P2X4 receptor in SG.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , RNA Longo não Codificante , Animais , Humanos , RNA Longo não Codificante/genética , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X4 , Gânglio Estrelado
19.
Dalton Trans ; 50(11): 4028-4035, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33662080

RESUMO

Three series of copper hydride clusters [Cu8H6L6]2+ (1), [Cu4HX2L4]+ where X- = Cl- (2a), Br- (2b), I- (2c), N3- (2d) and SCN- (2e), and [Cu4HX3L3] where X- = Br- (3b) and I- (3c) (L = 2-(diphenylphosphino)pyridine, dppy) were synthesized and characterized by single-crystal X-Ray crystallography and standard spectroscopic techniques. The metal core of 1, Cu8, can be described as a bicapped octahedron, while those of 2 and 3 series adopt tetrahedral structures. The hydride positions were deduced from difference electron density maps and corroborated by NMR and DFT calculations. For 1, there are two µ4-H-, one each in the two tetrahedral cavities of the two capping atoms and four µ3-H- on the six triangular faces around the waist of the octahedron. For [Cu4HX2L4]+ and [Cu4HX3L3] series, the single µ4-H- resides in the center of the Cu4 tetrahedron. It was found that these three series of copper clusters are intimately connected and can convert from one to another under specific reaction conditions. Their transformation pathways were investigated in detail. Spontaneous resolution to form optically pure enantiomeric single crystals was observed for [Cu4H(SCN)2L4]+ (2e) and [Cu4HBr3L3] (3b). Photoluminescence was observed for [Cu4HX2L4]+, as well as [Cu4HX3L3] with strong emissions from green to yellow regions.

20.
Neurol Sci ; 42(11): 4521-4529, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33606128

RESUMO

BACKGROUND: Many studies have described the relationship between kidney stones and stroke, but the results are controversial, so we conducted this meta-analysis to estimate the relationship between kidney stones and the risk of developing stroke. METHODS: Studies were marked with a comprehensive search of PubMed, EMBASE, Google, and ISI Web of Science databases through 25 March 2020. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted, and a random-effects model or fix-effects model was used to compute the pooled combined risk estimate. Heterogeneity was reported as I2. We performed subgroup and sensitivity analysis to assess potential sources of heterogeneity. RESULTS: Eight studies of seven articles involving 3,526,808 participants were included in the meta-analysis. Overall, kidney stones were associated with a moderate risk of stroke incidence (HR, 1.24; 95% CI, 1.11-1.40; I2=79.6%; p=0.000). We conducted a sensitivity analysis by removing the studies that had a high risk of bias. Heterogeneity subsequently decreased significantly, while an increased risk of stroke in patient with kidney stones was again demonstrated (HR, 1.16; 95% CI, 1.11-1.23; I2=28.7%; p=0.000). Stratifying analysis showed that the results were more pronounced for ischemic stroke (HR, 1.14; 95% CI, 1.08-1.22; I2=15.6%; p=0.00) and the follow-up duration ≥10 years (HR, 1.18; 95% CI, 1.10-1.27; I2=31.6%; p=0.003). CONCLUSIONS: Our meta-analysis suggests that patients with kidney stones may have a modestly increased risk of developing stroke, especially in ischemic stroke. More large-scaled and clinical trials should be done to identify the relative impact of kidney stones on stroke outcomes in the future.


Assuntos
Cálculos Renais , Acidente Vascular Cerebral , Humanos , Incidência , Cálculos Renais/epidemiologia , Acidente Vascular Cerebral/epidemiologia
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