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1.
J Ethnopharmacol ; 264: 113206, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32750460

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Berberine is generally extracted from Rhizoma Coptidis (Coptis chinensis Franch), a traditional Chinese medicine, which can be used in the treatment of intestinal diseases, respiratory infections and cardiovascular diseases. Berberine is especially effective for the treatment of gastrointestinal disorders such as diarrhea because of the effect of heat-clearing and detoxifying in traditional Chinese medicine theory. AIM OF THE STUDY: This study aimed to examine the protective effect of berberine (BBR) on the damaged colonic epithelial barrier caused by peritoneal dialysis fluid (PDF). METHODS: The damage to intestinal epithelial barrier was examined by intraperitoneally injecting 4.25% dextrose-containing PDF in mice and establishing a long-term PD model in rats with renal failure. Then, the therapeutic potential of berberine on PD-related colonic injuries was examined. T84 colonic epithelial cells were used to test the effect of PDF and berberine in vitro. The damaging effect of PDF and the protective effect of berberine were evaluated by histology staining, histofluorescence and transmission electron microscopy. The migration of colonic epithelial cell and actin-related protein 2 (Arp2) were tested by wound healing assay and Western blot to determine the possible mechanism in vitro. RESULTS: PD administration induced intestinal epithelial barrier dysfunction in the colon, and berberine alleviated the injury by increasing the tight junction and adhesion junction protein, both in vivo and in vitro. Berberine could also improve the morphology of microvillus. In the wound healing assay, berberine exhibited the ability to promote cell migration, indicating that berberine could probably recover the function of intestinal epithelial cells when the intestinal epithelial barrier was damaged by the PDF. CONCLUSIONS: The present study demonstrates that berberine can ameliorate intestinal epithelial barrier dysfunction in the colon caused by long-term PDF through improving cell migration.

2.
Nat Commun ; 11(1): 6020, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-33243995

RESUMO

Understanding the structure and function of vasculature in the brain requires us to monitor distributed hemodynamics at high spatial and temporal resolution in three-dimensional (3D) volumes in vivo. Currently, a volumetric vasculature imaging method with sub-capillary spatial resolution and blood flow-resolving speed is lacking. Here, using two-photon laser scanning microscopy (TPLSM) with an axially extended Bessel focus, we capture volumetric hemodynamics in the awake mouse brain at a spatiotemporal resolution sufficient for measuring capillary size and blood flow. With Bessel TPLSM, the fluorescence signal of a vessel becomes proportional to its size, which enables convenient intensity-based analysis of vessel dilation and constriction dynamics in large volumes. We observe entrainment of vasodilation and vasoconstriction with pupil diameter and measure 3D blood flow at 99 volumes/second. Demonstrating high-throughput monitoring of hemodynamics in the awake brain, we expect Bessel TPLSM to make broad impacts on neurovasculature research.

3.
Cell Chem Biol ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33186541

RESUMO

Pioneering microbial genomic surveys have revealed numerous untapped biosynthetic gene clusters, unveiling the great potential of new natural products. Here, using a combination of genome mining, mutasynthesis, and activity screening in an infection model comprising Caenorhabditis elegans and Pseudomonas aeruginosa, we identified candidate virulence-blocking amychelin siderophore compounds from actinomycetes. Subsequently, we developed unreported analogs of these virulence-blocking siderophores with improved potency by exploiting an Amycolatopsis methanolica strain 239T chorismate to salicylate a biosynthetic subpathway for mutasynthesis. This allowed us to generate the fluorinated amychelin, fluoroamychelin I, which rescued C. elegans from P. aeruginosa-mediated killing with an EC50 value of 1.4 µM, outperforming traditional antibiotics including ceftazidime and meropenem. In general, this paper describes an efficient platform for the identification and production of classes of anti-microbial compounds with potential unique modes of action.

5.
J Appl Toxicol ; 40(11): 1480-1490, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33020912

RESUMO

As an organophosphorus ester, tri-ortho-cresyl phosphate (TOCP) has been widely used in agriculture and industry. It is reported that TOCP can induce organophosphate-induced delayed neuropathy (OPIDN) in sensitive animal and human species. However, the exact molecular mechanisms underlying TOCP-induced neurotoxicity are still unknown. In this study, we found that TOCP could induce autophagy by activating protein kinase C alpha (PKCα) signaling in neuroblastoma SK-N-SH cells. PKCα activators could positively regulate TOCP-induced autophagy by increasing the expression levels of neighbor BRCA1 gene protein 1 (NBR1), LC3 and P62 autophagic receptor protein. Furthermore, PKCα activation impaired the ubiquitin-proteasome system (UPS), resulting in inhibition of proteasome activity and accumulation of ubiquitinated proteins. UPS dysfunction could stimulate autophagy to serve as a compensatory pathway, which contributed to the accumulation of the abnormally hyperphosphorylated tau proteins and degradation of impaired proteins of the MAP 2 and NF-H families in neurodegenerative disorders.

6.
Molecules ; 25(18)2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32962058

RESUMO

A co-crystal of rosiglitazone (Rsg) with berberine (Bbr), Rsg-Bbr, was prepared by the solvent evaporation method and characterized. The results showed that the electrostatic attraction existed between the nitrogen anion of rosiglitazone and the quaternary ammonium cation of berberine, and C-H···O hydrogen bonds were formed between Rsg and Bbr. In the crystal structure, rosiglitazone molecules stack into a supramolecular layer through π-π interactions while π-π interactions between berberine cations also result in a similar layer. The co-crystal presented a low moisture adsorption curve in the range of 0-95% relative humidity values at 25 °C. The improved dissolution rate of rosiglitazone in pH = 6.8 buffer solution could be achieved after forming co-crystal.

7.
Ann Palliat Med ; 9(5): 3222-3234, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32921119

RESUMO

BACKGROUND: An accurate assessment of the severity and prognosis of sepsis, especially septic shock, is vital for the tailored treatment of this condition. miRNA participates in the inflammatory response and cell apoptosis and regulates inflammation-related signaling pathways. Immune disorders often accompany sepsis. Since serum miRNA expression is superior to traditional biological markers in terms of sensitivity and specificity, its role in the assessment of sepsis has increasingly been recognized. METHODS: Serum miRNAs were extracted from septic patients and healthy individuals by using the ultracentrifugation method. The differential expressions of miRNAs in the serum samples were detected by high-throughput sequencing technology. The differentially expressed miRNAs between the two groups were analyzed by bioinformatics. The quantitative polymerase chain reaction real-time polymerase chain reaction (qRT-PCR) was used to amplify the sample size to verify the results and to screen the highly-expressed miR206 in septic patients. Subsequently, serum samples were collected from 63 septic patients, and 30 patients with septic shock and qRT-PCR were performed to analyze the expression of miR-206. These 93 patients were divided into the miR-206 low-expression group and miR-206 high-expression group according to miR206 expression level. The potential correlations between the miR-206 expression and the clinical data were analyzed by using SPSS 25.0. RESULTS: Serum miRNA expression significantly differed between septic patients and healthy individuals. High-throughput sequencing results showed that, compared with those in healthy individuals, 29 miRNA molecules were down-regulated, and 25 molecules were up-regulated in the serum samples of septic patients. qRT-PCR identified the significantly up-regulated miR-206 in septic patients. qRT-PCR also showed significantly higher miR-206 expression levels in patients with septic shock than in septic patients. Furthermore, we observed a significantly longer prothrombin time and activated partial thromboplastin time, and significantly higher SOFA score, APACHE-II score, and in-hospital mortality rate. miR-206 was positively correlated with SOFA sore and APACHE-II score. CONCLUSIONS: Serum miR-206 expression is positively correlated with the severity and prognosis of sepsis. Thus, it may be a potential biomarker for assessing the severity and prognosis of sepsis, although the specific mechanism warrants further investigations.

8.
Int J Biol Macromol ; 163: 1759-1767, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32961183

RESUMO

Leucine-rich repeat-containing genes (LRRs) have been reported to play important roles in responses to diseases. However, we poorly understood the response of LRRs to Fusarium wilt infection in tung tree (Vernicia fordii), which is an important economic tree. Here, 437 LRR-containing proteins containing nine types of LRR domains were identified in V. fordii genome. Phylogenetic analysis suggested that nine types of LRR domains could not be divided into separate classes, implying that these LRR domains had a common origin. Totally, 27 LRRs were related to possible resistance to Fusarium wilt after 2, 8, and 13 days post-inoculation. We further found that Vf06G1605 was up-regulate under Fusarium wilt infection after these three time points, Vf10G1602 and Vf02G1413 were up-regulated at 8, and 13 dpi, while Vf07G2320 was down-regulated at these three time points. The WGCNA and promoter elements suggested that WRKY possibly regulate the responses of LRRs to Fusarium wilt infection. This study highlighted the phylogeny and function of LRRs in V. fordii and provided a systematic analysis of these genes in the V. fordii genome. Our results presented here might clearly illustrate physiological mechanisms of resistance to Fusarium wilt infection and the target of marker-assisted breeding in V. fordii.

9.
J Matern Fetal Neonatal Med ; : 1-8, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967476

RESUMO

INTRODUCTION: Omega-3 fatty acids plus vitamin (e.g. vitamin D and E) may be beneficial to treat gestational diabetes mellitus (GDM), and we aimed to study the influence of omega-3 fatty acids plus vitamin versus placebo on the treatment efficacy of GDM. METHODS: We searched the databases including PubMed, Embase, and the Cochrane Central Register of Controlled Trials, and randomized controlled trials (RCTs) assessing the influence of omega-3 fatty acids and vitamins combination supplementation versus placebo on metabolic status of GDM were included. RESULTS: Five RCTs were included in the meta-analysis. Compared with control intervention for women with GDM or prediabetes, omega-3 fatty acids plus vitamin substantially reduced fasting plasma glucose (FPG, mean difference [MD] = -11.25; 95% confidence intervals [CI] = -13.73 to -8.77; p < .00001), insulin (MD=-6.16; 95% CI=-7.92 to -4.39; p < .00001), homeostasis model of assessment-insulin resistance (HOMA-IR, MD = 173.51; 95% CI = 164.72 to 182.30; p < .00001) and triglycerides (MD = 173.51; 95% CI = 164.72 to 182.30; p < .00001), as well as increased total antioxidant capacity (TAC, MD = 173.51; 95% CI = 164.72 to 182.30; p < .00001), but revealed no significant impact on total cholesterol (MD = 173.51; 95% CI = 164.72 to 182.30; p < .00001), low­density lipoprotein cholesterol (LDL-C, MD = 173.51; 95% CI = 164.72 to 182.30; p < .00001), preterm delivery (OR = 173.51; 95% CI = 164.72 to 182.30; p < .00001) or macrosomia > 4000 g (OR = 173.51; 95% CI = 164.72 to 182.30; p < .00001). CONCLUSIONS: The supplementation of omega-3 fatty acids in combination with vitamin D or E can improve glycemic control, alleviate oxidative stress, and reduce triglycerides, but had no effects on total cholesterol, preterm delivery or macrosomia > 4000 g in women with GDM or prediabetes.

10.
Cell Mol Neurobiol ; 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968928

RESUMO

Parkinson's disease (PD) seriously threatens human's health. Researches have shown a close correlation between long non-coding RNAs (lncRNAs) and PD. However, the biological function of lncRNA homeobox transcript antisense RNA (HOTAIR) in PD remains largely unknown. In this study, we established PD models in vivo and in vitro by using 1-methyl-4-phenyl-2, 3, 6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) to assess the role of HOTAIR in pyroptotic cell death and neuronal damage. RNA immunoprecipitation (RIP) and dual luciferase reporter assay were used to verify the interaction between miR-326 and HOTAIR or ELAV like RNA binding protein 1 (ELAVL1). LncRNA HOTAIR was upregulated in PD mice and MPP+ induced SH-SY5Y cells. Additionally, knockdown of HOTAIR notably attenuated the symptom of PD in vivo. Downregulation of HOTAIR could obviously promoted cell viability and suppressed NLR family pyrin domain containing 3 (NLRP3) mediated pyroptotic cell death of SH-SY5Y cells in the presence of MPP+. Further, lncRNA HOTAIR positively regulated ELAVL1 expression by targeting miR-326, and downregulation of HOTAIR or ELAVL1 notably suppressed promotive effects of miR-326 inhibitor on MPP+ induced pyroptosis via activation of NLRP3 inflammasome. Collectively, HOTAIR silencing significantly inhibits neuronal damage through repressing NLRP3 mediated pyroptosis activation via regulation of miR-326/ELAVL1 axis in PD, which may contribute to a better understanding of PD pathogenesis and provide new treatment strategies for this disease.

11.
Neural Plast ; 2020: 8838498, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922447

RESUMO

Background: Stroke can lead to disruption of the whole-brain network in patients. Acupuncture can modulate the functional network on a large-scale level in healthy individuals. However, whether and how acupuncture can make a potential impact on the disrupted whole-brain network after ischemic stroke remains elusive. Methods: 26 stroke patients with a right hemispheric subcortical infarct were recruited. We gathered the functional magnetic resonance imaging (fMRI) from patients with stroke and healthy controls in the resting state and after acupuncture intervention, to investigate the instant alterations of the large-scale functional networks. The graph theory analysis was applied using the GRETNA and SPM12 software to construct the whole-brain network and yield the small-world parameters and network efficiency. Results: Compared with the healthy subjects, the stroke patients had a decreased normalized small-worldness (σ), global efficiency (E g), and the mean local efficiency (E loc) of the whole-brain network in the resting state. There was a correlation between the duration after stroke onset and E loc. Acupuncture improved the patients' clustering coefficient (C p) and E loc but did not make a significant impact on the σ and E g. The postacupuncture variables of the whole-brain network had no association with the time of onset. Conclusion: The poststroke whole-brain network tended to a random network with reduced network efficiency. Acupuncture was able to modulate the disrupted patterns of the whole-brain network following the subcortical ischemic stroke. Our findings shed light on the potential mechanisms of the functional reorganization on poststroke brain networks involving acupuncture intervention from a large-scale perspective.

12.
Mol Genet Genomics ; 295(6): 1547-1558, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32915308

RESUMO

MicroRNAs (miRNAs) are key in the post-transcriptional regulation of gene expression and thus characterization of miRNAs and investigation of the relative abundance and specificity of tissue expression are essential for understanding gene expression in the golden snub-nosed monkey (GSM, Rhinopithecus roxellanae). Here, we report the first dataset of GSM miRNAs where we identified 460 miRNAs in seven tissues, with 246 conserved known mature miRNAs and 214 novel mature miRNAs. We determined miRNA abundance and expression in the seven tissues using a Tissue Specificity Index score and found that most novel GSM miRNAs showed a highly tissue-specific expression pattern. In particular, 67 novel miRNAs and the miR-34 family were expressed in abundance only in the lung. Five known miRNAs were highly abundant in digestive organs such as the pancreas and liver, and four novel miRNAs were highly expressed in the heart and muscle. Annotation of target genes of GSM miRNAs indicated that target genes were enriched in many important pathways, such as the HIF-1 signaling pathway and xenobiotic biodegradation-related pathways. Collectively, these results emphasize that miRNAs play important roles in GSM diet and high-elevation adaptation regulation. In summary, this study provides essential information on GSM miRNAs and will benefit further investigations of the function and mechanism of miRNAs in controlling gene expression in the GSM.


Assuntos
Adaptação Fisiológica , Colobinae/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , MicroRNAs/genética , Animais , Masculino , Especificidade de Órgãos
13.
Artigo em Inglês | MEDLINE | ID: mdl-32813491

RESUMO

Titanium dioxide (TiO2) is one of the most promising candidates for photoelectrochemistry applications. For a high photoelectrochemistry performance, the control of crystal structure and crystal facet is essential. The phase transformation of TiO2 is conventionally achieved by thermal annealing. Here, we report an approach for selective phase transformation of TiO2 containing exposed reactive facets with improved photoelectrochemistry performance. After femtosecond laser processing, TiO2 nanotubes with exposed reactive anatase {010} facets are prepared, and they have a maximum photocurrent density more than 5 times that of pure anatase. Additionally, this strategy can induce phase transformation in a selective area, which shows the advantages of patterning processing. Our method constructs a promising strategy for preparing functional nanomaterials with high performances and functionality.

14.
Biochimie ; 177: 40-49, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32800897

RESUMO

Mesenchymal stromal cell (MSC)-derived exosome therapy has emerged as an effective therapy strategy for the pathological scar formation. However, the underlying mechanisms have not been completely understood. In the current study, we investigate the therapeutic effect of TSG-6 modified MSC-derived exosomes on a mouse full-thickness wound model and provide evidence of a possible mechanism for MSC-derived exosomes to prevent from scar formation. Overexpression and knockdown of TSG-6 were conducted by lentivirus infection into hBMSCs. Exosomes were isolated from cell culture and identified by transmission electron microscopy and Western blot. C57BL/6J mice were performed of full-thickness skin wounds and treated with exosomal suspension or TSG-6-neutralizing antibody. H&E staining was subjected to observe the pathological changes of scar tissues. Immunohistochemistry, ELISA, real time-PCR and Western blot were applied to detect the expressions of relevant molecules. The results showed that subcutaneous injection of TSG-6 overexpressed MSC-derived exosomes effectively ameliorated scar pathological injury, decreased inflammatory molecular secretion and attenuated collagen deposition in a mouse skin wound model. Reversely, knockdown of TSG-6 abrogated the therapeutic effect of MSC-derived exosomes on scarring. Moreover, TSG-6-neutralizing antibody counteracted the effect of TSG-6 overexpressed MSC-derived exosomes in preventing scar formation. In conclusion, we demonstrated that exosomes derived from TSG-6 modified MSCs suppressed scar formation via reducing inflammation and inhibiting collagen deposition.

15.
Anim Genet ; 51(5): 731-740, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32767694

RESUMO

The Tibetan chicken is a native Chinese breed that lives at high elevations and has adapted to the extreme environmental conditions of the Tibetan Plateau. However, its hypoxic adaptation at the gene expression level is unclear. Here, we sequenced nine lung transcriptomes of the Tibetan chicken at three developmental stages (5 and 42 weeks and 4.5 years). A total of 1.02 billion clean reads were obtained. We identified 16 012 mRNAs and 6898 lncRNAs. The expression of mRNA showed that nine samples were significantly divided into three clusters, with higher correlation and closer relationship between the 5 and 42 week groups. We identified 399 differentially expressed genes (DEGs) between the 5 and 42 week groups, 3532 DEGs between the 5 week and 4.5 year groups, and 3909 DEGs between the 42 week and 4.5 year groups. The up-regulated DEGs in the 5 week group, compared with 42 week and 4.5 year groups, were enriched in GO terms associated with growth and development, whereas the up-regulated DEGs in the 4.5 year group were mainly enriched in many metabolic-related categories. Moreover, the enrichment results with up-regulated DEGs in the 5 and/or 42 week groups, compared with the 4.5 year group, were associated with hypoxic adaptation, such as oxygen transport, oxygen binding and oxygen carrier activity, and calcium signaling pathway. In addition, we identified 978 high-correlation lncRNA and protein-coding gene pairs, and 524 significant neighboring protein-coding genes were also DEGs. Our results provide new insights into gene expression of lung tissue in Tibetan chickens during the aging process.

16.
Chem Commun (Camb) ; 56(70): 10171-10174, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32748904

RESUMO

Two pairs of dibenzospiroketal racemates, (±)-epicospirocin A (1a/1b) and (±)-1-epi-epicospirocin A (2a/2b), and two (+)-enantiomers of aspermicrones, ent-aspermicrone B (3b) and ent-aspermicrone C (4b), together with two hemiacetal epimeric mixtures, epicospirocin B/1-epi-epicospirocin B (5/6) and epicospirocin C/1-epi-epicospirocin C (7/8), were investigated from the phytopathogenic fungus Epicoccum nigrum 09116 via MS/MS molecular networking guided isolation and chiral separation for the first time. A plausible epicospirocin biosynthetic pathway was elucidated through in silico gene function annotation together with knock-out experiments. This is the first report that has applied MS/MS molecular networking to identify intermediates correlated with a biosynthetic pathway.

17.
Front Plant Sci ; 11: 1087, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765567

RESUMO

BZR transcription factors play essential roles in plant growth and environmental stimuli, and they are also the positive regulators of Brassinosteroid (BR) signal transduction in diverse plants. In addition, BZR TFs, as crucial regulators of BR synthesis, may have multiple stress-resistance functions and their related regulatory mechanisms have been well illustrated in model plants. Here, we carried out a genome-wide identification of BZR members in Chinese pear (Pyrus bretschneideri) and identified 13 members. By comparative analysis in five Rosaceae genomes, BZR members in the pear genome may have undergone large-scale duplication events during evolution. Purifying selection played an important role in almost all of the orthologous and paralogous gene pairs. According to the expression analysis of the PbBZRs during fruit development, three PbBZRs were selected for detailed analysis. Transcriptional activation assays presented that PbBZR1 repressed the promoters of P. bretschneideri lignin biosynthetic genes, such as PbCES9, PbCOMT3, and PbHCT6. Our study traces the evolution of BZR gene family members in Rosaceae genomes and illustrates that the rates of gene loss and gain are far from equilibrium in different species. At the same time, our results suggest that PbBZR1 may be involved in the negative regulation of lignin biosynthesis.

18.
Cancer Cell Int ; 20: 393, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821246

RESUMO

Background: Glioblastoma multiforme (GBM) is the most seriously brain tumor with extremely poor prognosis. Recent research has demonstrated that competitive endogenous RNA (ceRNA) network which long noncoding RNAs (lncRNAs) act as microRNA (miRNA) sponges to regulate mRNA expression were closely related to tumor development. However, the regulatory mechanisms and functional roles of ceRNA network in the pathogenesis of GBM are remaining poorly understood. Methods: In this study, we systematically analyzed the expression profiles of lncRNA and mRNA (GSE51146 dataset) and miRNA (GSE65626 dataset) from GEO database. Then, we constructed a ceRNA network with the dysregulated genes by bioinformatics methods. The TCGA and GSE4290 dataset were used to confirm the expression and prognostic value of candidate mRNAs. Results: In total, 3413 differentially expressed lncRNAs and mRNAs, 305 differentially expressed miRNAs were indentified in GBM samples. Then a ceRNA network containing 3 lncRNAs, 5 miRNAs, and 60 mRNAs was constructed. The overall survival analysis of TCGA databases indicated that two mRNAs (C1s and HSD3B7) were remarkly related with the prognosis of GBM. Conclusion: The ceRNA network may increase our understanding to the pathogenesis of GBM. In general, the candidate mRNAs from the ceRNA network can be predicted as new therapeutic targets and prognostic biomarkers for GBM.

19.
Diabetes Res Clin Pract ; 166: 108289, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32615278

RESUMO

AIMS: Continuous glucose monitoring (CGM)-derived time-in-range (TIR) of 3.9-10 mmol/L is associated with diabetic retinopathy in type 2 diabetes (T2DM), but its relationship to peripheral nerve function has not been previously investigated. To explore the association between the TIR and nerve conduction study parameters in patients with T2DM, we performed a cross-sectional analysis. METHODS: A total of 740 patients with T2DM were enrolled in this study. All of the participants were divided into tertiles according to the TIR (TIR low: ≤53%; TIR medium: 54-76%; TIR high: ≥77%). Composite Z-scores of nerve conduction velocity (CV), latency, and amplitude were calculated. The linear correlation between the TIR and composite nerve function Z-score was evaluated and risk assessment was analysed using binary logistic regression. RESULTS: The composite Z-score of the CV and amplitude increased with higher TIR and the composite Z-score of latency significantly decreased as the TIR tertiles increased (all P trend < 0.05). After adjusting for age, diabetes duration, height, weight and other confounding factors, higher TIR was associated with a higher composite Z-score of CV (ß = 0.230, P < 0.001), amplitude (ß = 0.099, P = 0.010), and lower composite Z-score of latency (ß = -0.172, P < 0.001). The risk of TIR tertiles and low composite Z-score of CV remained significant even after adjustment of HbA1c (TIR medium: OR = 0.48, P = 0.001; TIR high: OR = 0.41, P < 0.001). CONCLUSIONS: Higher TIR tertiles were independently associated with better peripheral nerve function. CGM-derived TIR may be a promising approach to screen patients for further assessment of possible diabetic peripheral neuropathy.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/etiologia , Nervos Periféricos/fisiopatologia , Adulto , Idoso , Glicemia/metabolismo , Automonitorização da Glicemia/normas , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa/fisiologia , Planejamento de Assistência ao Paciente/normas , Valores de Referência , Fatores de Risco , Fatores de Tempo
20.
Eur J Med Chem ; 201: 112445, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603981

RESUMO

The c-Jun N-terminal kinase 3 (JNK3) plays key roles in a wide range of diseases, including neurodegeneration diseases, inflammation diseases, cancers, cardiovascular diseases, and metabolic disorders. Previously, we have identified a lead compound, (Z)-3-(2-(naphthalen-1-yl)-2-oxoethylidene)-3,4-dihydroquinoxalin-2(1H)-one (J46), which contains a 3,4-dihydroquinoxalin-2(1H)-one core structure as a key fragment to inhibit JNK3. However, compound J46 displayed high DDR1 and EGFR (T790M, L858R) inhibition and poor physicochemical properties, especially clogD and water-solubility, in its biological studies. Herein, we optimized compound J46 by structure-based drug design and exploiting the selectivity and physicochemical properties of various warhead groups to obtain compound J46-37, which not only exhibited a potent inhibition against JNK3 but also showed more than 50-fold potency better than DDR1 and EGFR (T790M, L858R). Furthermore, the selectivity and structure-activity relationship of novel synthesized 3,4-dihydroquinoxalin-2(1H)-one derivatives were analyzed by molecular docking and molecular dynamics simulation. Overall, compound J46-37, as a highly selective inhibitor of JNK3 with well physicochemical properties, is worth developing as therapies for the treatment of diseases related to JNK3.

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