Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 672
Filtrar
1.
Heliyon ; 10(9): e30015, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38707411

RESUMO

Here, we presented 6 patients who were admitted to our institution and diagnosed as myasthenia gravis (MG) with tongue muscle atrophy. All these 6 patients developed symptoms of bulbar muscle weakness in acetylcholine receptor antibodies positive MG (AChR-MG) (3/6), muscle-specific receptor tyrosine kinase antibodies positive MG (MuSK-MG) (1/6), and sero-negative MG (2/6). Most of patients had "triple-furrowed" tongue except for patient 2 with irregular atrophy of tongue muscle. Tongue muscle atrophy occurs in patients with MuSK-MG, AChR-MG, and sero-negative MG. Atrophied tongue muscles of five patients with MG were reversible after immunotherapy.

2.
Drug Des Devel Ther ; 18: 1439-1457, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38707616

RESUMO

Background: Acteoside, an active ingredient found in various medicinal herbs, is effective in the treatment of diabetic kidney disease (DKD); however, the intrinsic pharmacological mechanism of action of acteoside in the treatment of DKD remains unclear. This study utilizes a combined approach of network pharmacology and experimental validation to investigate the potential molecular mechanism systematically. Methods: First, acteoside potential targets and DKD-associated targets were aggregated from public databases. Subsequently, utilizing protein-protein interaction (PPI) networks, alongside GO and KEGG pathway enrichment analyses, we established target-pathway networks to identify core potential therapeutic targets and pathways. Further, molecular docking facilitated the confirmation of interactions between acteoside and central targets. Finally, the conjectured molecular mechanisms of acteoside against DKD were verified through experimentation on unilateral nephrectomy combined with streptozotocin (STZ) rat model. The underlying downstream mechanisms were further investigated. Results: Network pharmacology identified 129 potential intersected targets of acteoside for DKD treatment, including targets such as AKT1, TNF, Casp3, MMP9, SRC, IGF1, EGFR, HRAS, CASP8, and MAPK8. Enrichment analyses indicated the PI3K-Akt, MAPK, Metabolic, and Relaxin signaling pathways could be involved in this therapeutic context. Molecular docking revealed high-affinity binding of acteoside to PIK3R1, AKT1, and NF-κB1. In vivo studies validated the therapeutic efficacy of acteoside, demonstrating reduced blood glucose levels, improved serum Scr and BUN levels, decreased 24-hour urinary total protein (P<0.05), alongside mitigated podocyte injury (P<0.05) and ameliorated renal pathological lesions. Furthermore, this finding indicates that acteoside inhibits the expression of pyroptosis markers NLRP3, Caspase-1, IL-1ß, and IL-18 through the modulation of the PI3K/AKT/NF-κB pathway. Conclusion: Acteoside demonstrates renoprotective effects in DKD by regulating the PI3K/AKT/NF-κB signaling pathway and alleviating pyroptosis. This study explores the pharmacological mechanism underlying acteoside's efficacy in DKD treatment, providing a foundation for further basic and clinical research.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Glucosídeos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fenóis , Polifenóis , Estreptozocina , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Animais , Ratos , Glucosídeos/farmacologia , Glucosídeos/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Fenóis/farmacologia , Fenóis/química , Ratos Sprague-Dawley
3.
J Ethnopharmacol ; 330: 118264, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38692417

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Optimized New Shengmai Powder (ONSMP) is a sophisticated traditional Chinese medicinal formula renowned for bolstering vital energy, optimizing blood circulation, and mitigating fluid retention. After years of clinical application, ONSMP has shown a significant impact in improving myocardial injury and cardiac function and has a positive effect on treating heart failure. However, many unknowns exist about the molecular biological mechanisms of how ONSMP exerts its therapeutic effects, which require further research and exploration. AIM OF THE STUDY: Exploring the potential molecular biological mechanisms by which ONSMP ameliorates cardiomyocyte apoptosis and ferroptosis in ischemic heart failure (IHF). MATERIALS AND METHODS: First, we constructed a rat model of IHF by inducing acute myocardial infarction through surgery and using echocardiography, organ coefficients, markers of heart failure, antioxidant markers, and histopathological examination to assess the effects of ONSMP on cardiomyocyte apoptosis and ferroptosis in IHF rats. Next, we used bioinformatics analysis techniques to analyze the active components, signaling pathways, and core targets of ONSMP and calculated the interactions between core targets and corresponding elements. Finally, we detected the positive expression of apoptosis and ferroptosis markers and core indicators of signaling pathways by immunohistochemistry; detected the mean fluorescence intensity of core indicators of signaling pathways by immunofluorescence; detected the protein expression of signaling pathways and downstream effector molecules by western blotting; and detected the mRNA levels of p53 and downstream effector molecules by quantitative polymerase chain reaction. RESULTS: ONSMP can activate the Ser83 site of ASK by promoting the phosphorylation of the PI3K/AKT axis, thereby inhibiting the MKK3/6-p38 axis and the MKK4/7-JNK axis signaling to reduce p53 expression, and can also directly target and inhibit the activity of p53, ultimately inhibiting p53-mediated mRNA and protein increases in PUMA, SAT1, PIG3, and TFR1, as well as mRNA and protein decreases in SLC7A11, thereby inhibiting cardiomyocyte apoptosis and ferroptosis, effectively improving cardiac function and ventricular remodeling in IHF rat models. CONCLUSION: ONSMP can inhibit cardiomyocyte apoptosis and ferroptosis through the PI3K/AKT/p53 signaling pathway, delaying the development of IHF.

4.
iScience ; 27(5): 109733, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38689641

RESUMO

Intervertebral disc is a highly rhythmical tissue. As a key factor linking biorhythm and inflammatory response, the shielding effect of NR1D1 in the process of intervertebral disc degeneration remains unclear. Here, we first confirmed that NR1D1 in the nucleus pulposus tissue presents periodic rhythmic changes and decreases in expression with intervertebral disc degeneration. Second, when NR1D1 was activated by SR9009 in vitro, NLRP3 inflammasome assembly and IL-1ß production were inhibited, while ECM synthesis was increased. Finally, the vivo experiments further confirmed that the activation of NR1D1 can delay the process of disc degeneration to a certain extent. Mechanistically, we demonstrate that NR1D1 can bind to IL-1ß and NLRP3 promoters, and that the NR1D1/NLRP3/IL-1ß pathway is involved in this process. Our results demonstrate that the activation of NR1D1 can effectively reduce IL-1ß secretion, alleviate LPS-induced NPMSC pyroptosis, and protect ECM degeneration.

5.
Angew Chem Int Ed Engl ; : e202404271, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38700507

RESUMO

Integrating controllable spin states into single-molecule magnets (SMMs) enables precise manipulation of magnetic interactions at a molecular level, but remains a synthetic challenge. Herein, we developed a 3d-4f metallacrown (MC) magnet [DyNi5(quinha)5(Clsal)2(py)8](ClO4)∙4H2O (H2quinha = quinaldichydroxamic acid, HClsal = 5-chlorosalicylaldehyde) wherein a square planar NiII is stabilized by chemical stacking. Thioacetal modification was employed via post-synthetic ligand substitutions and yielded [DyNi5(quinha)5(Clsaldt)2(py)8](ClO4)·3H2O (HClsaldt = 4-chloro-2-(1,3-dithiolan-2-yl)phenol). Thanks to the additional ligations of thioacetal onto the NiII site, coordination-induced spin state switching (CISSS) took place with spin state altering from low-spin S = 0 to high-spin S = 1. The synergy of CISSS effect and magnetic interactions results in distinct energy splitting and magnetic dynamics. Magnetic studies indicate prominent enhancement of reversal barrier from 57 cm-1 to 423 cm-1, along with hysteresis opening and an over 200-fold increment in coercive field at 2 K. Ab initio calculations provide deeper insights into the exchange models and rationalize the relaxation/tunnelling pathways. These results demonstrate here provide a fire-new perspective in modulating the magnetization relaxation via the incorporation of controllable spin states and magnetic interactions facilitated by the CISSS approach.

6.
Artigo em Inglês | MEDLINE | ID: mdl-38719166

RESUMO

OBJECTIVE: To investigate the effects of physiotherapeutic scoliosis-specific exercises (PSSE) on coronal, horizontal, and sagittal deformities of the spine in adolescent idiopathic scoliosis (AIS) as well as how curve severity, intervention duration, and intervention type could modify these effects. DATA SOURCES: Data sources included the PubMed, Web of Science, Embase, Cochrane Library, and Scopus databases, searched from their inception to September 5, 2023. STUDY SELECTION: Clinical controlled trials reporting the effects of PSSE on the Cobb angle, angle of trunk rotation (ATR), thoracic kyphosis (TK), or lumbar lordosis (LL) in AIS patients aged 10 to 18 years. The experimental groups received PSSE; the control groups received standard care (observation or bracing) or conventional exercise such as core stabilization exercise, pilates, PNF, and other non-specific exercise. DATA EXTRACTION: Two researchers independently extracted key information from eligible studies. The quality of the studies was assessed using the Cochrane Handbook version 5.1.0 risk of bias assessment and the JBI Center for Evidence-Based Health Care (2016) of quasi-experimental research authenticity assessment tool. The level and certainty of evidence was rated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The protocol for this study was registered in PROSPERO (CRD42023404996). DATA SYNTHESIS: Twelve randomized controlled trials (RCTs) and five non-RCTs (NRCTs) were meta-analyzed separately. The results indicated that compared with other non-surgical management, PSSE significantly improved the Cobb angle, ATR, and TK, whereas the LL improvement was not statistically significant. Additionally, the efficacy of PSSE on Cobb angle was not significant in patients with curve severity ≥30° compared with controls. Nevertheless, the pooled effect of PSSE on Cobb angle was not significantly modified by intervention duration and intervention type, and on ATR was not significantly modified by intervention duration. The overall quality of evidence according to GRADE was moderate to low for RCT and very low for NRCT. CONCLUSIONS: PSSE exhibited positive benefits on the Cobb angle, ATR, and TK in patients with AIS compared to other non-surgical therapies. In addition, the effectiveness of PSSE may be independent of intervention duration and intervention type, but may be influenced by the initial Cobb angle. However, more RCTs are needed in the future to validate the efficacy of PSSE in moderate AIS with a mean Cobb ≥30°. Current evidence is limited by inconsistent control group interventions and small sample size of the studies.

7.
World J Gastroenterol ; 30(13): 1887-1898, 2024 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-38659480

RESUMO

BACKGROUND: Differences in the preoperative characteristics and weight loss outcomes after sleeve gastrectomy (SG) between patients with familial aggregation of obesity (FAO) and patients with sporadic obesity (SO) have not been elucidated. AIM: To explore the impact of SG on weight loss and the alleviation of obesity-related comorbidities in individuals with FAO. METHODS: A total of 193 patients with obesity who underwent SG were selected. Patients with FAO/SO were matched 1:1 by propensity score matching and were categorized into 4 groups based on the number of first-degree relatives with obesity (1SO vs 1FAO, 2SO vs 2FAO). The baseline characteristics, weight loss outcomes, prevalence of obesity-related comorbidities and incidence of major surgery-related complications were compared between groups. RESULTS: We defined FAO as the presence of two or more first-degree relatives with obesity. Patients with FAO did not initially show significant differences in baseline data, short-term postoperative weight loss, or obesity-related comorbidities when compared to patients with SO preoperatively. However, distinctions between the two groups became evident at the two-year mark, with statistically significant differences in both percentage of total weight loss (P = 0.006) and percentage of excess weight loss (P < 0.001). The FAO group exhibited weaker remission of type 2 diabetes mellitus (T2DM) (P = 0.031), hyperlipidemia (P = 0.012), and non-alcoholic fatty liver disease (NAFLD) (P = 0.003) as well as a lower incidence of acid reflux (P = 0.038). CONCLUSION: FAO patients is associated with decreased mid-to-long-term weight loss outcomes; the alleviation of T2DM, hyperlipidemia and NAFLD; and decreased incidence of acid reflux postoperatively.


Assuntos
Gastrectomia , Redução de Peso , Humanos , Masculino , Feminino , Gastrectomia/efeitos adversos , Gastrectomia/métodos , Adulto , Resultado do Tratamento , Pessoa de Meia-Idade , Estudos Retrospectivos , Diabetes Mellitus Tipo 2/cirurgia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Comorbidade , Obesidade/cirurgia , Obesidade/diagnóstico , Obesidade/complicações , Obesidade/epidemiologia , Obesidade Mórbida/cirurgia , Obesidade Mórbida/complicações , Cirurgia Bariátrica/métodos , Pontuação de Propensão , Hepatopatia Gordurosa não Alcoólica/cirurgia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Incidência
8.
Eur J Pharmacol ; 971: 176524, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38561102

RESUMO

The present study aimed to explore how resveratrol (Res) confers myocardial protection by attenuating ferroptosis. In vivo and in vitro myocardial ischemia/reperfusion injury (MIRI) models were established, with or without Res pretreatment. The results showed that Res pretreatment effectively attenuated MIRI, as evidenced by increased cell viability, reduced lactate dehydrogenase activity, decreased infarct size, and maintained cardiac function. Moreover, Res pretreatment inhibited MIRI-induced ferroptosis, as shown by improved mitochondrial integrity, increased glutathione level, decreased prostaglandin-endoperoxide synthase 2 level, inhibited iron overload, and abnormal lipid peroxidation. Of note, Res pretreatment decreased or increased voltage-dependent anion channel 1/glutathione peroxidase 4 (VDAC1/GPX4) expression, which was increased or decreased via anoxia/reoxygenation (A/R) treatment, respectively. However, the overexpression of VDAC1 via pAd/VDAC1 and knockdown of GPX4 through Si-GPX4 reversed the protective effect of Res in A/R-induced H9c2 cells, whereas the inhibition of GPX4 with RSL3 abolished the protective effect of Res on mice treated with ischemia/reperfusion.Interestingly, knockdown of VDAC1 by Si-VDAC1 promoted the protective effect of Res on A/R-induced H9c2 cells and the regulation of GPX4. Finally, the direct interaction between VDAC1 and GPX4 was determined using co-immunoprecipitation. In conclusion, Res pretreatment could protect the myocardium against MIRI-induced ferroptosis via the VDAC1/GPX4 signaling pathway.


Assuntos
Ferroptose , Traumatismo por Reperfusão Miocárdica , Animais , Camundongos , Miócitos Cardíacos , Resveratrol/farmacologia , Canal de Ânion 1 Dependente de Voltagem , Isquemia , Hipóxia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Reperfusão
9.
Molecules ; 29(7)2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38611793

RESUMO

Reported herein is a Paternò-Büchi reaction of aromatic double bonds with quinones under visible light irradiation. The reactions of aromatics with quinones exposed to blue LED irradiation yielded oxetanes at -78 °C, which was attributed to both the activation of double bonds in aromatics and the stabilization of oxetanes by thiadiazole, oxadiazole, or selenadiazole groups. The addition of Cu(OTf)2 to the reaction system at room temperature resulted in the formation of diaryl ethers via the copper-catalyzed ring opening of oxetanes in situ. Notably, the substrate scope was extended to general aromatics.

10.
Shanghai Kou Qiang Yi Xue ; 33(1): 64-70, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38583027

RESUMO

PURPOSE: To analyze the bone remodeling around the implant 10 years after disk-up sinus reamer(DSR)-based internal sinus floor elevation with implantation and to investigate the influence of different factors on implant retention. METHODS: The clinical and imaging data of patients undergoing DSR-based sinus floor elevation with simultaneous implantation were collected from the Department of Dental Implantology, Affiliated Hospital of Qingdao University from January 2008 to December 2011. Panoramic film and CBCT were used to measure the changes of bone mass around implant in different periods. Kaplan-Meier and Log-rank tests were used to analyze the effects of different factors on implant retention with SPSS 26.0 software package. RESULTS: The study included 98 patients with a total of 128 implants. During the follow-up of 0-168 months, 7 implants failed, and the remaining formed good osseointegration and functioned, with a 10-year cumulative retention rate of 94.53%. The height of bone formation was (0.29±0.15) mm at the top and (2.74±0.66) mm in the sinus of 75 implant sites with complete imaging data obtained ten years after surgery. Kaplan-Meier and Log-rank tests showed that 8 factors including initial bone height, elevated bone height, mucosal perforation, implant length, implant torsion, diabetes, smoking and periodontitis had significant effects on implant retention. CONCLUSIONS: The DSR-based internal sinus floor elevation with implantation is a reliable and stable bone augmentation operation for vertical bone defect in maxillary posterior region, with a 10-year cumulative retention rate of no less than 94%. Initial bone height, elevated bone height, mucosal perforation, implant length, implant torsion, diabetes, smoking and periodontitis are the important factors affecting the long-term retention rate of implants.


Assuntos
Implantação Dentária Endóssea , Implantes Dentários , Levantamento do Assoalho do Seio Maxilar , Humanos , Implantação Dentária Endóssea/métodos , Diabetes Mellitus/cirurgia , Maxila/diagnóstico por imagem , Maxila/cirurgia , Seio Maxilar/diagnóstico por imagem , Seio Maxilar/cirurgia , Periodontite , Resultado do Tratamento
11.
Nat Commun ; 15(1): 2819, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561338

RESUMO

Previous genetic studies of venous thromboembolism (VTE) have been largely limited to common variants, leaving the genetic determinants relatively incomplete. We performed an exome-wide association study of VTE among 14,723 cases and 334,315 controls. Fourteen known and four novel genes (SRSF6, PHPT1, CGN, and MAP3K2) were identified through protein-coding variants, with broad replication in the FinnGen cohort. Most genes we discovered exhibited the potential to predict future VTE events in longitudinal analysis. Notably, we provide evidence for the additive contribution of rare coding variants to known genome-wide polygenic risk in shaping VTE risk. The identified genes were enriched in pathways affecting coagulation and platelet activation, along with liver-specific expression. The pleiotropic effects of these genes indicated the potential involvement of coagulation factors, blood cell traits, liver function, and immunometabolic processes in VTE pathogenesis. In conclusion, our study unveils the valuable contribution of protein-coding variants in VTE etiology and sheds new light on its risk stratification.


Assuntos
Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Fatores de Risco , Fatores de Coagulação Sanguínea/genética , Exoma , Estudo de Associação Genômica Ampla , Fatores de Processamento de Serina-Arginina/genética , Fosfoproteínas/genética
12.
Nat Hum Behav ; 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589703

RESUMO

While numerous genomic loci have been identified for neuropsychiatric conditions, the contribution of protein-coding variants has yet to be determined. Here we conducted a large-scale whole-exome-sequencing study to interrogate the impact of protein-coding variants on 46 neuropsychiatric diseases and 23 traits in 350,770 adults from the UK Biobank. Twenty new genes were associated with neuropsychiatric diseases through coding variants, among which 16 genes had impacts on the longitudinal risks of diseases. Thirty new genes were associated with neuropsychiatric traits, with SYNGAP1 showing pleiotropic effects across cognitive function domains. Pairwise estimation of genetic correlations at the coding-variant level highlighted shared genetic associations among pairs of neurodegenerative diseases and mental disorders. Lastly, a comprehensive multi-omics analysis suggested that alterations in brain structures, blood proteins and inflammation potentially contribute to the gene-phenotype linkages. Overall, our findings characterized a compendium of protein-coding variants for future research on the biology and therapeutics of neuropsychiatric phenotypes.

13.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 46(2): 176-183, 2024 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-38686713

RESUMO

Objective To evaluate the clinical efficacy and safety of intensive insulin therapy in the patients with acute myocardial infarction and provide guidance for improving the prognosis. Methods The articles involving the randomized controlled trials(RCT)focusing on the effects of intensive versus conventional insulin therapy on the clinical outcomes of the patients with acute myocardial infarction were retrieved from Cochrane,Embase,PubMed,CNKI,Wanfang Data,VIP,and CBM with the time interval from inception to October 2022.The data of each RCT were extracted and used for meta-analysis in RevMan5.4. Results A total of 8 articles were included in this study,involving 726 patients(372 in the intensive insulin group and 354 in the normal insulin group).The meta-analysis results showed that the intensive insulin group had lower incidence of major cardiovascular adverse events (RR=0.53, 95%CI=0.44-0.64, P<0.001), lower all-cause mortality (RR=0.51, 95%CI=0.33-0.78, P=0.002),lower high-sensitivity C-reactive protein level on day 7(WMD=-2.00,95%CI=-2.17- -1.83,P<0.001),higher left ventricular ejection fraction on day 30 (WMD=3.94, 95%CI=2.45-5.43,P<0.001), and higher incidence of hypoglycemia events (RR=2.96, 95%CI=1.12-7.83,P=0.030) than the normal insulin group.There was no significant difference between the two groups in terms of no-reflow event after percutaneous coronary intervention(RR=0.39,95%CI=0.14-1.13,P=0.080). Conclusion Intensive insulin therapy might be associated with more clinical benefits in the patients with acute myocardial infarction,while the conclusion remains to be confirmed by more studies.


Assuntos
Insulina , Infarto do Miocárdio , Humanos , Infarto do Miocárdio/tratamento farmacológico , Insulina/uso terapêutico , Insulina/administração & dosagem , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteína C-Reativa
14.
Chem Commun (Camb) ; 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38687569

RESUMO

A Prussian blue analogue was synthesized using biomass leather waste as a precursor by doping with Co2+ ions. This material, demonstrates good performance in both the oxygen reduction reaction and oxygen evolution reaction, and exhibits excellent charge-discharge performance and stability in zinc-air batteries.

15.
Eur J Med Chem ; 271: 116406, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38688064

RESUMO

NRAS mutation is the second most common oncogenic factor in cutaneous melanoma. Inhibiting NRAS translation by stabilizing the G-quadruplex (G4) structure with small molecules seems to be a potential strategy for cancer therapy due to the NRAS protein's lack of a druggable pocket. To enhance the effects of previously reported G4 stabilizers quindoline derivatives, we designed and synthesized a novel series of quindoline derivatives with fork-shaped side chains by introducing (alkylamino)alkoxy side chains. Panels of experimental results showed that introducing a fork-shaped (alkylamino)alkoxy side chain could enhance the stabilizing abilities of the ligands against NRAS RNA G-quadruplexes and their anti-melanoma activities. One of them, 10b, exhibited good antitumor activity in the NRAS-mutant melanoma xenograft mouse model, showing the therapeutic potential of this kind of compounds.

16.
Int J Biol Macromol ; 267(Pt 1): 131473, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38614185

RESUMO

Actinoplanes utahensis deacylase (AAC)-catalyzed deacylation of echinocandin B (ECB) is a promising method for the synthesis of anidulafungin, the newest of the echinocandin antifungal agents. However, the low activity of AAC significantly limits its practical application. In this work, we have devised a multi-dimensional rational design strategy for AAC, conducting separate analyses on the substrate-binding pocket's volume, curvature, and length. Furthermore, we quantitatively analyzed substrate properties, particularly on hydrophilic and hydrophobic. Accordingly, we tailored the linoleic acid-binding pocket of AAC to accommodate the extended long lipid chain of ECB. By fine-tuning the key residues, the resulting AAC mutants can accommodate the ECB lipid chain with a lower curvature binding pocket. The D53A/I55F/G57M/F154L/Q661L mutant (MT) displayed 331 % higher catalytic efficiency than the wild-type (WT) enzyme. The MT product conversion was 94.6 %, reaching the highest reported level. Utilizing a multi-dimensional rational design for a customized mutation strategy of the substrate-binding pocket is an effective approach to enhance the catalytic efficiency of enzymes in handling complicated substrates.


Assuntos
Equinocandinas , Proteínas Fúngicas , Interações Hidrofóbicas e Hidrofílicas , Equinocandinas/química , Especificidade por Substrato , Sítios de Ligação , Mutação , Modelos Moleculares , Amidoidrolases/química , Amidoidrolases/genética , Amidoidrolases/metabolismo , Ligação Proteica
17.
Dalton Trans ; 53(18): 8011-8019, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38651951

RESUMO

Designing efficient, inexpensive, and stable photocatalysts to degrade organic pollutants and antibiotics has become an effective way for environmental remediation. In this work, we successfully performed in situ growth of CdS QDs on the surface of elliptical BiVO4 to try to show the advantage of the binary heterojuncted photocatalyst (BVO@CdS) for the photocatalytic degradation of tetracycline (TC). The In situ growth of CdS QDs can provide a large number of reactive sites and also generate a larger contact area with BiVO4. In addition, compared with mechanical composite materials, in situ growth can significantly reduce the energy barrier at the interface between BiVO4 and CdS, providing more channels for the separation and migration of photogenerated charge carriers, and further improving reaction activity. As a result, BVO@CdS-0.05 shows the best degradation efficiency, with a degradation rate of 88% after 30 min under visible light. The TC photodegradation follows a pseudo-second-order reaction with a dynamic constant of 0.472 min-1, which is 6.47 times that of pure BiVO4, 7.24 times that of pure CdS QDs and 2 times that of the mechanical composite. The degradation rate of BVO@CdS-0.05 decreases to 77.8% with a retention rate of 88.5% after four cycles, demonstrating excellent stability. Through liquid chromatography-mass spectrometry (LC-MS) analysis, two possible pathways for TC degradation are proposed. Through free radical capture experiments, electron spin resonance measurements, and photoelectrochemical comprehensive analysis, it is confirmed that BVO@CdS composites have constructed an efficient Z-scheme heterojunction via in situ growth, thereby highly enhancing the separation and transport efficiency of charge carriers.

18.
Nat Commun ; 15(1): 3455, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658548

RESUMO

Understanding how distinct functional circuits are coordinated to fine-tune mood and behavior is of fundamental importance. Here, we observe that within the dense projections from basolateral amygdala (BLA) to bed nucleus of stria terminalis (BNST), there are two functionally opposing pathways orchestrated to enable contextually appropriate expression of anxiety-like behaviors in male mice. Specifically, the anterior BLA neurons predominantly innervate the anterodorsal BNST (adBNST), while their posterior counterparts send massive fibers to oval BNST (ovBNST) with moderate to adBNST. Optogenetic activation of the anterior and posterior BLA inputs oppositely regulated the activity of adBNST neurons and anxiety-like behaviors, via disengaging and engaging the inhibitory ovBNST-to-adBNST microcircuit, respectively. Importantly, the two pathways exhibited synchronized but opposite responses to both anxiolytic and anxiogenic stimuli, partially due to their mutual inhibition within BLA and the different inputs they receive. These findings reveal synergistic interactions between two BLA-to-BNST pathways for appropriate anxiety expression with ongoing environmental demands.


Assuntos
Ansiedade , Complexo Nuclear Basolateral da Amígdala , Optogenética , Núcleos Septais , Animais , Masculino , Núcleos Septais/fisiologia , Núcleos Septais/metabolismo , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/fisiologia , Camundongos , Comportamento Animal/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Camundongos Endogâmicos C57BL , Vias Neurais/fisiologia
19.
Dalton Trans ; 53(17): 7470-7476, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38595157

RESUMO

A series of two-dimensional (2D) spin-crossover coordination polymers (SCO-CPs) [FeII(TPE)(NCX)2]·solv (1: X = BH3, solv = H2O·2CH3OH·DMF; 2: X = Se, solv = H2O·2CH3OH·0.5DMF; 3: X = S, solv = H2O·2CH3OH·0.5DMF) were synthesized by employing 1,1,2,2-tetra(pyridin-4-yl)ethene (TPE) and pseudohalide (NCX-) coligands. Magnetic measurements indicated that complexes 1-3 exhibited SCO behaviors with diminishing thermal hysteresis (7/4/0 K) upon decreasing the ligand-field strength. The critical temperatures (Tc) during spin transition were found to be inversely proportional to the coordination ability parameters (a™) with a linear correlation. The guest effect was also investigated in the solvent-exchanged phases 1-SE/2-SE/3-SE wherein the DMF molecules were replaced by methanol molecules. Compared with 1-3, 1-SE/2-SE/3-SE displayed more abrupt and complete single-step SCO behaviors but narrower thermal hysteretic loops. The results reported here demonstrate that the Tc values of these two families were dominated by the ligand-field strength of the NCX- anions (NCBH3 > NCSe > NCS), whereas the guest effect only modulated the kinetic factor of the SCO nature in this system.

20.
Biomed Pharmacother ; 174: 116542, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38574620

RESUMO

Previous studies have demonstrated that the underlying mechanisms of myocardial ischemia/reperfusion injury (MIRI) are complex and involve multiple types of regulatory cell death, including ferroptosis, apoptosis, and autophagy. Thus, we aimed to identify the mechanisms underlying MIRI and validate the protective role of epigallocatechin-3-gallate (EGCG) and its related mechanisms in MIRI. An in vivo and in vitro models of MIRI were constructed. The results showed that pretreatment with EGCG could attenuate MIRI, as indicated by increased cell viability, reduced lactate dehydrogenase (LDH) activity and apoptosis, inhibited iron overload, abnormal lipid metabolism, preserved mitochondrial function, decreased infarct size, maintained cardiac function, decreased reactive oxygen species (ROS) level, and reduced TUNEL-positive cells. Additionally, EGCG pretreatment could attenuate ferroptosis, apoptosis, and autophagy induced by MIRI via upregulating 14-3-3η protein levels. Furthermore, the protective effects of EGCG could be abolished with pAd/14-3-3η-shRNA or Compound C11 (a 14-3-3η inhibitor) but not pAd/NC-shRNA. In conclusion, EGCG pretreatment attenuated ferroptosis, apoptosis, and autophagy by mediating 14-3-3η and protected cardiomyocytes against MIRI.


Assuntos
Proteínas 14-3-3 , Apoptose , Autofagia , Catequina , Catequina/análogos & derivados , Ferroptose , Traumatismo por Reperfusão Miocárdica , Catequina/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Proteínas 14-3-3/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Cardiotônicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Ratos Sprague-Dawley
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...