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AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.
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Ácido Clorogênico , Nefropatias Diabéticas , Fibrose , Rim , Metabolismo dos Lipídeos , Receptor Notch1 , Fator de Transcrição STAT3 , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Receptor Notch1/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Animais , Transdução de Sinais/efeitos dos fármacos , Fibrose/tratamento farmacológico , Ácido Clorogênico/farmacologia , Ácido Clorogênico/uso terapêutico , Humanos , Camundongos , Masculino , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Camundongos Endogâmicos C57BL , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Linhagem CelularRESUMO
Analyzing the molecular structure-photophysical property correlations of metal nanoclusters to accomplish function-oriented photocatalysis could be challenging. Here, the selective heteroatom alloying has been exploited to a Au15 nanocluster, making up a structure-correlated nanocluster series, including homogold Au15, bimetallic AgxAu15-x and CuxAu15-x, trimetallic AgxCuyAu15-x-y, and tetrametallic Pt1AgxCuyAu15-x-y. Their structure-dependent photophysical properties were investigated due to the atomically precise structures of these nanoclusters. Cu-alloyed CuxAu15-x showed intense phosphorescence and the highest singlet oxygen production efficiency. Moreover, the generation of 1O2 species from excited nanoclusters enabled CuxAu15-x as a suitable catalyst for efficient photocatalytic oxidation of silyl enol ethers to produce α,ß-unsaturated carbonyl compounds. The generality and applicability of the CuxAu15-x catalysts toward different photocatalytic oxidations were assessed. Overall, this study presents an intriguing Au15-based cluster series enabling an atomic-level understanding of structure-photophysical property correlations, which hopefully provides guidance for the fabrication of cluster-based catalysts with customized photocatalytic performance.
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We disclosed herein an enantioselective formal siloxycarbene insertion reaction enabled by chiral phosphoric acid and blue LED irradiation. This is the first time the asymmetric siloxycarbene insertion into an sp3 C-H bond under transition-metal free conditions has been realized. The reaction features good isolated yields (up to 92%), high enantioselectivity (up to 99:1 er), mild reaction conditions, and good compatibility. Moreover, this method also provides a green and efficient method to construct a chiral quaternary carbon center.
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The asymmetric total syntheses of four pleurotin natural products, namely, (-)-pleurotin, (+)-leucopleurotin, (+)-leucopleurotinic acid, and (+)-dihydropleurotinic acid, were described in a concise manner. Key transformations feature a Johnson-Claisen rearrangement, a diastereo-controlled sequential hydroboration-oxidation, a SOMO/photoredox activated aldehyde α-alkylation, and oxidative cyclizations.
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Electrochemistry offers a sustainable synthesis route to value-added fine chemicals but is often constrained by competing electron transfer between the electrode and redox-sensitive functionalities distinct from the target site. Here, we describe an ion-shielding heterogeneous photoelectrocatalysis strategy to impose mass-transfer limitations that invert the thermodynamically determined order of electron transfer. This strategy is showcased to enable decarboxylative trifluoromethylation of sensitive (hetero)arenes by using trifluoroacetate, an inexpensive yet relatively inert trifluoromethyl group (CF3) source. An ion-shielding layer, formed by trifluoroacetate anions electrostatically adsorbed on a positive molybdenum-doped tungsten trioxide (WO3) photoanode, prevents undesired electron transfer between substrates and photogenerated holes. The practicality of the developed method was demonstrated with robust photoanode stability (approximately 380 hours), a good substrate scope, and scaling capability to achieve 100-gram synthesis by using photoelectrochemical flow cells.
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This study aimed to explore the hub genes and related key pathways in Spinal Cord Injury (SCI) based on the bioinformatics analysis. Two microarray datasets (GSE45006, GSE45550) were obtained from the GEO database and were merged and batch-corrected. The differentially expressed genes (DEGs) in SCI were explored with the Limma, and the weighted gene co-expression network analysis (WGCNA) was conducted to explore the module genes. Functional enrichment analysis and Gene set variation analysis (GSVA) were used to investigate the biological functions and key pathways of the key genes related to SCI. Then the protein-protein interaction (PPI) network was generated using the STING online tool, and the hub genes in SCI were identified. Receiver operating characteristic (ROC) curves were applied to assess the diagnostic value of the selected hub genes. We identified 554 DEGs in SCI, and 1236 key genes in SCI were selected via WGCNA. Totally 111 key genes related to SCI were discovered. Furthermore, the functional enrichment analysis showed that these key mRNAs were primarily enriched in the extracellular matrix (ECM)-related pathways and processes associated with wound healing and cell growth. The PPI network further filtered six hub genes (Cd44, Timp1, Loxl1, Col6a1, Col3a1, Col5a1) ranked by the degree, and the diagnostic value of the six hub genes was confirmed by the ROC curves. Six hub genes including Cd44, Timp1, Loxl1, Col6a1, Col3a1, and Col5a1 were identified in SCI, with differential expression and excellent diagnostic value, which might provide insight into the targeted therapy of SCI.
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Biologia Computacional , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Mapas de Interação de Proteínas , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/genética , Biologia Computacional/métodos , Mapas de Interação de Proteínas/genética , Humanos , Perfilação da Expressão Gênica/métodos , Curva ROC , Bases de Dados Genéticas , Transdução de Sinais/genética , Regulação da Expressão GênicaRESUMO
PURPOSE: To evaluate cytokine levels of aqueous humor in patients with cytomegalovirus (CMV) corneal endotheliitis and their relationships with CMV DNA load. METHODS: 44 aqueous humor samples were obtained from 26 patients with CMV corneal endotheliitis at various stages of treatment. 33 samples obtained from cataract patients during the same period were selected as a control group. Each sample was used to measure the concentration of the CMV DNA load using real-time quantitative polymerase chain reaction, and to examine the levels of IL-6, IL-8, IL-10, MCP-1, VCAM-1, VEGF, IP-10, G-CSF, ICAM-1 and IFN-γ using a cytometric bead array. RESULTS: All 10 cytokines were found to have statistically significant differences between the CMV endotheliitis and cataract groups. The Spearman correlation test showed that the concentration of CMV DNA load was significantly associated with the levels of IL-6 (P = 0.005, r = 0.417), IL-8 (P < 0.001, r = 0.514), IL-10 (P < 0.001, r = 0.700), MCP-1 (P = 0.001, r = 0.487), VEGF (P < 0.001, r = 0.690), IP-10 (P = 0.001, r = 0.469), G-CSF (P < 0.001, r = 0.554) and ICAM-1 (P < 0.001, r = 0.635), but not significantly associated with VCAM-1 (P = 0.056) and IFN-γ (P = 0.219). CONCLUSIONS: There was a combined innate and adaptive immune response in aqueous humor in patients with CMV endotheliitis. Levels of multiple cytokines were significantly correlated with viral particle. Cytokines are potential indicators to help diagnose CMV endotheliitis, evaluate disease activity and assess treatment response.
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Humor Aquoso , Citocinas , Infecções por Citomegalovirus , Citomegalovirus , DNA Viral , Endotélio Corneano , Infecções Oculares Virais , Humanos , Humor Aquoso/virologia , Humor Aquoso/metabolismo , Masculino , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/tratamento farmacológico , Feminino , Citocinas/metabolismo , Citomegalovirus/genética , Citomegalovirus/isolamento & purificação , Endotélio Corneano/virologia , Endotélio Corneano/metabolismo , Endotélio Corneano/patologia , Infecções Oculares Virais/virologia , Infecções Oculares Virais/diagnóstico , Infecções Oculares Virais/metabolismo , Infecções Oculares Virais/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , DNA Viral/análise , Ceratite/virologia , Ceratite/diagnóstico , Ceratite/metabolismo , Adulto , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Light-emitting electrochemical cells (LECs) promise low-cost, large-area luminescence applications with air-stabilized electrodes and a versatile fabrication that enables the use of solution processes. Nevertheless, the commercialization of LECs is still encountering many obstacles, such as low electroluminescence (EL) efficiencies of the ionic materials. In this paper, we propose five blue to yellow ionic Ir complexes possessing 4-fluoro-4'-pyrazolyl-(1,1'-biphenyl)-2-carbonitrile (ppfn) as a novel cyclometalating ligand and use them in LECs. In particular, the device within di[4-fluoro-4'-pyrazolyl-(1,1'-biphenyl)-2-carbonitrile]-4,4'-di-tert-butyl-2,2'-bipyridyl iridium(III) hexafluorophosphate (DTBP) shows a remarkable photoluminescence quantum yield (PLQY) of 70%, and by adjusting the emissive-layer thickness, the maximal external quantum efficiency (EQE) reaches 22.15% at 532 nm under the thickness of 0.51 µm, showing the state-of-the-art value for the reported blue-green LECs.
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We disclose herein a photocatalytic radical cascade cyclization of diazoalkanes for the divergent synthesis of important carbocycles and heterocycles. Under the optimal reaction conditions, various indanone, pyrone, and pyridinone derivatives can be obtained in moderate to good yields. Mechanistic experiments support the formation of carbon-centered radicals from diazoalkanes through the proton-coupled electron transfer process. Scale-up reaction using continuous flow technology and useful downstream application of the formed heterocycles further render the strategy attractive and valuable.
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Cascade reactions represent an efficient and economical synthetic approach, enabling the rapid synthesis of a wide array of structurally complex organic compounds. These compounds, previously inaccessible, can now be synthesized in a remarkably limited number of steps. Concurrently, the photochemical reactions of organic molecules have gained prominence as a potent strategy for accessing a diverse range of radical species and intermediates. This is achieved in a controlled manner under mild conditions. Owing to the relentless endeavors of chemists, significant strides have been made in the realm of photochemical cascade reactions. These advancements have facilitated the synthesis of novel molecular structures with high complexity, structures that are typically challenging to generate under thermal conditions. In this review, we comprehensively summarize and underscore the recent pivotal advancements in visible-light-induced cascade reactions. Our focus is on the elucidation of multiple photochemical catalytic cycles, emphasizing the catalytic activation modes and the types of reactions involved.
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Heterocyclic skeletons are commonly found in various bioactive molecules and pharmaceutical compounds, making them crucial in areas such as medicinal chemistry, materials science, and the realm of natural product synthesis. In recent years, the rapid advancements of visible light methodologies in organic synthesis have shown promising potential for the development of light-induced carbene transfer reactions. This is particularly significant as most organic molecules do not absorb visible light. Free carbene, known for its high activity, is frequently utilized for insertion reactions or cyclopropanation reactions. This review focuses on the photochemical strategy for the construction of heterocyclic skeletons, specifically highlighting the methods that employ visible light-promoted carbene transfer reactions.
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Vinyldiazo compounds are one of the most important synthons in the construction of a cyclic ring. Most photochemical transformations of vinyldiazo compounds are mainly focusing on utilization of their CâC bond site, while reactions taking place at terminal nitrogen atom are largely unexplored. Herein, a photocatalytic cascade radical cyclization of LBRs with vinyldiazo reagents through sequential BâN/CâN bond formation is described. The reaction starts with the addition of LBRs (Lewis base-boryl radicals) at diazo site, followed by intramolecular radical cyclization to access a wide range of important boron-handled pyrazoles in good to excellent yields. Control experiments, together with detailed mechanism studies well explain the observed reactivity. Further studies demonstrate the utility of this approach for applications in pharmaceutical and agrochemical research.
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BACKGROUND: Several recent observational studies have associated obesity, lifestyle factors (smoking, sleep duration, and alcohol drinking), and glycemic traits with facial aging. However, whether this relationship is causal due to confounding and reverse causation is yet to be substantiated. AIMS: We aimed to assess these relationships using Mendelian randomization (MR). METHODS: For the instrumental variables, this paper selected independent single nucleotide polymorphisms (SNPs) linked to the exposures at a genome-wide state (P < 5 × 10-8) in equivalent genome-wide association studies (GWAS). Using the UK Biobank, we obtained summary-level data for facial aging on 423,999 individuals. The primary assessments were performed through the combination of complementing techniques (simple method approaches, weighted model, MR-Egger, and weighted median) and the inverse-variance-weighted method. Along with that, we examined the heterogeneity and horizontal pleiotropy through different types of sensitivity analyses. RESULTS: The correlations were (a) facial aging for body mass index (BMI, OR = 1.054, 95% CI 1.044-1.64), (b) waist/hip ratio (OR = 1.056, 95% CI 1.023-1.091), and (c) smoking (OR = 1.023, 95% CI 1.007-1.039). Equally important, the correlations for waist/hip ratio remained robust after adjusting for the genetically predicted BMI (OR = 1.028, 95% CI 1.003-1.054). However, no causal effects of alcoholic drinking, glycemic traits, and sleep duration on facial aging were observed. CONCLUSIONS: The outcomes shed light on the potential correlation of obesity and cigarette smoking with facial aging while putting forward a more comprehensive and credible foundation for the optimization of facial aging strategies. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Animais , Humanos , Estilo de Vida , Envelhecimento , Obesidade/epidemiologia , Obesidade/genéticaRESUMO
Herein we report the rhodium-catalyzed one-pot three-component reaction of diazo compounds, nitriles, and nitrosoarenes to construct 2,5-dihydro-1,2,4-oxadiazole derivatives. Mechanistic studies indicate that the transformation may proceed through the formation of nitrile ylides intermediates, which then undergo [3+2]-cycloaddition with nitrosoarenes. The strategy exhibits several synthetic advantages, including operational simplicity, good functional group tolerance, and scalability.
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Deoxofluor-promoted intramolecular cyclopropanation of 1,2-(3-indole)fullerenols has been developed as a straightforward and efficient protocol for the synthesis of various spiro[indolenine]-methanofullerenes. This approach exhibits low cost, operational simplicity, and convenient conditions, and thus has potential application value.
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The azoxy functional group is an important structural motif and represents the formally oxidized counterpart of the azo group. Azoxy compounds find numerous applications ranging from pharmaceuticals to functional materials, yet their synthesis remains underdeveloped with a main focus on the formation symmetric azoxy compounds. To overcome challenges in the synthesis of such unsymmetric azoxy compounds, we designed a process employing readily accessible nitroso compounds and iminoiodinanes. This method builds on the use of visible light irradiation to generate a triplet nitrene from iminoiodinanes, which is trapped by nitroso arenes to give access to sulfonyl-protected azoxy compounds with a good substrate scope and functional group tolerance. We further describe two applications of these sulfonyl-protected azoxy compounds as radical precursors in synthesis, where the whole azoxy group can be transferred and employed in C(sp3 )-H functionalization of ethers or 1,2-difunctionalization of vinyl ethers. All of the reactions occurred at room temperature under visible light irradiation without the addition of any photoredox catalysts and additives. Control experiments, mechanism investigations, and DFT studies well explained the observed reactivity.
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Hesperetin is a natural flavonoid with many biological activities. In view of hyperuricemia treatment, the effects of hesperetin in vivo and in vitro, and the underlying mechanisms, were explored. Hyperuricemia models induced by yeast extract (YE) or potassium oxonate (PO) in mice were created, as were models based on hypoxanthine and xanthine oxidase (XOD) in L-O2 cells and sodium urate in HEK293T cells. Serum level of uric acid (UA), creatinine (CRE), and urea nitrogen (BUN) were reduced significantly after hesperetin treatment in vivo. Hesperetin provided hepatoprotective effects and inhibited xanthine oxidase activity markedly, altered the level of malondialdehyde (MDA), glutathione peroxidase (GSH-PX) and catalase (CAT), downregulated the XOD protein expression, toll-like receptor (TLR)4, nucleotide binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, interleukin-18 (IL-18), upregulated forkhead box O3a (FOXO3a), manganese superoxide dismutase (MnSOD) in a uric acid-synthesis model in mice. Protein expression of organic anion transporter 1 (OAT1), OAT3, organic cationic transporter 1 (OCT1), and OCT2 was upregulated by hesperetin intervention in a uric acid excretion model in mice. Our results proposal that hesperetin exerts a uric acid-lowering effect through inhibiting xanthine oxidase activity and protein expression, intervening in the TLR4-NLRP3 inflammasome signaling pathway, and up-regulating expression of FOXO3a, MnSOD, OAT1, OAT3, OCT1, and OCT2 proteins. Thus, hesperetin could be a promising therapeutic agent against hyperuricemia.
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A three-component umpolung cascade coupling reaction of phenols, C60 , and different nucleophiles which includes H2 O, alcohols, triphenylamines and carbazoles was developed. Furthermore, one-pot 1,4-bisphenol coupling on C60 has been realized by this method. This practical protocol features high chemo- and regioselectivity, wide substrate range, easy operation and low cost, thus providing a robust method for the one-pot synthesis of various unsymmetrical 1,4-[60]fullerephenols.
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BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), peculiarly nonalcoholic steatohepatitis (NASH), has become the main cause of liver transplantation and liver-related death. However, the US Food and Drug Administration has not approved a specific medication for treating NASH. Neferine (NEF), a natural bisbenzylisoquinoline alkaloid separated from the traditional Chinese medicine Nelumbinis plumula, has a variety of pharmacological properties, especially on metabolic diseases. Nevertheless, the anti-NASH effect and mechanisms of NEF remain unclear. PURPOSE: This study aimed to investigate the amelioration of NEF on NASH and the potential mechanisms. STUDY DESIGN: HepG2 cells, hepatic stellate cells (HSCs) and high-fat diet (HFD)+carbon tetrachloride (CCl4) induced C57BL/6 mice were used to observe the effect of NEF against NASH and investigate the engaged mechanism. METHODS: HSCs and HepG2 cells stimulated by oleic acid (OA) were treated with NEF. C57BL/6 mice were fed with HFD+CCl4 to induce NASH mouse model and treated with or without NEF (5 mg/kg or 10 mg/kg, once daily, i.p) for 4 weeks. RESULTS: NEF significantly attenuated the accumulation of lipid droplets, intracellular triglyceride (TG) levels and hepatocytes apoptosis in OA-exposed HepG2 cells. NEF not only enhanced the AMPK and ACC phosphorylation in OA-stimulated HepG2 cells, but also reduced inflammatory response and fibrosis in lipopolysaccharide (LPS)-stimulated HepG2 and in LX-2, respectively. In HFD+CCl4-induced NASH mice, pathological staining confirmed NEF treatment mitigated hepatic lipid deposition, inflammatory cell infiltration as well as hepatic fibrosis. Furthermore, the liver weight, serum and hepatic TG and total cholesterol (TC) and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were decreased compared with the model group. HFD+CCl4 also induced the upregulation of specific proteins and genes associated to inflammation (ILs, TNF-α, NLRP3, ASC, CCL2 and CXCL10) and hepatic fibrosis (collagens, α-SMA, TGF-ß and TIPM1), which were also suppressed by NEF treatment. CONCLUSION: Our results demonstrated that NEF played a protective role in hepatic steatosis via the regulation of AMPK pathways, which may serve as an attractive candidate for a potential novel strategy on prevention and treatment of NASH.
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Benzilisoquinolinas , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos Endogâmicos C57BL , Fígado , Benzilisoquinolinas/farmacologia , Cirrose Hepática/tratamento farmacológico , Dieta HiperlipídicaRESUMO
Increasing low-density lipoprotein receptor (LDLR) protein levels represents a key strategy for the prevention and treatment. Berberine can reportedly alleviate non-alcoholic fatty liver disease (NAFLD) by increasing the LDLR expression in an ERK1/2 signaling-dependent manner of NAFLD. Studies have shown that caffeine can inhibit fat deposition in the livers of mice; however, caffeine has not been reported to alleviate NAFLD by augmenting the LDLR expression via targeting EGFR. Here, an MTT assay, western blotting, RT-qPCR, immunohistochemistry, and surface plasmon resonance (SPR) analysis were used to investigate the role of caffeine in low-density lipoprotein cholesterol (LDL-C) clearance both in vitro and in vivo. In vitro, we found that caffeine could activate the EGFR-ERK1/2 signaling pathway in HepG2 cells, leading to increased LDLR mRNA and protein expression, and this effect could be inhibited by cetuximab. The SPR assay results have indicated that caffeine may increase the LDLR expression by directly binding to the EGFR extracellular domain and activating the EGFR-ERK1/2 signaling pathway. In vivo, caffeine markedly improved fatty liver and related blood indices in ApoE KO mice with high-fat-diet-induced NAFLD. Consistent with our in vitro results, we found that caffeine could also activate EGFR-ERK1/2 signaling and promote the LDLR expression in ApoE KO mice. In summary, caffeine can enhance the LDLR expression by directly binding to EGFR and activating the EGFR-ERK1/2 signaling pathway. EGFR signaling may represent a novel target for the prevention and treatment of NAFLD.