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1.
Front Pharmacol ; 15: 1456796, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39188952

RESUMEN

Osteoporosis is a common systemic metabolic disease characterized by a decrease in bone density and bone mass, destruction of bone tissue microstructure, and increased bone fragility leading to fracture susceptibility. Pharmacological treatment of osteoporosis is the focus of current research, and anti-osteoporosis drugs usually play a role in inhibiting bone resorption, promoting bone formation, and having a dual role. However, most of the drugs have the disadvantages of single target and high toxic and side effects. There are many types of traditional Chinese medicines (TCM), from a wide range of sources and mostly plants. Herbal plants have unique advantages in regulating the relationship between osteoporosis and the immune system, acupuncture therapy has significant therapeutic effects in combination with medicine for osteoporosis. The target cells and specific molecular mechanisms of TCM in preventing and treating osteoporosis have not been fully elucidated. At present, there is a lack of comprehensive understanding of the pathological mechanism of the disease. Therefore, a better understanding of the pathological signaling pathways and key molecules involved in the pathogenesis of osteoporosis is crucial for the design of therapeutic targets and drug development. In this paper, we review the development and current status of anti-osteoporosis drugs currently in clinical application and under development to provide relevant basis and reference for drug prevention and treatment of osteoporosis, with the aim of promoting pharmacological research and new drug development.

2.
Chemistry ; : e202402886, 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39212526

RESUMEN

The chemoselective [4+2] annulation/aromatization reactions between benzofuran-derived azadienes and N-Ts cyanamides are developed, affording a convenient method for synthesizing benzofuro[3,2-d]pyrimidin-2-amines under mild conditions. Herein, N-Ts cyanamides selectively participated in reactions absolutely via carbodiimide anion intermediates and the corresponding cyanamide anion intermediates derived products were not observed. The proposed chemoselective stepwise reaction mechanism was well supported by DFT calculations.

3.
Front Neurol ; 15: 1373306, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38952470

RESUMEN

Background: Cerebral small vessel disease (CSVD) is a common neurodegenerative condition in the elderly, closely associated with cognitive impairment. Early identification of individuals with CSVD who are at a higher risk of developing cognitive impairment is crucial for timely intervention and improving patient outcomes. Objective: The aim of this study is to construct a predictive model utilizing LASSO regression and binary logistic regression, with the objective of precisely forecasting the risk of cognitive impairment in patients with CSVD. Methods: The study utilized LASSO regression for feature selection and logistic regression for model construction in a cohort of CSVD patients. The model's validity was assessed through calibration curves and decision curve analysis (DCA). Results: A nomogram was developed to predict cognitive impairment, incorporating hypertension, CSVD burden, apolipoprotein A1 (ApoA1) levels, and age. The model exhibited high accuracy with AUC values of 0.866 and 0.852 for the training and validation sets, respectively. Calibration curves confirmed the model's reliability, and DCA highlighted its clinical utility. The model's sensitivity and specificity were 75.3 and 79.7% for the training set, and 76.9 and 74.0% for the validation set. Conclusion: This study successfully demonstrates the application of machine learning in developing a reliable predictive model for cognitive impairment in CSVD. The model's high accuracy and robust predictive capability provide a crucial tool for the early detection and intervention of cognitive impairment in patients with CSVD, potentially improving outcomes for this specific condition.

4.
Signal Transduct Target Ther ; 9(1): 181, 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38992067

RESUMEN

Mitotic catastrophe (MC), which occurs under dysregulated mitosis, represents a fascinating tactic to specifically eradicate tumor cells. Whether pyroptosis can be a death form of MC remains unknown. Proteasome-mediated protein degradation is crucial for M-phase. Bortezomib (BTZ), which inhibits the 20S catalytic particle of proteasome, is approved to treat multiple myeloma and mantle cell lymphoma, but not solid tumors due to primary resistance. To date, whether and how proteasome inhibitor affected the fates of cells in M-phase remains unexplored. Here, we show that BTZ treatment, or silencing of PSMC5, a subunit of 19S regulatory particle of proteasome, causes G2- and M-phase arrest, multi-polar spindle formation, and consequent caspase-3/GSDME-mediated pyroptosis in M-phase (designated as mitotic pyroptosis). Further investigations reveal that inhibitor of WEE1/PKMYT1 (PD0166285), but not inhibitor of ATR, CHK1 or CHK2, abrogates the BTZ-induced G2-phase arrest, thus exacerbates the BTZ-induced mitotic arrest and pyroptosis. Combined BTZ and PD0166285 treatment (named BP-Combo) selectively kills various types of solid tumor cells, and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 monotreatment. Studies using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment, and no obvious toxicity is observed in BP-Combo-treated mice. These findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase, characterize pyroptosis as a new death form of mitotic catastrophe, and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.


Asunto(s)
Bortezomib , Proteínas de Ciclo Celular , Mitosis , Complejo de la Endopetidasa Proteasomal , Proteínas Tirosina Quinasas , Piroptosis , Piroptosis/efectos de los fármacos , Humanos , Ratones , Animales , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Mitosis/efectos de los fármacos , Mitosis/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Bortezomib/farmacología , Línea Celular Tumoral , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Inhibidores de Proteasoma/farmacología , Pirimidinas/farmacología , Pirazoles/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Gasderminas , Pirimidinonas
5.
Diabetes Obes Metab ; 26(10): 4490-4500, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39075922

RESUMEN

AIM: To evaluate the effects of bariatric arterial embolization (BAE) on gastric emptying of, and the glycaemic response to, an oral glucose load in an obese canine model with impaired glucose tolerance. METHODS: Eleven male dogs were fed a high-fat, high-fructose diet for 7 weeks before receiving BAE, which involved selective embolization of the left gastric artery (n = 5; 14.9 ± 0.8 kg), or the sham (n = 6; 12.6 ± 0.8 kg) procedure. Postprocedural body weight was measured weekly for 4 weeks. Prior to and at 4 weeks postprocedure, a glucose solution containing 13C-acetate was administered orally for evaluation of the gastric half-emptying time (T50) and the glycaemic response. The relationship between the changes in the blood glucose area under the curve over the first 60 minutes (AUC0-60min) and the T50 was also assessed. RESULTS: At 4 weeks postprocedure, BAE reduced body weight (BAE vs. the sham procedure: -5.7% ± 0.9% vs. 3.5% ± 0.9%, P < .001), slowed gastric emptying (T50 at baseline vs. postprocedure: 75.5 ± 2.0 vs. 82.5 ± 1.8 minutes, P = .021 in the BAE group; 73.8 ± 1.8 vs. 74.3 ± 1.9 minutes in the sham group) and lowered the glycaemic response to oral glucose (AUC0-60min at baseline vs. postprocedure: 99.2 ± 13.7 vs. 67.6 ± 9.8 mmol·min/L, P = .043 in the BAE group; 100.2 ± 13.4 vs. 103.9 ± 14.6 mmol·min/L in the sham group). The change in the glucose AUC0-60min correlated inversely with that of the T50 (r = -0.711; P = .014). CONCLUSIONS: In a canine model with impaired glucose tolerance, BAE, while reducing body weight, slowed gastric emptying and attenuated the glycaemic response to an oral glucose load.


Asunto(s)
Glucemia , Embolización Terapéutica , Vaciamiento Gástrico , Intolerancia a la Glucosa , Obesidad , Animales , Perros , Vaciamiento Gástrico/efectos de los fármacos , Masculino , Glucemia/metabolismo , Obesidad/terapia , Obesidad/complicaciones , Obesidad/fisiopatología , Intolerancia a la Glucosa/terapia , Embolización Terapéutica/métodos , Periodo Posprandial , Artería Gástrica , Prueba de Tolerancia a la Glucosa , Modelos Animales de Enfermedad
6.
Food Chem X ; 22: 101289, 2024 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-38544933

RESUMEN

Oligosaccharides are low-molecular-weight carbohydrates between monosaccharides and polysaccharides. They can be extracted directly from natural products by physicochemical methods or obtained by chemical synthesis or enzymatic reaction. Oligosaccharides have important physicochemical and physiological properties. Their research and production involve many disciplines such as medicine, chemical industry, and biology. Functional oligosaccharides, as an excellent functional food base, can be used as dietary fibrer and prebiotics to enrich the diet; improve the microecology of the gut; exert antitumour, anti-inflammatory, antioxidant, and lipid-lowering properties. Therefore, the industrial applications of oligosaccharides have increased rapidly in the past few years. It has great prospects in the field of food and medicinal chemistry. This review summarized the preparation, structural features and biological activities of oligosaccharides, with particular emphasis on the application of functional oligosaccharides in the food industry and human nutritional health. It aims to inform further research and development of oligosaccharides and food chemistry.

7.
Sci Total Environ ; 897: 165429, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-37437627

RESUMEN

The bright coniferous forest area in the cold temperate zone of China is a terrestrial ecosystem primarily dominated by low mountain Larix gmelinii trees. Limited information is available regarding the assembly mechanisms and interactions of microbial communities in the soil in this region. This study employed high-throughput techniques to obtain DNA from myxomycetes, bacteria, and fungi in the soil, evaluated their diversity in conjunction with environmental factors, associated them with the assembly process, and explored the potential interaction relationships between these microorganisms. The findings of our study showed that environmental factors had a more significant influence on the α and ß diversity of bacteria compared to myxomycetes and fungi. Microbial communities were influenced by environmental selection and geographical diffusion, although environmental selection appeared to have a more significant impact than geographical diffusion. Our study suggested that different microorganisms exhibited unique evolutionary patterns and may have different assembly modes within phylogenetic groups. Myxomycetes and fungi exhibited a similar assembly process that was mainly influenced by stochastic dispersal limitation and drift. In contrast, bacteria's assembly process was primarily influenced by stochastic drift and deterministic homogeneous selection. The community of myxomycetes and fungi is greatly influenced by spatial distribution and random events, while bacteria have a relatively stable population composition in specific regions and may also be subject to environmental constraints. Finally, this study revealed that Humicolopsis cephalosporioides, a fungus that exclusively resided in cold environments, may play a critical role as a keystone species in maintaining molecular ecological networks and was considered a core member of the microbiome.


Asunto(s)
Suelo , Tracheophyta , Ecosistema , Filogenia , Microbiología del Suelo , Bosques , Hongos
8.
BMC Health Serv Res ; 23(1): 531, 2023 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-37226241

RESUMEN

BACKGROUND: In 2013, the Shanghai Hospital Development Center issued a policy to advocate public hospitals to report their information about costs on diseases. The objective was to evaluate the impact of interhospital disclosure of costs on diseases on medical costs and compare costs per case following information disclosure between hospitals of different rankings. METHODS: The study uses the hospital-level performance report issued by Shanghai Hospital Development Center in the fourth quarter of 2013, which covers quarterly aggregated hospital-level discharge data from 14 tertiary public hospitals participating in thyroid malignant tumors and colorectal malignant tumors information disclosure from the first quarter of 2012 to the third quarter of 2020. An interrupted time series model with segmented regression analysis is employed to examine changes in quarterly trends with respect to costs per case and length of stay before and after information disclosure. We identified high- and low-cost hospitals by ranking them on a costs per case basis per disease group. RESULTS: This research identified significant differences in cost changes for thyroid malignant tumors and colorectal malignant tumors between hospitals after disclosing information. A hospital's discharge costs per case for thyroid malignant tumors increased significantly among top-cost hospitals (1629.251 RMB, P = 0.019), while decreased for thyroid and colorectal malignant tumors among low-cost hospitals (-1504.189 RMB, P = 0.003; -6511.650 RMB, P = 0.024, respectively). CONCLUSION: Our findings indicate that information disclosure of costs on diseases results in changes in discharge costs per case. And low-cost hospitals continued to maintain their leading edge, whereas the high-cost hospitals changed their position in the industry by reducing discharge costs per case after information disclosure.


Asunto(s)
Neoplasias Colorrectales , Revelación , Humanos , Proyectos Piloto , China , Hospitales Públicos , Neoplasias Colorrectales/terapia
9.
Inquiry ; 60: 469580231167011, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37083281

RESUMEN

The aim of this meta-analysis was to comprehensively evaluate the effectiveness of Diagnosis-related group (DRG) based payment on inpatient quality of care. A comprehensive literature search was conducted in PubMed, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science from their inception to December 30, 2022. Included studies reported associations between DRGs-based payment and length of stay (LOS), re-admission within 30 days and mortality. Two reviewers screened the studies independently, extracted data of interest and assessed the risk of bias of eligible studies. Stata 13.0 was used in the meta-analysis. A total of 29 studies with 36 214 219 enrolled patients were analyzed. Meta-analysis showed that DRG-based payment was effective in LOS decrease (pooled effect: SMD = -0.25, 95% CI = -0.37 to -0.12, Z = 3.81, P < .001), but showed no significant overall effect in re-admission within 30 days (RR = 0.79, 95% CI = 0.62-1.01, Z = 1.89, P = .058) and mortality (RR = 0.91, 95% CI = 0.72-1.15, Z = 0.82, P = .411). DRG-based payment demonstrated statistically significant superiority over cost-based payment in terms of LOS reduction. However, owing to limitations in the quantity and quality of the included studies, an adequately powered study is necessary to consolidate these findings.


Asunto(s)
Atención a la Salud , Pacientes Internos , Humanos , Tiempo de Internación , Grupos Diagnósticos Relacionados , Calidad de la Atención de Salud
10.
Chem Commun (Camb) ; 59(28): 4189-4192, 2023 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-36939750

RESUMEN

Dimensionality plays a vital role at the nanoscale in tuning the electronical and photophysical properties and surface features of perovskite nanocrystals. Here, 3D and 1D all-inorganic CsPbBr3 nanocrystals were chosen as model materials to systemically reveal the dimensionality-dependent effect in photocatalytic H2 evolution. In terms of facilitating photoinduced electron-hole pair separation and charge transfer, as well as inducing proton reduction potential with the presence of fewer Br vacancies, 1D CsPbBr3 nanorods gave about a 5-fold improvement for solar H2 evolution.

11.
BMC Health Serv Res ; 23(1): 160, 2023 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-36793088

RESUMEN

CONTEXT: A patient classification-based payment system called diagnosis-intervention packet (DIP) was piloted in a large city in southeast China in 2018. OBJECTIVE: This study evaluates the impact of DIP payment reform on total costs, out-of-pocket (OOP) payments, length of stay (LOS), and quality of care in hospitalised patients of different age. METHODS: An interrupted time series model was employed to examine the monthly trend changes of outcome variables before and after the DIP reform in adult patients, who were stratified into a younger (18-64 years) and an older group (≥ 65 years), further stratified into young-old (65-79 years) and oldest-old (≥ 80 years) groups. RESULTS: The adjusted monthly trend of costs per case significantly increased in the older adults (0.5%, P = 0.002) and oldest-old group (0.6%, P = 0.015). The adjusted monthly trend of average LOS decreased in the younger and young-old groups (monthly slope change: -0.058 days, P = 0.035; -0.025 days, P = 0.024, respectively), and increased in the oldest-old group (monthly slope change: 0.107 days, P = 0.030) significantly. The changes of adjusted monthly trends of in-hospital mortality rate were not significant in all age groups. CONCLUSION: Implementation of the DIP payment reform associated with increase in total costs per case in the older and oldest-old groups, and reduction in LOS in the younger and young-old groups without deteriorating quality of care.


Asunto(s)
Gastos en Salud , Pacientes Internos , Anciano , Anciano de 80 o más Años , Humanos , China , Análisis de Series de Tiempo Interrumpido , Tiempo de Internación
12.
Angew Chem Int Ed Engl ; 62(7): e202214944, 2023 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-36510781

RESUMEN

A new way to form fluorenones via the direct excitation of substrates instead of photocatalyst to activate the C(sp2 )-H bond under redox-neutral condition is reported. Our design relies on the photoexcited aromatic aldehyde intermediates that can be intercepted by cobaloxime catalyst through single electron transfer for following ß-H elimination. The generation of acyl radical and successful interception by a metal catalyst cobaloxime avoid the use of a photocatalyst and stoichiometric external oxidants, affording a series of highly substituted fluorenones, including six-membered ketones, such as xanthone and thioxanthone derivatives in good to excellent yields, and with hydrogen as the only byproduct. This catalytic system features a readily available metal catalyst, mild reaction conditions and broad substrate scope, in which sunlight reaction and scale-up experiments by continuous-flow approach make the new methodology sustainable and amenable for potentially operational procedures.

13.
Mol Oncol ; 17(5): 901-916, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36495128

RESUMEN

The biological functions of short open reading frame (sORF)-encoded micropeptides remain largely unknown. Here, we report that LINC00998, a previously annotated lncRNA, was upregulated in multiple cancer types and the sORF on LINC00998 encoded a micropeptide named SMIM30. SMIM30 was localized in the membranes of the endoplasmic reticulum (ER) and mitochondria. Silencing SMIM30 inhibited the proliferation of hepatoma cells in vitro and suppressed the growth of tumor xenografts and N-nitrosodiethylamine-induced hepatoma. Overexpression of the 5'UTR-sORF sequence of LINC00998, encoding wild-type SMIM30, enhanced tumor cell growth, but this was abolished when a premature stop codon was introduced into the sORF via single-base deletion. Gain- and loss-of-function studies revealed that SMIM30 peptide but not LINC00998 reduced cytosolic calcium level, increased CDK4, cyclin E2, phosphorylated-Rb and E2F1, and promoted the G1/S phase transition and cell proliferation. The effect of SMIM30 silencing was attenuated by a calcium chelator or the agonist of sarco/endoplasmic reticulum calcium ATPase (SERCA) pump. These findings suggest a novel function of micropeptide SMIM30 in promoting G1/S transition and cell proliferation by enhancing SERCA activity and reducing cytosolic calcium level.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , Calcio/metabolismo , ATPasas Transportadoras de Calcio/metabolismo , Ciclo Celular , Micropéptidos
14.
Front Aging Neurosci ; 14: 985679, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36437987

RESUMEN

Objective: Reliable electrophysiological indicators are urgently needed in the precise evaluation of Parkinson's disease (PD). It is still elusive whether oculomotor performance is impaired or has clinical value in early PD. This study aims to explore oculomotor performance in newly diagnosed, drug-naïve PD and its correlation with clinical phenotype. Methods: Seventy-five patients with de novo PD, 75 patients with essential tremor (ET), and 46 gender-and age-matched healthy controls (HCs) were included in this cross-sectional study. All subjects underwent oculomotor test via videonystagmography. Visually guided saccade latency, saccadic accuracy and gain in smooth pursuit eye movement (SPEM) at three frequencies of the horizontal axis were compared among the three groups. Patients with PD also received detailed motor and non-motor evaluation by serial scales. The association between key oculomotor parameters and clinical phenotypes were explored in PD patients. Results: Both de novo PD and ET patients showed prolonged saccadic latency and decreased saccadic accuracy relative to HCs. SPEM gain in PD was uniformly reduced at each frequency. SPEM gain at 0.4 Hz was also decreased in ET compared with HCs. However, there was no significant difference of oculomotor parameters between de novo PD and ET patients. Furthermore, prolonged saccadic latency was correlated with long disease duration, whereas decreased SPEM gain was associated with severe motor symptoms in de novo PD patients. Conclusion: Ocular movements are impaired in de novo, drug naïve PD patients; these changes could be indicators for disease progression in PD.

16.
Eur J Med Chem ; 244: 114848, 2022 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-36274277

RESUMEN

Myocardial ischemia/reperfusion (MI/R) injury is still the huge unmet medical need without effective therapy in clinic. It is critical to develop pharmacological intervention to scavenge ROS and inhibit NLRP3 activation to have a double benefit against MI/R injury. Cinnamamide derivatives have been demonstrated to possess anti-oxidative and anti-inflammatory activities. Previously, we have reported that a cinnamamide derivative 2 exerts excellent cardioprotective effect via mediation of intracellular oxidative stress via Nrf2 up-regulation against MI/R. In the present study, seventeen compounds have been optimized using cinnamamide-barbiturate hybrid 2 as the lead compound and their cardioprotective activities against MI/R were further determined in vitro and in vivo. Among them, compound 7 showed the most potent cardioprotective effect and low cytotoxicity. While cardiomyocytes were invased by hydrogen peroxide, compound 7 exhibited more excellent cardioprotective effect than that of luteolin and metoprolol, the positive control employed in the present study, as demonstrated by dramatically elevated cell survival rate and decreased LDH leakage rate. Moreover, compound 7 markedly inhibited cardiac expressions of inflammasome activation and pro-inflammatory cytokines release (i.e. NLRP3, IL-1ß, IL-18), simultaneouly increasing endogenous antioxidative proteins (i.e. Nrf2, HO-1 and SOD) in vitro. In the rat MI/R model, compound 7 pretreatment profoundly reduced cardiac infarct size in MI/R rats and reversed abnormal changes in myocardial enzymes and lipid peroxidation levels in heart tissues. Mechanistically, compound 7 revealed significant cardioprotective effects by inhibiting NLRP3 and its downstream inflammatory chemokine IL-1ß, as well as up-regulating Nrf2 in vivo. Furthermore, at the active site of the co-crystal of NLRP3 and Nrf2, compound 7 exhibited higher binding force in the molecular docking study, which was consistent with the in vitro results. Therefore, compound 7 is expected to be a potential cardioprotective agent possessing dual anti-inflammatory and anti-oxidative activities. Our work provides an important therapeutic strategy for the treatment of ischemic-reperfused heart disease.


Asunto(s)
Antiinflamatorios , Cardiotónicos , Cinamatos , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Animales , Ratas , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Cardiotónicos/química , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Simulación del Acoplamiento Molecular , Isquemia Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Cinamatos/química , Cinamatos/farmacología , Cinamatos/uso terapéutico
17.
J Am Chem Soc ; 144(37): 17261-17268, 2022 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-36070360

RESUMEN

Direct CAr-F arylation is effective and sustainable for synthesis of polyfluorobiaryls with different degrees of fluorination, which are important motifs in medical and material chemistry. However, with no aid of transition metals, the engagement of CAr-F bond activation has proved difficult. Herein, an unprecedented transition-metal-free strategy is reported for site-selective CAr-F arylation of polyfluoroarenes with simple (het)arenes. By merging N,N-bis(2,6-diisopropylphenyl)perylene-3,4,9,10-bis(dicarboximide)-catalyzed electrophotocatalytic reduction and anodic nitroxyl radical oxidation in an electrophotocatalytic cell, various polyfluoroaromatics (2F-6F and 8F), especially inactive partially fluorinated aromatics, undergo sacrificial-reagents-free C-F bond arylation with high regioselectivity, and the yields are comparable to those for reported transition-metal catalysis. This atom- and step-economic protocol features a paired electrocatalysis with organic mediators in both cathodic and anodic processes. The broad substrate scope and good functional-group compatibility highlight the merits of this operationally simple strategy. Moreover, the easy gram-scale synthesis and late-stage functionalization collectively advocate for the practical value, which would promote the vigorous development of fluorine chemistry.


Asunto(s)
Perileno , Elementos de Transición , Catálisis , Flúor/química , Estructura Molecular
18.
Bioorg Chem ; 124: 105828, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35490584

RESUMEN

Myocardial ischemia/reperfusion (MI/R) has been a challenge for global public health. Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling could attenuate MI/R injury by maintaining cell redox balance and reducing oxidative damage. Cinnamamide derivatives have been proven to be a class of potential Nrf2 activators and cardioprotective agents. The development of novel cinnamamide derivatives to combat oxidative stress in cardiomyocytes is highly desirable. In this study, twenty-three cinnamamide-barbiturate hybrids were studied. Cell-based assays showed that most of the compounds exhibited excellent protective activity against H2O2-induced oxidative injury in H9c2 cells. Notably, compound 7w, which had the highest activity and low cytotoxicity, was demonstrated to remarkably reduce intracellular ROS accumulation by activating the mRNA expression of Nrf2 and its downstream antioxidant gene HO-1, indicating a novel promising antioxidant and Nrf2 activator. The probable binding mode between protein Keap1 and compound 7w was also studied via molecule docking. Furthermore, we found that the administration of compound 7w could significantly reduce the cardiac infarct size and improve the cardiac function against MI/R injury in rats, as well as decrease cardiac oxidative stress. Taken together, we report, for the first time, that cinnamamide-barbiturate hybrids are a novel class of potential cardioprotective agents. The excellent cardioprotective action of such compounds rely on enhancing the endogenous antioxidative system by upregulating the Nrf2 signaling pathway in vitro and in vivo against MI/R damage. These findings provide a new perspective for designing cinnamamide-barbiturate hybrids as a novel class of Nrf2 activator against cardiovascular diseases.


Asunto(s)
Daño por Reperfusión Miocárdica , Animales , Antioxidantes/farmacología , Barbitúricos/farmacología , Cardiotónicos/metabolismo , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Cinamatos , Peróxido de Hidrógeno/farmacología , Proteína 1 Asociada A ECH Tipo Kelch , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Ratas
19.
Cell Death Dis ; 12(11): 970, 2021 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-34671012

RESUMEN

Oncogenic c-Myc is a master regulator of G1/S transition. Long non-coding RNAs (lncRNAs) emerge as new regulators of various cell activities. Here, we found that lncRNA SnoRNA Host Gene 17 (SNHG17) was elevated at the early G1-phase of cell cycle. Both gain- and loss-of function studies disclosed that SNHG17 increased c-Myc protein level, accelerated G1/S transition and cell proliferation, and consequently promoted tumor cell growth in vitro and in vivo. Mechanistically, the 1-150-nt of SNHG17 physically interacted with the 1035-1369-aa of leucine rich pentatricopeptide repeat containing (LRPPRC) protein, and disrupting this interaction abrogated the promoting role of SNHG17 in c-Myc expression, G1/S transition, and cell proliferation. The effect of SNHG17 in stimulating cell proliferation was attenuated by silencing c-Myc or LRPPRC. Furthermore, silencing SNHG17 or LRPPRC increased the level of ubiquitylated c-Myc and reduced the stability of c-Myc protein. Analysis of human hepatocellular carcinoma (HCC) tissues revealed that SNHG17, LRPPRC, and c-Myc were significantly upregulated in HCC, and they showed a positive correlation with each other. High level of SNHG17 or LRPPRC was associated with worse survival of HCC patients. These data suggest that SNHG17 may inhibit c-Myc ubiquitination and thus enhance c-Myc level and facilitate proliferation by interacting with LRPPRC. Our findings identify a novel SNHG17-LRPPRC-c-Myc regulatory axis and elucidate its roles in G1/S transition and tumor growth, which may provide potential targets for cancer therapy.


Asunto(s)
Proliferación Celular/genética , Fase G1/genética , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Largo no Codificante/metabolismo , Fase S/genética , Animales , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Células HEK293 , Humanos , Masculino , Ratones , Modelos Biológicos , Proteínas de Neoplasias/genética , Fosforilación , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-myc/genética , ARN Largo no Codificante/genética , Regulación hacia Arriba/genética
20.
Org Lett ; 23(20): 8082-8087, 2021 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-34609892

RESUMEN

An aerobic metal-free, visible-light-induced regioselective thiolation of phenols with thiophenols is reported. The cross-coupling protocol exhibits great functional group tolerance and high regioselectivity. Mechanistic studies reveal that the disulfide radical cation plays a crucial role in the visible-light catalysis of aerobic thiolation. Simply controlling the equivalent ratio of substrates enables the selective formation of sulfide or sulfoxide products with high activity in a one-pot reaction.

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