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1.
Curr Drug Metab ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33605854

RESUMO

BACKGROUND: Caesalpinia sappan L. is a traditional medicinal plant that is used to promote blood circulation and treat stroke in China. Protosappanin B (PTB) is a unique homoisoflavone compound isolated from Sappan Lignum (the heartwood of Caesalpinia sappan L). In a previous study, the metabolic fate of PTB remained unknown. OBJECTIVE: To explore whether PTB is extensively metabolized, the metabolites of PTB in bile, plasma, urine, feces, and intestinal bacteria samples in rats were investigated. METHOD: The biosamples were investigated by ultraperformance liquid chromatography combined with time-of-flight mass spectrometry (UPLC-TOF-MS/MS) with MetabolitePilot software. RESULT: 28 metabolites were identified in the biosamples: 18 metabolites in rat bile, 8 in plasma, 20 in feces, 7 in urine and 2 in intestinal bacteria samples. Both phase I and phase II metabolites were observed. Metabolite conversion occurred via 9 proposed pathways: sulfate conjugation, glucuronide conjugation, bis-glucuronide conjugation, glucose conjugation, dehydration, oxidation, hydrolysis, methylation and hydroxymethylene loss. The metabolic pathways differed among biosamples and exhibited different distributions. Among these pathways, the most important were sulfate and glucuronide conjugation. CONCLUSION: The results showed that the small intestinal and biliary routes play an important role in the clearance and excretion of PTB. The main sites of metabolism in the PTB chemical structure were the phenolic hydroxyl and the side-chains on the eight-element ring.

2.
Eur J Med Chem ; 215: 113273, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33601310

RESUMO

In this study, a series of pyrrolo [2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one fragment were synthesized and their biological activity were tested. Most of the target compounds displayed moderate to excellent activity against one or more cancer cell lines and low activity against human normal cell LO2 in vitro. The most promising compound 51, of which the IC50 values were 0.66 µM, 0.38 µM and 0.44 µM against cell lines A549, Hela and MCF-7, shown more remarkable activity and better apoptosis effect than the positive control Cabozantinib. The structure-activity relationships (SARs) indicated that double-EWGs (such as R3 = 2-Cl-4-CF3) on the terminal phenyl rings was a key factor in improving the biological activity. In addition, the further research on compound 51 mainly included c-Met kinase activity and selectivity, concentration dependence, and molecular docking.

3.
J Org Chem ; 86(3): 2827-2839, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33467848

RESUMO

A protocol for the preparation of 7-amido indoles via regioselective C-H bond functionalization has been first accomplished under Ru(II) catalysis. Indole derivatives and 4-aryl/heteroaryl/benzyl/alkyl dioxzaolines containing various substituents were applicable for this transformation, readily providing the amidated indoles in moderate to good yields. This novel process has many advantages, including good compatibility with diverse functional groups, broad substrate scopes, and mild reaction conditions. Deuteration studies and control experiments have been performed to understand the mechanism of this transformation.

4.
Aging (Albany NY) ; 13(3): 4409-4427, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33495414

RESUMO

Vascular remodeling is a pertinent target for cardiovascular therapy. Vascular smooth muscle cell (VSMC) dysfunction plays a key role in vascular remodeling. Myeloid differentiation 2 (MD2), a cofactor of toll-like receptor 4 (TLR4), is involved in atherosclerotic progress and cardiac remodeling via activation of chronic inflammation. In this study, we explored the role of MD2 in vascular remodeling using an Ang II-induced mouse model and cultured human aortic VSMCs. MD2 deficiency suppressed Ang II-induced vascular fibrosis and phenotypic switching of VSMCs without affecting blood pressure in mice. Mechanistically, MD2 deficiency prevented Ang II-induced expression of inflammatory cytokines and oxidative stress in mice and cultured VSMCs. Furthermore, MD2 deficiency reversed Ang II-activated MAPK signaling and Ang II-downregulated SIRT1 expression. Taken together, MD2 plays a significant role in Ang II-induced vascular oxidative stress, inflammation, and remodeling, indicating that MD2 is a potential therapeutic target for the treatment of vascular remodeling-related cardiovascular diseases.

5.
Biochim Biophys Acta Mol Basis Dis ; 1867(3): 166043, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33338595

RESUMO

Angiotensin II (Ang II)-induced vascular inflammation and injury entails endothelial to mesenchymal transition (EndMT). Recent studies have shown that Ang II engages toll-like receptor 4 (TLR4) in the vasculature to mediate adverse effects. Here, we aimed to investigate whether myeloid differentiation protein 2 (MD2), an extracellular molecule indispensable for TLR4 activation, mediates Ang II-induced vascular injury and EndMT. We utilized MD2 knockout mice and wildtype mice treated with a specific MD2 inhibitor to decipher its role in aortas of Ang II-challenged mice. To confirm our results and to provide mechanistic insights, we exposed cultured endothelial cells to Ang II, with or without MD2 silencing. We show that Ang II causes deleterious remodeling and EndMT in aortas of mice within two weeks. These Ang II effects were largely absent in MD2 knockout mice and in wildtype mice treated with a MD2 inhibitor. MD2 silencing in cultured endothelial cells confirmed the essential role of MD2 in Ang II-induced inflammatory factor induction, and EndMT-associated phenotypic change. We also found that Ang II-MD2-EndMT axis involves the activation of nuclear factor-κB. Our studies highlight an essential role of MD2 in Ang II-induced vascular inflammation and EndMT contributing to vascular injury. These results also imply that MD2 may be targeted to dampen inflammatory cardiovascular and EndMT-associated diseases.

6.
Aging (Albany NY) ; 13(2): 2553-2574, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33318302

RESUMO

Excessive vascular remodeling has been shown in hypertensive patients. In experimental models of hypertensive vascular injury, such as angiotensin II (Ang II) challenged mice, toll like receptor 2 (TLR2) initiates inflammatory responses. More recently, studies have reported atypical endothelial to mesenchymal transition (EndMT) in vascular injuries and inflammatory conditions. Here, we aimed to investigate whether TLR2 mediates Ang II-induced vascular inflammation and initiates EndMT. In a mouse model of angiotensin II-induced hypertension, we show that aortas exhibit increased medial thickening, fibrosis, and features of EndMT. These alterations were not observed in TLR2 knockout mice in response to Ang II. TLR2 silencing in cultured endothelial cells confirmed the essential role of TLR2 in Ang II-induced inflammatory factor induction, and EndMT-associated phenotypic change. Mechanistically, we found Ang II activates nuclear factor-κB signaling, inducing pro-inflammatory cytokine production, and mediates EndMT in both cultured endothelial cells and in mice. These studies illustrate a novel role of TLR2 in regulating Ang II-induced deleterious vascular remodeling through the induction of EndMT. The studies also suggest that TLR2 may be targeted to alleviate hypertension-associated vascular injury.

7.
Toxicol Appl Pharmacol ; 409: 115322, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33171189

RESUMO

Diabetic nephropathy is the leading cause of renal failure worldwide. Elevated inflammatory signaling has been shown to lead to deterioration of renal function in human and experimental diabetes. We recently developed a salviadione derivative (compound 15a) that prevented microbial lipopolysaccharide-induced inflammatory responses, which are largely driven by nuclear factor-κB (NF-κB). In the present study, we have tested the hypothesis that 15a will protect kidneys from diabetes-induced dysfunction by suppressing NF-κB activation and inflammatory signaling. Treatment of diabetic mice with 15a inhibited diabetes-induced renal fibrosis, NF-κB activation, and upregulation of proinflammatory cytokines. Histologically, kidney specimens from diabetic mice treated with 15a were indistinguishable from non-diabetic controls. We confirmed our findings in cultured renal tubular epithelial cells exposed to high levels of glucose. In these cultured cells, 15a pretreatment prevented high glucose-induced NF-κB activation and expression of inflammatory cytokines. These protective effects were also reflected in reduced levels of proteins involved in matrix expansion. Overall, our studies show that a salviadione derivative, 15a, is effective in suppressing diabetes-induced NF-κB activation and inflammatory signaling.

8.
J Ethnopharmacol ; : 113553, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33152432

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Kaempferia rhizome is a famous traditional herbal medical in tropical and subtropical areas. Kaempferol (KPF) is one of the main bioactive compounds in Kaempferia rhizome, with anti-oxidant/anti-inflammatory effects demonstrated in various disease models, including cancers, obesity and diabetes. AIM OF THE STUDY: Inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). TRAF6 functions as a signal transducer in toll-like receptor 4 and NF-κB pro-inflammatory signaling pathway. We aimed at investigate whether KPF is able to mitigate inflammatory responses by regulating TRAF6 in DN. MATERIAL AND METHODS: C57BL/6 mice were injected with streptozotocin to induce type 1 DN. NRK-52E, a tubular epithelial cell line, was used for in vitro analysis. TRAF6 was knockdown using siRNA in vitro and AAV2/2-shRNA in vivo. The anti-DN and inflammatory effects of KPF or knockdown of TRAF6 were evaluated by investigating renal filtration index, pathological changes of kidney tissue. Proinflammatory cytokine levels were detected using ELISA. NF-κB pathway and protein levels of related pathways were detected through Western blot. RESULTS: KPF significantly reduced renal inflammation, fibrosis, and kidney dysfunction in diabetic mice. These effects were associated with a downregulation of TRAF6 in diabetic mouse kidneys, indicating the potential role of TRAF6. Knockdown of TRAF6 in mice through AAV2-shTRAF6 confirmed the importance of TRAF6 in DN. In vitro, treatment of KPF in NRK-52E cells attenuated high glucose (HG)-induced inflammatory and fibrogenic responses, associated with downregulated TRAF6 expression. The conclusion was further confirmed in NRK-52E cells by knocking down the expression and by overexpression of TRAF6. CONCLUSION: Our findings provide direct evidence that TRAF6 mediates diabetes-induced inflammation leading to renal dysfunction. We also show that KPF is a potential therapeutic agent to reduce inflammatory responses in DN. Also, TRAF6 may represent an interesting target to combat DN.

9.
Front Cell Dev Biol ; 8: 580517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072762

RESUMO

Colon cancer is one of the leading causes of cancer-related death in the world. The development of new drugs and therapeutic strategies for patients with colon cancer are urgently needed. Isodeoxyelephantopin (ESI), a sesquiterpene lactone isolated from the medicinal plant Elephantopus scaber L., has been reported to exert antitumor effects on several cancer cells. However, the molecular mechanisms underlying the action of ESI is still elusive. In the present study, we found that ESI potently suppressed cell proliferation in human colon cancer cells. Furthermore, our results showed that ESI treatment markedly increased cellular reactive oxygen species (ROS) levels by inhibiting thioredoxin reductase 1 (TrxR1) activity, which leads to activation of the JNK signaling pathway and eventually cell death in HCT116 and RKO cells. Importantly, we found that ESI markedly enhanced cisplatin-induced cytotoxicity in HCT116 and RKO cells. Combination of ESI and cisplatin significantly increased the production of ROS, resulting in activation of the JNK signaling pathway in HCT116 and RKO cells. In vivo, we found that ESI combined with cisplatin significantly suppressed tumor growth in HCT116 xenograft models. Together, our study provide a preclinical proof-of-concept for ESI as a potential strategy for colon cancer treatment.

10.
J Clin Transl Hepatol ; 8(3): 285-291, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33083251

RESUMO

Background and Aims: This study was designed to analyze the effects of age and clinicopathological characteristics on prognosis of Chinese patients with hepatocellular carcinoma (HCC). Methods: The clinical data of 2032 HCC patients who were first diagnosed with HCC and underwent curative hepatectomy in our hospital between January 2006 and January 2011 were retrospectively analyzed. Results: Younger HCC patients (age <40 years, n=465) had a significantly higher hepatitis B infection rate, larger tumors, higher alpha-fetoprotein levels, higher preoperative liver function, and more frequent vascular invasions than older patients. Most younger patients were suitable for anatomical hepatectomy, and their tumors were found to be at a highly advanced stage. The recurrence-free survival and overall survival rates of younger HCC patients were significantly worse than those of older patients but this difference disappeared after propensity score matching. Multivariate analysis of pre-matched samples showed that age ≤40 years was one of the independent risk factors associated with poor overall survival. Conclusions: Younger patients showed different clinicopathological characteristics than older patients, such as higher rates of hepatitis B infection and advanced tumors. The recurrence-free survival and overall survival rates of younger HCC patients after hepatectomy may be similar to those of older patients.

11.
Theranostics ; 10(22): 10290-10308, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32929349

RESUMO

Background: Oxidative stress from elevated reactive oxygen species (ROS) has been reported to induce cell apoptosis and may provide a means to target cancer cells. Celastrol is a natural bioactive compound that was recently shown to increase ROS levels and cause apoptosis in cancer cells. However, the underlying mechanism for this cytotoxic action remains unclear and direct molecular targets of Celastrol have not been identified. Methods: Proteome microarray, surface plasmon resonance, isothermal titration calorimetry and molecular simulation were used to identify the molecular target of Celastrol. Binding and activity assays were used to validate the interaction of Celastrol with target protein in cell-free and gastric cancer cell lysates. We then assessed target transcript levels in in biopsy specimens obtained from patients with gastric cancer. Gastric cancer growth-limiting and cytotoxic activity of Celastrol was evaluated in BALB/c nu/nu mice. Results: Our data show that Celastrol directly binds to an antioxidant enzyme, peroxiredoxin-2 (Prdx2), which then inhibits its enzyme activity at both molecular and cellular level. Inhibition of Prdx2 by Celastrol increased cellular ROS levels and led to ROS-dependent endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis in gastric cancer cells. Functional tests demonstrated that Celastrol limits gastric cancer cells, at least in part, through targeting Prdx2. Celastrol treatment of mice implanted with gastric cancer cells also inhibited tumor growth, associated with Prdx2 inhibition and increased ROS. Analysis of human gastric cancer also showed increased Prdx2 levels and correlation with survival. Conclusion: Our studies have uncovered a potential Celastrol-interacting protein Prdx2 and a ROS-dependent mechanism of its action. The findings also highlight Prdx2 as a potential target for the treatment of gastric cancer.

12.
Phytomedicine ; 78: 153319, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32950951

RESUMO

BACKGROUND: Inflammation and oxidative stress play essential roles in the occurrence and progression of diabetic cardiomyopathy (DCM). Isoliquiritigenin (ISL), a natural chalcone, exhibits strong anti-inflammatory and antioxidant activities. HYPOTHESIS/PURPOSE: In this study, we aimed to investigate the protective effects of ISL on DCM using high glucose (HG)-challenged cultured cardiomyocytes and streptozotocin (STZ)-induced diabetic mice. STUDY DESIGN AND METHODS: Embryonic rat heart-derived H9c2 cells challenged with a high concentration of glucose were used to evaluate the anti-inflammatory and antioxidant effects of ISL. STZ-induced diabetic mice were used to study the effects of ISL in DCM in vivo. Furthermore, cardiac fibrosis, hypertrophy, and apoptosis were explored both in vitro and in vivo. RESULTS: ISL effectively inhibited HG-induced hypertrophy, fibrosis, and apoptosis probably by alleviating the inflammatory response and oxidative stress in H9c2 cells. Results from in vivo experiments showed that ISL exhibited anti-inflammatory and antioxidant stress activities that were characterized by the attenuation of cardiac hypertrophy, fibrosis, and apoptosis, which resulted in the maintenance of cardiac function. The protective effects of ISL against inflammation and oxidative stress were mediated by the inhibition of mitogen-activated protein kinases (MAPKs) and induction of nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway, respectively. CONCLUSION: Our results provided compelling evidence that ISL, by virtue of neutralizing excessive inflammatory response and oxidative stress, could be a promising agent in the treatment of DCM. Targeting the MAPKs and Nrf2 signaling pathway might be an effective therapeutic strategy for the prevention and treatment of DCM.


Assuntos
Antioxidantes/farmacologia , Chalconas/farmacologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Glucose/metabolismo , Glucose/farmacologia , Hiperglicemia/tratamento farmacológico , Hiperglicemia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina
13.
J Med Chem ; 63(22): 13316-13329, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-32931267

RESUMO

Myeloid differentiation primary response protein 88 (MyD88) is a ubiquitously expressed cytoplasmic adaptor protein that plays a central role in the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways. TLR/IL-1R pathways regulate the proliferation and differentiation of cells involved in the innate and adaptive immunity. Although the general TLR/IL-1R activation cascade is well understood, the molecular mechanisms involving MyD88 have only begun to surface in the past decade. In this review, we explore MyD88 structural biology, the role of posttranslational modifications (PTMs), and the recent developments in MyD88 inhibitor discovery and use. We also highlight the potential application of MyD88-targeted therapies in human diseases.

14.
Cell Death Dis ; 11(8): 666, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820146

RESUMO

Macrophages, with diverse functions and variable phenotypes, are considered as an important executor of inflammatory diseases. And it has been proved that autophagy is deeply connected with the development of inflammation, while the exact regulatory mechanism still remains unclear, and the application of autophagy regulators in anti-inflammation needs to be further confirmed. Here, we firstly verified that neochromine S5 (hereinafter referred to as S5) significantly inhibited M1-like macrophage polarization with decrease of the proinflammatory cytokines and downregulation of NF-κB and STAT1 signals. Then, in vivo experiments demonstrated S5 improved cecal ligation and puncture (CLP)-induced sepsis specially based on the regulation of M1-like macrophages. Mechanistic studies indicated that S5 treatment dramatically upregulated cellular autophagy in M1-like macrophage. Furthermore, by multiple methods, S5 was revealed to directly bind with ubiquitin-specific proteases 14 (USP14) at Ser404, Phe405, and Cys414 by hydrogen bond to inhibit its deubiquitinating activity, and block USP14-TRAF6 (TNF receptor associated factor 6) interaction, subsequently promoting ubiquitination of Beclin1, interrupting Beclin1-Bcl2 interaction, and accumulating the autophagosome in macrophages, which finally resulted in the blockade of M1-like macrophage polarization. Animal experiments also confirmed the protection of S5 in CLP mice was dependent on activation of macrophage autophagy. What's more, as a novel USP14 inhibitor, S5 exhibited higher efficiency and safety than IU1, the known USP14 inhibitor. Therefore, this study has demonstrated that typically inhibiting USP14 promotes autophagy in M1-like macrophages and alleviates CLP-induced sepsis. Moreover, we provide a new candidate compound, S5, for sensitizing autophagy to interfere with the macrophage inflammation.

15.
Trends Endocrinol Metab ; 31(10): 712-724, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32807598

RESUMO

Metabolic diseases pose a tremendous health threat in both developed and developing countries. The pathophysiology of metabolic diseases is complex but has been shown to be closely associated with sterile inflammation, which is initiated by various danger molecules derived from metabolic overload, such as oxidized low-density lipoproteins (OxLDLs), free fatty acids (FFAs), glucose, advanced glycation end products (AGEs), and cholesterol. These danger signals are sensed by pattern recognition receptors (PRRs) to activate proinflammatory signaling pathways and promote the release of proinflammatory mediators, leading to chronic low-grade inflammation. Although these harmful metabolic stimuli are generally regarded as damage-associated molecular patterns (DAMPs), a more specific definition and accurate classification for these DAMPs is still missing. In this opinion, we classify the harmful metabolic stimuli that can incite inflammatory responses and tissue damage via instigating PRRs as metabolism-associated molecular patterns (MAMPs), and we summarize their roles in metaflammation-mediated metabolic diseases.

16.
Med Res Rev ; 40(6): 2466-2484, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32648967

RESUMO

The innate immune system contains multiple classes of pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the intracellular and extracellular space. Although PRRs are indispensable for the detection and clearance of invading pathogens, dysregulated PRR activation by extrinsic and intrinsic factors leads to inflammatory diseases. PRR-mediated inflammation has been shown to play a pivotal role in the pathogenesis of diabetic vascular complications (DVCs), which are the leading causes of morbidity and mortality in diabetic patients. Upon sensing hyperglycemia-generated DAMPs, PRRs activate intracellular signaling pathways leading to the production of proinflammatory cytokines and chemokines in various cells of the kidney, brain, eye, and heart. The resulting chronic, low-grade inflammation contributes to DVCs. In this review, we summarize the role of PRRs in DVCs including diabetic nephropathy, neuropathy, retinopathy, and cardiomyopathy. We propose that targeting PRRs and associated signaling pathways may be beneficial for the management of DVCs.

17.
Cell Death Dis ; 11(7): 571, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709922

RESUMO

Oxysterol-binding protein like protein 3 (OSBPL3) has been shown involving in the development of several human cancers. However, the relationship between OSBPL3 and colorectal cancer (CRC), particularly the role of OSBPL3 in the proliferation, invasion and metastasis of CRC remains unclear. In this study, we investigated the role of OSBPL3 in CRC and found that its expression was significantly higher in CRC tissues than that in normal tissues. In addition, high expression of OSBPL3 was closely related to poor differentiation, advanced TNM stage and poor prognosis of CRC. Further experiments showed that over-expression of OSBPL3 promoted the proliferation, invasion and metastasis of CRC in vitro and in vivo models. Moreover, we revealed that OSBPL3 promoted CRC progression through activation of RAS signaling pathway. Furthermore, we demonstrated that hypoxia induced factor 1 (HIF-1A) can regulate the expression of OSBPL3 via binding to the hypoxia response element (HRE) in the promoter of OSBPL3. In summary, Upregulation of OSBPL3 by HIF1A promotes colorectal cancer progression through activation of RAS signaling pathway. This novel mechanism provides a comprehensive understanding of both OSBPL3 and the RAS signaling pathway in the progression of CRC and indicates that the HIF1A-OSBPL3-RAS axis is a potential target for early therapeutic intervention in CRC progression.

18.
J Org Chem ; 85(14): 9230-9243, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32578431

RESUMO

An efficient route for the coupling of maleimides with chromones at the C5-position has been developed under Ru(II) catalysis. It could provide 1,4-addition products and oxidative Heck-type products by switching additives. Benzoic acid led to the formation of 1,4-addition products under solvent-free conditions, and silver acetate was promoted to the generation of oxidative Heck-type products. Various maleimides and chromones were suitable for this transformation, affording the desired products with good to excellent yields in a short reaction time. To understand the mechanism of this reaction, deuteration studies and control experiments have been performed.

19.
J Chem Inf Model ; 60(6): 3231-3245, 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32364718

RESUMO

Hemolytic toxicity, as one of the key toxicity endpoints for small molecules, can cause lysis of the erythrocyte membrane and subsequent release of hemoglobin into blood plasma, leading to multiple acute and chronic adverse effects. Hence, it is necessary to assess the hemolytic toxicity of small molecules in an early stage of drug discovery and development process, and it is more significant to quantitatively predict the hemolytic toxicity of small molecules before costly and time-consuming experiments. Nevertheless, this endpoint has never been quantitatively predicted due to the lack of an appropriate dataset. In this work, we manually collected a quantitative hemolytic toxicity dataset containing 805 small molecules with experimental values of HD50 (50% hemolytic dose) from a variety of literature, built the first machine learning-based regression model to quantitatively predict the hemolytic toxicity of small molecules, and developed a pragmatic software for automatic prediction. Based on this model, we further implemented an automatic recursive fragmentation module to predict the hemolytic fragments with high fragment efficiency for the given compound(s), which may be of particular interest to experimental medicinal chemists. Therefore, we anticipate that this quantitative model may help medicinal chemists boost the development of promising lead compounds with low hemolytic toxicity or fuel the discovery of highly hemolytic chemical probes to delve into the in-depth mechanism of the hemolytic process.

20.
Nat Commun ; 11(1): 2148, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358497

RESUMO

Hyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM). However, the mechanisms of TLR4 activation remain unclear. Here we examine the role of myeloid differentiation 2 (MD2), a co-receptor of TLR4, in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. We show increased MD2 in heart tissues of diabetic mice and serum of human diabetic subjects. MD2 deficiency in mice inhibits TLR4 pathway activation, which correlates with reduced myocardial remodeling and improved cardiac function. Mechanistically, we show that HG induces extracellular advanced glycation end products (AGEs), which bind directly to MD2, leading to formation of AGEs-MD2-TLR4 complex and initiation of pro-inflammatory pathways. We further detect elevated AGE-MD2 complexes in heart tissues and serum of diabetic mice and human subjects with DCM. In summary, we uncover a new mechanism of HG-induced inflammatory responses and myocardial injury, in which AGE products directly bind MD2 to drive inflammatory DCM.


Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/imunologia , Cardiomiopatias Diabéticas/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Animais , Western Blotting , Calorimetria , Linhagem Celular , Humanos , Imunoprecipitação , Antígeno 96 de Linfócito/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo
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