Thiazolidinediones improve hepatic fibrosis in rats with non‐alcoholic steatohepatitis by activating the adenosine monophosphate‐activated protein kinase signalling pathway

相似文献   

Synthesis and structure–activity relationships of pyrazolo‐[3,4‐b]pyridine derivatives as adenosine 5'‐monophosphate‐activated protein kinase activators

A series of pyrazolo[3,4‐b]pyridine derivatives were designed, synthesized, and evaluated for their activation activity toward adenosine 5'‐monophosphate‐activated protein kinase (AMPK). According to the enzyme activity, the pyrazole N?H exposure and para substitution on the diphenyl group were proved to be essential for the activation potency. Compound 17f showed equal activation compared with A‐769662. In the molecular modeling study, compound 17f exhibited important hydrogen bond interaction with Lys29, Asp88, and Arg83. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays on the NRK‐49F cell line showed that potent enzyme activators could effectively inhibit cell proliferation, especially for 17f (EC₅₀ [AMPKα1γ1β1] = 0.42 μM, efficacy = 79%; IC₅₀ [NRK‐49F cell line] = 0.78 μM). These results might provide new insights to explore novel AMPK activators.     

Design,synthesis and evaluations of spiro‐fused benzoxaborin derivatives as novel boron‐containing compounds

Drug design using boron‐containing heterocycles has attracted a great deal of attention because these compounds are believed to possess high biological activity. However, information on the synthetic methodology and pharmacokinetic profiling of boron‐containing compounds is limited. In this study, we provide a new synthetic route for preparation of spiro‐fused benzoxaborin derivatives and investigate their in vitro pharmacokinetic properties. Our efforts led to the successful construction of a chemical library of spiro‐fused benzoxaborin derivatives with appropriate physicochemical and in vitro pharmacokinetic properties for oral drugs. These results indicate that the synthesized boron‐containing compounds are therefore eligible for classification in a novel chemical library.     

Advanced glycation end‐products impair Na+/K+‐ATPase activity in diabetic cardiomyopathy: Role of the adenosine monophosphate‐activated protein kinase/sirtuin 1 pathway

相似文献   

Antimycobacterial evaluation of novel [4,5‐dihydro‐1H‐pyrazole‐1‐carbonyl]pyridine derivatives synthesized by microwave‐mediated Michael addition

The focus of this study is the synthesis and biological activity evaluation of a series of dibenzalaceton derivatives (3a‐3n) and novel [4,5‐dihydro‐1H‐pyrazole‐1‐carbonyl]pyridine derivatives (5a‐5g) against Mycobacterium bovis, Bacillus Calmette–Guerin (BCG). Dibenzalacetone derivatives were synthesized by benzaldehyde derivatives. The [4,5‐dihydro‐1H‐pyrazole‐1‐carbonyl]pyridine derivatives were synthesized by Michael addition reaction and using green chemistry microwave‐mediated method. All compounds were evaluated against BCG and the activity expressed as minimum inhibitory concentration (MIC) in μM. The result showed good activity for all the compounds especially compounds (3a), (3n), and (5a) illustrated high activity (7.03, 8.10 and 5.37 μM, respectively). Copyright © 2014 John Wiley & Sons, Ltd.     

Involvement of the delayed rectifier outward potassium channel Kv2.1 in methamphetamine‐induced neuronal apoptosis via the p38 mitogen‐activated protein kinase signaling pathway

Methamphetamine (Meth) is an illicit psychostimulant with high abuse potential and severe neurotoxicity. Recent studies have shown that dysfunctions in learning and memory induced by Meth may partially reveal the mechanisms of neuronal channelopathies. Kv2.1, the primary delayed rectifying potassium channel in neurons, is responsible for mediating apoptotic current surge. However, whether Kv2.1 is involved in Meth‐mediated neural injury remains unknown. In the present study, the treatment of primary cultured hippocampal neurons with Meth indicated that Meth induced a time‐ and dose‐dependent augmentation of Kv2.1 protein expression, accompanied by elevated cleaved‐caspase 3 and declined bcl‐2/bax ratio. The blockage of Kv2.1 with the inhibitor GxTx‐1E or the knockdown of the channel noticeably abrogated the pro‐apoptotic effects mediated by Meth, demonstrating the specific roles of Kv2.1 in Meth‐mediated neural damage. Additionally, the p38 mitogen‐activated protein kinase (MAPK) signaling was demonstrated to be involved in Meth‐mediated Kv2.1 upregulation and in the subsequent pro‐apoptotic effects, as treatment with a p38 MAPK inhibitor significantly attenuated Meth‐mediated Kv2.1 upregulation and cell apoptosis. Of note, PRE‐084, a sigma‐1 receptor agonist, obviously attenuated Meth‐induced upregulation of Kv2.1 expression, neural apoptosis and p38 MAPK activation. Taken together, these results reveal a novel mechanism involved in Meth‐induced neural death with implications for therapeutic interventions for Meth users.     

Allopurinol induces innate immune responses through mitogen‐activated protein kinase signaling pathways in HL‐60 cells

Allopurinol, an inhibitor of xanthine oxidase, is a frequent cause of severe cutaneous adverse reactions (SCARs) in humans, including drug rash with eosinophilia and systemic symptoms, Stevens–Johnson syndrome and toxic epidermal necrolysis. Although SCARs have been suspected to be immune‐mediated, the mechanisms of allopurinol‐induced SCARs remain unclear. In this study, we examined whether allopurinol has the ability to induce innate immune responses in vitro using human dendritic cell (DC)‐like cell lines, including HL‐60, THP‐1 and K562, and a human keratinocyte cell line, HaCaT. In this study, we demonstrate that treatment of HL‐60 cells with allopurinol significantly increased the mRNA expression levels of interleukin‐8, monocyte chemotactic protein‐1 and tumor necrosis factor α in a time‐ and concentration‐dependent manner. Furthermore, allopurinol induced the phosphorylation of mitogen‐activated protein kinases (MAPK), such as c‐Jun N‐terminal kinase and extracellular signal‐regulated kinase, which regulate cytokine production in DC. In addition, allopurinol‐induced increases in cytokine expression were inhibited by co‐treatment with the MAPK inhibitors. Collectively, these results suggest that allopurinol has the ability to induce innate immune responses in a DC‐like cell line through activation of the MAPK signaling pathways. These results indicate that innate immune responses induced by allopurinol might be involved in the development of allopurinol‐induced SCARs. Copyright © 2015 John Wiley & Sons, Ltd.     

Interleukin‐6 enhances matrix metalloproteinase‐14 expression via the RAF–mitogen‐activated protein kinase kinase–extracellular signal‐regulated kinase 1/2–activator protein‐1 pathway

1. Interleukin (IL)‐6 is a pivotal cytokine that regulates extracellular matrix (ECM) metabolism by increasing collagen degradation via activation of matrix metalloproteinases (MMPs), such as MMP‐14. In the present study, we investigated the role of IL‐6 in atherosclerotic plaque and signalling pathways in apolipoprotein E‐deficient (ApoE^?/?) mice. 2. Twenty‐five male ApoE^?/? mice were fed a high‐fat diet and atherosclerotic lesions in the right common carotid artery were induced by perivascular placement of a constrictive collar. Immunohistochemical analysis detected expression of IL‐6 and MMP‐14 in atherosclerotic lesions of the right common carotid artery. 3. On silencing activator protein (AP)‐1 expression with a specific small interfering RNA, 75% of the IL‐6‐induced increase in MMP‐14 expression was abolished through the RAF–mitogen‐activated protein kinase kinase–extracellular signal‐regulated kinase 1/2–AP‐1 pathway. 4. These findings suggest a novel molecular pathway for inflammation‐associated ECM dysregulation, which may account for atherosclerotic plaque rupture.     

Flavonoid compounds: a review of anticancer properties and interactions with cis‐diamminedichloroplatinum(II)

Flavonoid compounds, especially quercetin and genistein, have antitumor activity. These compounds are cytotoxic to cancer cells but have no or insignificant activity in normal cells. These beneficial properties prompted synthesis of flavonoid synthetic derivatives, e.g., flavopiridol; 5‐amino‐2,3‐fluorophenyl)‐6,8‐difluoro‐7‐methyl‐4H‐1‐benzopyran‐4‐one; B43‐genistein and EGF‐genistein). cis‐DDP (cis‐diamminedichloroplatinum(II)) is one of the most effective drugs used for chemotherapy, but its actions are limited by many side effects. Beneficial synergistic effects of flavonoids (e.g., quercetin, genistein, butein, tannic acid) and cis‐DDP were found in cis‐DDP‐sensitive and resistant cancer cells that resulted in a lower toxicity for cis‐DDP. Further studies focused on the synthesis of complexes of compounds belonging to different groups, e.g., cis‐bis(3‐aminoflavone)dichloroplatinum(II) where introduction of the flavone ligand altered the DNA‐binding properties of the complex as compared to cis‐DDP alone. The beneficial anticancer and antioxidant properties of flavonoids and their synthetic derivatives have prompted further research on the synergistic interactions of these compounds with routinely applied chemotherapeutic drugs, e.g. cis‐DDP. Drug Dev. Res. 63:200–211, 2004. © 2004 Wiley‐Liss, Inc.     

Quinazoline based 1,3,5‐triazine derivatives as cancer inhibitors by impeding the phosphorylated RET tyrosine kinase pathway: Design,synthesis, docking,and QSAR study

The present research focused on designing a quinazoline skeleton, framed via 1,3,5‐triazine derivatives (QBT) through field mapping and alignment studies. The QBT derivatives were synthesized via time‐ and cost‐effective protocol. The 3D‐QSAR study, computational physicochemical properties, and ADME calculation of the derivatives were performed to establish the affinity towards the biological system. Molecular docking in the adenosine triphosphate binding site of the RET tyrosine kinase domain (PDB ID: 7IVU) was studied to elucidate vital structural residues necessary for bioactivity. The derivatives were evaluated for anticancer potency against TPC‐1 cells (thyroid cancer), MCF‐7 cells (breast cancer), and one normal cell line (human foreskin fibroblasts) via 3‐(4,5‐dimethylthiazol‐2‐y1)‐2,5‐diphenyltetrazolium bromide assay followed by an in ovo CAM assay. The entire series of derivatives ( 8a–o ) showed mild to significant anticancer potency against the selected cancer cell lines.     

Design,synthesis, and biological evaluation of novel 3‐(thiophen‐2‐ylthio)pyridine derivatives as potential multitarget anticancer agents

A series of novel 3‐(thiophen‐2‐ylthio)pyridine derivatives as insulin‐like growth factor 1 receptor (IGF‐1R) inhibitors was designed and synthesized. IGF‐1R kinase inhibitory activities and cytotoxicities against HepG2 and WSU‐DLCL2 cell lines were tested. For all of these compounds, potent cancer cell proliferation inhibitory activities were observed, but not through the inhibition of IGR‐1R. Selected compounds were further screened against various kinases. Typical compound 22 (50% inhibitory concentration [IC₅₀] values, HepG2: 2.98 ± 1.11 μM and WSU‐DLCL2: 4.34 ± 0.84 μM) exhibited good inhibitory activities against fibroblast growth factor receptor‐2 (FGFR2), FGFR3, epidermal growth factor receptor, Janus kinase, and RON (receptor originated from Nantes), with IC₅₀ values ranging from 2.14 to 12.20 μM. Additionally, the cell‐cycle analysis showed that compound 22 could arrest HepG2 cells in the G1/G0 phase. Taken together, all the experiments confirmed that the compounds in this series were multitarget anticancer agents worth further optimizing.     

Mitogen‐activated protein kinase signaling and its association with oxidative stress and apoptosis in lead‐exposed hepatocytes

Lead toxicity has become a serious public health concern all over the world. Previous studies have shown that lead induces biochemical and structural changes in liver. However, although lead is known to alter liver functions, the underlying molecular mechanisms of hepatotoxicity are not yet clear. We hypothesized that a correlation exists between oxidative stress, apoptosis and mitogen‐activated protein kinases (MAPKs) in lead‐exposed liver. Wistar rats were treated with 0, 0.5%, and 1% lead acetate for 3d, 14d, and 35d and sacrificed the next day. On 4d, oxidative stress and apoptosis were correlated with downregulated expressions of ERK1/2 and p38‐MAPKα/β, and upregulated expressions of JNK1/3 in males. In females, the correlation was with downregulated expressions of ERK1/2 and upregulated expressions of p38‐MAPKα/β and JNK1/3. On 15d, the correlation was observed with upregulated expressions of p38‐MAPKα/β in males and downregulated expressions of p38‐MAPKα/β in females. In both sexes, a correlation was observed with upregulated expressions of ERK1/2 and JNK1/3 in 1% groups. On 36d, the correlation was observed with downregulated expressions of p38‐MAPKα/β in males and their upregulated expressions in females. Time‐dependent increase in lipid peroxidation on 15d and 36d correlated with upregulated expressions of p38‐MAPKα/β in females and ERK1/2 in 1% groups in both sexes. The lower dose induced more apoptosis up to 15d in females and the higher dose induced in males on 36d. Generally, the female livers had more p38‐MAPKα/β than the male livers. On 36d, the female livers showed more p38‐MAPKα/β and JNK1/3 than the male livers. In conclusion, although not clearly defined, a correlation exists among oxidative stress, apoptosis, and the MAPKs in lead‐exposed hepatocytes. The sex‐dependent effects may be due to differences in hormonal or other physiological mechanisms. In lead‐exposed hepatocytes, the apoptosis may be induced via oxidative stress‐mediated alterations in the MAPKs. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 513–529, 2015.     

Synthesis and pharmacological evaluation of 99mTc‐labeled imidazolyl‐containing diphosphonic acid as a novel bone imaging agent

In order to develop a superior bone imaging agent, a new radiotracer ^99mTc‐1‐hydroxy‐5‐(2‐butyl‐1H‐imidazol‐1‐yl)pentane‐1,1‐diyldiphosphonic acid (BIPeDP) was designed and prepared with good radiochemical yield and stability. The biodistribution in mice shows that ^99mTc‐BIPeDP has high specificity in the skeleton with the maximum uptake of 17.30 ± 0.14 injected dose per gram at 60 min. Kinetics of blood clearance shows that the distribution half‐life (T_1/2α) and elimination half‐life (T_1/2β) of ^99mTc‐BIPeDP are 3.7 and 49.7 min, respectively. An excellent image can be obtained at 1‐h post‐injection with the single photon emission computed tomography bone scanning, which is clearer and quicker than ^99mTc‐zoledronic acid, ^99mTc‐1‐hydroxy‐5‐(1H‐imidazol‐1‐yl)pentane‐1,1‐diyldiphosphonic acid, and ^99mTc‐methylenediphosphonic acid All results indicate that ^99mTc‐BIPeDP holds great potential as a novel promising bone imaging agent. Copyright © 2013 John Wiley & Sons, Ltd.     

4‐amino‐6‐alkyloxy‐2‐alkylthiopyrimidine derivatives as novel non‐nucleoside agonists for the adenosine A1 receptor

Three 4‐amino‐6‐alkyloxy‐2‐alkylthiopyrimidine derivatives ( 4 – 6 ) were investigated as potential non‐nucleoside agonists at human adenosine receptors (ARs). When tested in competition binding experiments, these compounds exhibited low micromolar affinity (K_i values comprised between 1.2 and 1.9 μm ) for the A₁ AR and no appreciable affinity for the A_2A and A₃ ARs. Evaluation of their efficacy profiles by measurement of intracellular cAMP levels revealed that 4 and 5 behave as non‐nucleoside agonists of the A₁ AR with EC₅₀ values of 0.47 and 0.87 μm , respectively. No clear concentration‐response curves could be instead obtained for 6 , probably because this compound modulates one or more additional targets, thus masking the putative effects exerted by its activation of A₁ AR. The three compounds were not able to modulate A_2B AR‐mediated cAMP accumulation induced by the non‐selective AR agonist NECA, thus demonstrating no affinity toward this receptor.