查找使用阿拉丁产品的科研文献

Design and synthesis of novel curcumin derivatives as potent PDE4 inhibitors for the treatment of depression

Haodong Zhou,Yulan Zhu,Xianfeng Huang

PDE4 is a potential target for treating mental diseases including depression, Alzheimer’s disease and schizophrenia involving in the hydrolysis of cAMP. Curcumin is well-known for its potential as a neuroprotective compound against depression. It was able to inhibit PDE4 with IC50 value in the range of 10 to 20 μM with low selectivity. However, curcumin itself cannot be used clinically because of its poor drug-like properties. Herein, a series of new curcumin derivatives were designed and synthesized. Their PDE4 inhibitory activities and antidepressant effects in vivo were also evaluated. Consequently, most of these curcumin derivatives demonstrated good inhibitory activities against PDE4. Furthermore, compound 4e exhibited the most potent activity at nanomolar level (IC50 value: 23 nM). It also could improve depression-like behaviors induced by chronic stress including sugar forced swimming and water consumption tests in vivo.

Design and synthesis of novel PDE4 inhibitors as potential candidates for antidepressant agents

Yingcong Yu,Yan Zhao,Yajing Wang,Xianfeng Huang

PDE4 inhibitors exhibit anti-stress and antidepressant-like abilities by catalyzing the hydrolysis of cAMP, a primary regulator for intracellular communication in the brain. Herein, novel diarylpyrazole derivatives are synthesized and investigated for their ability to inhibit PDE4. In vitro studies indicate that most of the synthesized compounds show significant potency for the inhibition of PDE4. Specifically, N-(4-(3-(3,5-dimethoxyphenyl)-1H-pyrazol-5-yl)benzyl)-2-morpholinoethan-1-amine exhibits the most potent PDE4 inhibition, with an IC50 value of ca. 0.09 μM. It also produces antidepressant-like activities in sugar water consumption and in forced swimming tests in vivo.

Sappanone A: A natural PDE4 inhibitor with dual anti-inflammatory and antioxidant activities from the heartwood of Caesalpinia sappan L.

You-Zhi Wang,Yu-Long Wang,Hao-Jie Che,Yi-He Jia,Hui-Fang Wang,Lin-Fei Zuo,Kan Yang,Ting-Ting Li,Jin-Xin Wang

Ethnopharmacological relevance Sumu ( Lignum sappan ), the dry heartwood of Caesalpinia sappan L., is a traditional Chinese medicine used as an analgesic and anti-inflammatory agent. Aim of the study The study aspired to discover natural phosphodiesterase 4 (PDE4) inhibitors with dual anti-inflammatory and antioxidant activities from Sumu for the treatment of chronic obstructive pulmonary disease (COPD). Materials and methods To accurately and efficiently identify natural PDE4 inhibitors from Sumu, molecular docking and molecular dynamics (MD) analysis methods were used for structure-based virtual screening of a self-built database of primary polyphenols in Sumu. According to the previous studies of Sumu and the free radical scavenging mechanism of polyphenols, the reported antioxidant components from Sumu and the potential antioxidants with the antioxidant pharmacophore of catechol and π-conjugated moieties were selected from the potential PDE4 inhibitors predicted by docking. Sappanone A, a potential PDE4 inhibitor with antioxidant activity from Sumu, was selected, calculated and synthesized to evaluate its dual anti-inflammatory and antioxidant functions in vitro and in vivo studies. Herein sappanone A was assayed for its inhibitory effects against PDE4 enzyme activity, tumor necrosis factor-alpha (TNF-α) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages and malondialdehyde (MDA) production induced by Fe 2+ in mouse lung homogenate; sappanone A was also assayed for its abilities of radical (DPPH) scavenging, reducing Fe 3+ and complexing Fe 2+ in vitro. Additionally, LPS-induced acute lung injury (ALI) in mice was used to evaluate its anti-inflammatory activity as a PDE4 inhibitor in vivo, and the levels of TNF-α and total protein in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the lung were assayed. Results The present study predicted and validated that sappanone A was a promising PDE4 inhibitor from Sumu with dual anti-inflammation and antioxidant activities from Sumu. In vitro, sappanone A remarkably inhibited PDE4 enzyme activity and reduced TNF-α production induced by LPS in RAW264.7 macrophages and MDA production induced by Fe 2+ in mouse lung homogenate. Meanwhile, it showed outstanding abilities of scavenging DPPH radicals, reducing Fe 3+ and complexing Fe 2+ . In vivo, sappanone A (25 mg/kg and 50 mg/kg, i.p., twice daily for 7 days) distinctly prevented LPS-induced ALI in mice by reducing the levels of TNF-α and total protein in BALF and MPO activity in the lung. Conclusion Sappanone A is a natural PDE4 inhibitor with dual anti-inflammatory and antioxidant activities from the traditional Chinese medicine Sumu, which may be a promising therapeutic agent to prevent the vicious cycle of COPD inflammation and oxidative stress.

Design and synthesis of a novel class of PDE4 inhibitors with antioxidant properties as bifunctional agents for the potential treatment of COPD

Youzhi Wang,Huifang Wang,Guoqing Yang,Qingjing Hao,Kan Yang,Huizhen Shen,Yulong Wang,Jinxin Wang

It is well known that chronic obstructive pulmonary disease (COPD) patients are always trapped in the vicious circle of inflammation and oxidative stress , therefore anti-inflammatory and antioxidant bifunctional agents may interrupt this vicious cycle in COPD. Phosphodiesterase 4 (PDE4) inhibitors, as anti-inflammatory drugs, have been used for COPD treatment in clinical, and the PDE4 inhibitors with antioxidant properties may be a good strategy to design bifunctional agents for COPD. Sappanone A was the first PDE4 inhibitor with antioxidant properties we identified from natural products in our previous study, which was used by us as a hit compound to design new bifunctional agents for COPD in this study. 27 derivatives of sappanone A including homoisoflavonoids , aurones and chalcones were designed and synthesized by innovatively fusing the antioxidant pharmacophore of catechol from polyphenols and the pharmacophore of catechol ether abstracted from the PDE4 inhibitors of the catechol ether class such as rolipram , roflumilast and apremilast respectively. All the compounds were assayed for the PDE4 inhibitory and radical scavenging against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) activities in vitro. Herein we obtained a series of bifunctional compounds with better PDE4 inhibitory activity than sappanone A, and their free radical scavenging activities were superior to edaravone in vitro. In addition, they can reduce tumour necrosis factor-alpha (TNF-α) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages and malondialdehyde (MDA) production induced by Fe 2+ in mouse lung homogenate . Meanwhile, it showed outstanding abilities in reducing Fe 3+ and complexing Fe 2+ . 6o , as the candidate anti-inflammatory and antioxidant bifunctional compound, exhibited good drug-likeness, ADME (Absorption, Distribution, Metabolism, Excretion) properties and human liver microsomal stability. In vivo, 6o (50 mg/kg and 100 mg/kg, i. p.) distinctly prevented LPS-induced serum levels of TNF-α in mice. In conclusion, the preliminary investigation provided a novel class of PDE4 inhibitors with antioxidant properties as bifunctional agents for the potential treatment of COPD, which can interrupt the vicious cycle of chronic inflammation and oxidative stress in COPD.

The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol

Yingcong Yu,Jinhui Wang,Xianfeng Huang

Hypericum sampsonii attenuates inflammation in mice with ulcerative colitis via regulation of PDE4/PKA/CREB signaling pathway

Yinsi Lin,Jianhui Su,Mingqiang Wang,Yanzhen Li,Zhongxiang Zhao,Zhanghua Sun

Ethnopharmacological relevance Hypericum sampsonii Hance (Yuanbaocao), a traditional herbal medicine with various pharmacological properties, is traditionally used to treat diarrhea and enteritis in China for hundreds of years. Investigations have uncovered its anti-inflammatory effects and corresponding bioactive constituents in H. sampsonii , however, the mechanisms of action for the treatment of enteritis are still unclear. Aims of the study This study aims to investigate the therapeutic effects and molecular mechanisms of H. sampsonii in a dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice model. Materials and methods The major ingredients of the ethyl acetate extract (HS) in H. sampsonii were analyzed by UPLC-QTOF-MS. The inflammatory state of UC mice was caused by 3% DSS once daily for seven days. During DSS treatment, the mice in the positive drug group and the other three groups were orally administered 5-ASA (positive control) or HS daily. After treatment with HS or 5-ASA for a week, colonic pathological observation and the molecular biological index were performed for therapeutic evaluation, including visual inspection in the length and weight of colons and spleens, pathological morphology by hematoxylin and eosin (HE) staining, determination of oxidative markers, inflammatory cytokines and tumor necrosis factor-alpha (TNF-α) levels in colonic tissues as well as spleen index. Gene expression levels of inflammatory cytokines, antioxidant enzymes and PDE4 were detected using kits and PCR, while the expression of colonic tight junction proteins and relative signals of PKA/CREB signaling pathway were analyzed by Western blot . Results The main components in HS were found to be polycyclic polyprenylated acylphloroglucinols (PPAPs). HS distinctly alleviated DSS-stimulated UC-like lesions symptoms as evidenced by a significant recovery from body weight, colon lengths, and histological injuries of colons. HS reduced the accumulation of pro-inflammatory cytokines and improved the mRNA level of IL-10. Simultaneously, the colonic mRNA expression levels of IL-1β, IL-17, iNOS and COX-2 were all significantly suppressed by HS in a dose-dependent manner. Furthermore, HS restored the protein expression of tight junction-associated protein (ZO-1 and occluding). Besides, HS significantly inhibited the protein level of PDE4 and decreased the expressions of PKA and phosphorylated CREB. Conclusion This is the first work about main composition and anti-UC effect of Hypericum sampsonii Hance. For the first time, this study reveals HS is not toxic in a single dose and exert significantly protective effect in DSS-colitis mice. The underlying mechanisms may involve the improvement to inflammatory status, the protection for intestinal barrier function, the inhibition of PDE4, and the activation of PKA/CREB signaling pathway. This study provided an experimental basis for the traditional application of H. sampsonii Hance in the treatment of diarrhea and dysentery .

Influence of heat processing on the anti-inflammatory activity of fresh Smilax glabra based on PDE4 inhibition

Youjiao Wu,Lili He,Yi Yang,Zhigang Yan,Zhifeng Zhang,Xiaojun Yao,Pei Luo

Smilax glabra Roxb. (SG) is widely used as functional food with various beneficial effects. Fresh SG without processing has been eaten directly for anti-inflammation from ancient China, while the underlying mechanism remains underexplored. This study aims to investigate the anti-inflammatory activity of fresh SG by using metabolites profiles, affinity ultrafiltration mass spectrometry, PDE4 enzyme inhibition assay, and in silico analysis. Encouragingly, fresh SG showed promising anti-inflammatory effect with IC 50 value (0.009 μg/μL) on PDE4 was about 12 times higher than that of processed SG (0.110 μg/μL). Astilbin was identified as the main bioactive compound of fresh SG responsible for PDE4 inhibitory activity. We found that heat processing strongly affected astilbin isomerization, leading to significant changes in contents and PDE4 inhibitory activities of four astilbin isomers, resulting in decreased anti-inflammatory activity of fresh SG. This finding will provide theoretical basis for systematic research and food/nutraceutical applications of fresh Smilax glabra in the future.

Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis

Zhendong Song,Yi-You Huang,Ke-Qiang Hou,Lu Liu,Feng Zhou,Yue Huang,Guohui Wan,Hai-Bin Luo,Xiao-Feng Xiong

Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and phosphodiesterase 4 (PDE4) is an effective target for the treatment of inflammatory diseases such as psoriasis. Toddacoumalone is a natural PDE4 inhibitor with moderate potency and imperfect drug-like properties. To discover novel and potent PDE4 inhibitors with considerable druggability, a series of toddacoumalone derivatives were designed and synthesized, leading to the compound (2R,4S)-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one (33a) with high inhibitory potency (IC50 = 3.1 nM), satisfactory selectivity, favorable skin permeability, and a well-characterized binding mechanism. Encouragingly, topical administration of 33a exhibited remarkable therapeutic effects in an imiquimod-induced psoriasis mouse model.

Discovery and Optimization of α-Mangostin Derivatives as Novel PDE4 Inhibitors for the Treatment of Vascular Dementia

Jinhao Liang,Yi-You Huang,Qian Zhou,Yuqi Gao,Zhe Li,Deyan Wu,Si Yu,Lei Guo,Zhen Chen,Ling Huang,Steven H. Liang,Xixin He,Ruibo Wu,Hai-Bin Luo

To validate PDE4 inhibitors as novel therapeutic agents against vascular dementia (VaD), 25 derivatives were discovered from the natural inhibitor α-mangostin (IC50 = 1.31 μM). Hit-to-lead optimization identified a novel and selective PDE4 inhibitor 4e (IC50 = 17 nM), which adopted a different binding pattern from PDE4 inhibitors roflumilast and rolipram. Oral administration of 4e at a dose of 10 mg/kg exhibited remarkable therapeutic effects in a VaD model and did not cause emesis to beagle dogs, indicating its potential as a novel anti-VaD agent.

Discovery, Synthesis, and Biological Evaluation of Novel Quinoline-Based PDE4 Inhibitors with Potent Anti-Chronic Obstructive Pulmonary Disease Activity

Gang Xing,Yucong Bi,Zhenli Li,Zhengxing Zhi,Haitao Li,Maosheng Cheng

Phosphodiesterase 4 (PDE4) is a key target for COPD anti-inflammatory drugs. The approved oral PDE4 inhibitor for COPD causes side effects such as nausea and vomiting due to high systemic exposure. Developing highly selective PDE4 inhibitors suitable for inhaled delivery represents an effective alternative strategy. Herein, we report the identification of P29, a PDE4 inhibitor exhibiting picomolar inhibitory potency (IC50 = 0.019 nM) and high selectivity (>10,000) over other PDEs. Subsequent studies demonstrated that P29 effectively suppressed LPS-induced TNF-α release in PBMCs. Notably, the fractions absorbed via pulmonary deposition and orally absorbed fractions were rapidly metabolized, reducing systemic exposure and minimizing adverse reactions. P29 significantly improved pulmonary function, inhibited inflammatory cell activity, reduced release of inflammatory cytokines, and ameliorated lung tissue damage in rat models of COPD induced by cigarette smoke and LPS. Collectively, our data highlight the therapeutic potential of P29 in COPD.

Roflupram, a novel phosphodiesterase 4 inhibitor, inhibits lipopolysaccharide-induced neuroinflammatory responses through activation of the AMPK/Sirt1 pathway

Dan Li,Jiangping Xu,Yunyun Qin,Ningbo Cai,Yufang Cheng,Haitao Wang

Roflupram (ROF) is a novel phosphodiesterase 4 inhibitor. We previously found that ROF suppressed the production of pro-inflammatory factors in microglial cells; however, the underlying mechanisms are largely unknown. The present study aimed to elucidate the underlying molecular mechanisms of the anti-neuroinflammatory effects of ROF in lipopolysaccharide (LPS)-activated microglial cells and LPS-challenged mice. Treatment with ROF suppressed LPS-induced expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in BV-2 microglia cell line. Immunofluorescence and Western blotting analysis showed that ROF significantly inhibited the activation of microglia, as evidenced by decreased expression of ionized calcium binding adaptor molecule-1 (Iba1). Similar results were obtained in primary cultured microglial cells. ROF induced the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of Sirtuin 1 (Sirt1). Interestingly, the AMPK inhibitor, compound C, blocked the role of ROF in both the phosphorylation of AMPK and the expression of Sirt1 in BV-2 cells stimulated with LPS. More importantly, the Sirt1 inhibitor, EX527, abolished the inhibitory role of ROF on the production of pro-inflammatory factors, and reactivated BV-2 cells. In mice challenged with LPS, ROF improved cognition and decreased the levels of IL-6 and TNF-α in both the cortex and hippocampus. In contrast, EX527 weakened the effects of ROF on cognitive enhancement and reduction of pro-inflammatory factors in the cortex and hippocampus. Furthermore, EX527 blocked the inhibitory role of ROF in the activation of microglial cells in both the hippocampus and cortex. Taken together, our results indicated that ROF attenuated LPS-induced neuroinflammatory responses in microglia, and the AMPK/Sirt1 pathway is essential for the anti-inflammatory effects of ROF.

MnO2 and roflumilast-loaded probiotic membrane vesicles mitigate experimental colitis by synergistically augmenting cAMP in macrophage

Chengjun Song,Jiamin Wu,Jinhui Wu,Fangyu Wang

Background Ulcerative colitis (UC) is one chronic and relapsing inflammatory bowel disease. Macrophage has been reputed as one trigger for UC. Recently, phosphodiesterase 4 (PDE4) inhibitors, for instance roflumilast, have been regarded as one latent approach to modulating macrophage in UC treatment. Roflumilast can decelerate cyclic adenosine monophosphate (cAMP) degradation, which impedes TNF-α synthesis in macrophage. However, roflumilast is devoid of macrophage-target and consequently causes some unavoidable adverse reactions, which restrict the utilization in UC. Results Membrane vesicles (MVs) from probiotic Escherichia coli Nissle 1917 (EcN 1917) served as a drug delivery platform for targeting macrophage. As model drugs, roflumilast and MnO 2 were encapsulated in MVs (Rof&MnO 2 @MVs). Roflumilast inhibited cAMP degradation via PDE4 deactivation and MnO 2 boosted cAMP generation by activating adenylate cyclase (AC). Compared with roflumilast, co-delivery of roflumilast and MnO 2 apparently produced more cAMP and less TNF-α in macrophage. Besides, Rof&MnO 2 @MVs could ameliorate colitis in mouse model and regulate gut microbe such as mitigating pathogenic Escherichia–Shigella and elevating probiotic Akkermansia . Conclusions A probiotic-based nanoparticle was prepared for precise codelivery of roflumilast and MnO 2 into macrophage. This biomimetic nanoparticle could synergistically modulate cAMP in macrophage and ameliorate experimental colitis. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12951-024-02558-6.