Major anti-inflammatory agents, steroids and cyclooxygenase, were proved to have serious side effects. Here, a series of chalcone derivatives were synthesized and screened for anti-inflammatory activities. QSAR study revealed that the presence of electron-withdrawing groups in B-ring and electron-donating groups in A-ring of chalcones was important for inhibition of LPS-induced IL-6 expression. Further, compounds 22, 23, 26, 40, and 47 inhibited TNF-α and IL-6 release in a dose-dependent manner and decreased LPS-induced TNF-α, IL-1β, IL-6, IL-12, and COX-2 mRNA production. Mechanistically, compounds 23 and 26 interfered with JNK/NF-κB signaling and dose-dependently prevented ERK and p38 activation. In addition, 23 and 26 exhibited a significant protection against LPS-induced death and were able to block high glucose-activated cytokine profiles in macrophages. Together, these data show a series of anti-inflammatory chalcones with potential therapeutic effects in inflammatory diseases.

Curcumin has been extensively studied for its anti-inflammatory activities. However, its potential beneficial effects on various disease preventions and treatments are limited by its unstable structure. The β-diketone moiety renders curcumin to be rapidly metabolized by aldoketo reductase in liver. In the present study, a series of curcumin analogues with more stable chemical structures were synthesized and several compounds showed an enhanced ability to inhibit lipopolysaccharide (LPS)-induced TNF-α and IL-6 synthesis in macrophages.Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, Fig. 1] is the major active constituent of turmeric, a yellow compound originally isolated from the plant Curcuma longa L. Tumeric has been widely used for centuries as a dietary spice and pigment. 1 In addition to its unique flavor and color, tumeric has been extensively used in traditional medicine in China and India, particularly as an anti-inflammatory agent. 2 During the last two decades, numerous studies have shown that curcumin has a variety of biological and pharmacological activities such as anti -carcinogen, immuno-modulation, anti-oxidant, antiangiogenesis, and chemo-prevention. 3-9 Recent studies have demonstrated that inflammation is implicated in the pathogenesis of various diseases including cancer, atherosclerosis, diabetes, fatty liver, rheumatoid arthritis, and inflammatory bowel disease. 10-13 Anti-inflammation is the major focus of current drug development. 14 Cytokines are local mediators produced by lymphocytes and macrophages as well as by epithelial and mesenchymal cells. 15 It has been demonstrated that cytokines are involved in a variety of biological processes and play a central role in the development of inflammation and immunity. TNF-α is a multifunctional cytokine produced primarily by activated monocytes/macrophages and plays a critical role in the initiation and continuation of inflammation and immunity. 16 It is well-known that TNF-α is a key proinflammatory cytokine in the pathogenesis of various inflammatory diseases and cancer. 13, 17 In addition to directly *Corresponding authors: Huiping Zhou: 1217 East Marshall Street, MSB#533, Richmond, VA 23298, USA. E-mail: hzhou@vcu.edu; Tel:804-828-6817; Fax:804-828-0676., Xiaokun Li: College of Pharmacy, Wenzhou Medical College., E-mail: xiaokunli@163.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In order to identify the crucial structural motifs leading to anti-inflammatory activity and gain insight into future directions for designing new analogues with better activity, thre...

Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, Fig. 1], a compound isolated from Curcuma longa L., has been used for centuries as dietary pigment and spice. Curcumin has been found to possess a variety of traditional pharmaceutical applications on diseases, including external/internal wounds, liver diseases (particularly jaundice), blood purification, microbial effects and inflamed joints.1-4) Over a period of research, curcumin was reported to inhibit carcinogen-induced mutations and the formation of tumour in several experimental systems, 5-7) and exhibit anti-proliferation capability as a potent tool in cancer therapy. 8,9) Curcumin has also been reported to inhibit bacterial lipopolysaccharide-induced TNF-a overexpression and the transcription factor nuclear factor kappa B (NF-kB) activation which are involved in several pathogen-infected diseases. 2,10) Preclinical and clinic studies showed that, however, curcumin possesses several disadvantages in pharmacokinetics such as poor bioavailability, fast metabolism and requiring repetitive oral doses, 11,12) which limited its applications. However, curcumin is still an excellent lead compound for drug design and development on the basis of the explicit bioactivities, non-toxicity and easy synthesis. [13][14][15][16] Curcumin is stable at a pH below 6.5. The instability of curcumin at a pH above 6.5 is caused by the methylene group. 17)Omitting the methylene group and one carbonyl group, B. M. Markaverich, 18) M. Artico, 19) and H. I. El-Subbagh 20) synthesized series of mono-carbonyl curcumin analogues, 1,5-diaryl-1,4-pentadiene-3-ones, and evaluated their bioactivity. The result that the mono-carbonyl analogues exhibit more powerful inhibition in a variety of cancer cells than curcumin indicated that the central methylene group which had been considered the main active group of curcuminoids in antitumor property may be of decreasing importance.Therefore, in the present paper three series of mono-carbonyl curcumin analogues without the central methylene functional groups, 1,5-diaryl-1,4-pentadiene-3-ones (B), together with cyclopentanone (A) and cyclohexanone (C) analogues (Fig. 2), were prepared and their anti-bacterial properties in vitro were evaluated and compared using seven multidrug-resistant bacteria specially causing secondary infections in human being.21) These compounds were also designed to examine the role of different substitutes in the benzene ring and the influence of the space structure of the linking C-strain. It is hoped that continued research will lead to development of new lead compounds from curcumin as antibacterial agents and extrapolated agents for bacteria-infected diseases. Bioreactor and Pharmaceutical Development, Jilin Agricultural University; Changchun 130118, P. R. China. Received August 14, 2007; accepted November 7, 2007 The synthesis of three series of curcumin analogues with mono-carbonyl is described. Their in vitro antibacterial activities against seven Gram-positive and Gram-negative bacteria ...

Traditional Chinese medicine (TCM) has unique therapeutic effects for complex chronic diseases. However, for the lack of an effective systematic approach, the research progress on the effective substances and pharmacological mechanism of action has been very slow. In this paper, by incorporating network biology, bioinformatics and chemoinformatics methods, an integrated approach was proposed to systematically investigate and explain the pharmacological mechanism of action and effective substances of TCM. This approach includes the following main steps: First, based on the known drug targets, network biology was used to screen out putative drug targets; Second, the molecular docking method was used to calculate whether the molecules from TCM and drug targets related to chronic kidney diseases (CKD) interact or not; Third, according to the result of molecular docking, natural product-target network, main component-target network and compound-target network were constructed; Finally, through analysis of network characteristics and literature mining, potential effective multi-components and their synergistic mechanism were putatively identified and uncovered. Bu-shen-Huo-xue formula (BSHX) which was frequently used for treating CKD, was used as the case to demonstrate reliability of our proposed approach. The results show that BSHX has the therapeutic effect by using multi-channel network regulation, such as regulating the coagulation and fibrinolytic balance, and the expression of inflammatory factors, inhibiting abnormal ECM accumulation. Tanshinone IIA, rhein, curcumin, calycosin and quercetin may be potential effective ingredients of BSHX. This research shows that the integration approach can be an effective means for discovering active substances and revealing their pharmacological mechanisms of TCM.

Ischaemia‐reperfusion injury (I/RI) is a common cause of acute kidney injury (AKI). The molecular basis underlying I/RI‐induced renal pathogenesis and measures to prevent or reverse this pathologic process remains to be resolved. Basic fibroblast growth factor (FGF2) is reported to have protective roles of myocardial infarction as well as in several other I/R related disorders. Herein we present evidence that FGF2 exhibits robust protective effect against renal histological and functional damages in a rat I/RI model. FGF2 treatment greatly alleviated I/R‐induced acute renal dysfunction and largely blunted I/R‐induced elevation in serum creatinine and blood urea nitrogen, and also the number of TUNEL‐positive tubular cells in the kidney. Mechanistically, FGF2 substantially ameliorated renal I/RI by mitigating several mitochondria damaging parameters including pro‐apoptotic alteration of Bcl2/Bax expression, caspase‐3 activation, loss of mitochondrial membrane potential and KATP channel integrity. Of note, the protective effect of FGF2 was significantly compromised by the KATP channel blocker 5‐HD. Interestingly, I/RI alone resulted in mild activation of FGFR, whereas FGF2 treatment led to more robust receptor activation. More significantly, post‐I/RI administration of FGF2 also exhibited robust protection against I/RI by reducing cell apoptosis, inhibiting the release of damage‐associated molecular pattern molecule HMBG1 and activation of its downstream inflammatory cytokines such as IL‐1α, IL‐6 and TNF α. Taken together, our data suggest that FGF2 offers effective protection against I/RI and improves animal survival by attenuating mitochondrial damage and HMGB1‐mediated inflammatory response. Therefore, FGF2 has the potential to be used for the prevention and treatment of I/RI‐induced AKI.