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Valsartan has the potential to attenuate neointimal hyperplasia and to suppress the inflammatory response. This study aimed to evaluate the role of valsartan in neointimal hyperplasia and the toll-like receptor 4 (TLR4)-nitric oxide synthase (NOS) pathway in the balloon-injured rat aorta. Forty-eight Wistar rats were randomly allocated to three groups: sham control (control), balloon-injured group (surgery), and balloon-injured+valsartan-treated group (valsartan). Rats were killed at 14 and 28 days after balloon-injury, and then the aortic tissues were collected for morphometric analysis as well as for measurements of the mRNA or protein expression of angiotensin II, angiotensin II type 1 (AT1) receptor, angiotensin II type 2 (AT2) receptor, TLR4, endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), serine/arginine-rich splicing factor 1(SRSF1) and extracellular signal regulated kinase (ERK). Valsartan at a dose of 20 mg/kg/day markedly decreased neointimal hyperplasia in the aorta of balloon-injured rats, and significantly reduced the mRNA or protein expression of TLR4, AT1 receptor, SRSF1 and phosphorylated-ERK (p-ERK) as well as the aortic levels of iNOS (all p

Over the past decades, peptide as a therapeutic candidate has received increasing attention in drug discovery, especially for antimicrobial peptides (AMPs), anticancer peptides (ACPs) and antiinflammatory peptides (AIPs). It is considered that the peptides can regulate various complex diseases which are previously untouchable. In recent years, the critical problem of antimicrobial resistance drives the pharmaceutical industry to look for new therapeutic agents. Compared to organic small drugs, peptide- based therapy exhibits high specificity and minimal toxicity. Thus, peptides are widely recruited in the design and discovery of new potent drugs. Currently, large-scale screening of peptide activity with traditional approaches is costly, time-consuming and labor-intensive. Hence, in silico methods, mainly machine learning approaches, for their accuracy and effectiveness, have been introduced to predict the peptide activity. In this review, we document the recent progress in machine learning-based prediction of peptides which will be of great benefit to the discovery of potential active AMPs, ACPs and AIPs.

Blockade of the human ether-à-go-go-related gene (hERG) channel by small molecules induces the prolongation of the QT interval which leads to fatal cardiotoxicity and accounts for the withdrawal or severe restrictions on the use of many approved drugs. In this study, we develop a deep learning approach, termed deephERG, for prediction of hERG blockers of small molecules in drug discovery and postmarketing surveillance. In total, we assemble 7,889 compounds with well-defined experimental data on the hERG and with diverse chemical structures. We find that deephERG models built by a multitask deep neural network (DNN) algorithm outperform those built by single-task DNN, naı̈ve Bayes (NB), support vector machine (SVM), random forest (RF), and graph convolutional neural network (GCNN). Specifically, the area under the receiver operating characteristic curve (AUC) value for the best model of deephERG is 0.967 on the validation set. Furthermore, based on 1,824 U.S. Food and Drug Administration (FDA) approved drugs, 29.6% drugs are computationally identified to have potential hERG inhibitory activities by deephERG, highlighting the importance of hERG risk assessment in early drug discovery. Finally, we showcase several novel predicted hERG blockers on approved antineoplastic agents, which are validated by clinical case reports, experimental evidence, and the literature. In summary, this study presents a powerful deep learning-based tool for risk assessment of hERG-mediated cardiotoxicities in drug discovery and postmarketing surveillance.

The characterization of leaf rust (caused by Puccinia triticina) and stripe rust (caused by Puccinia striiformis f. sp. tritici) resistance genes is the basis for breeding resistant wheat varieties and managing epidemics of these diseases in wheat. A cross between the susceptible wheat variety ‘Apav#1’ and resistant variety ‘Neimai 836’ was used to develop a mapping population containing 148 F5 recombinant inbred lines (RILs). Leaf rust phenotyping was done in field trials at Ciudad Obregón, Mexico, in 2017 and 2018, and stripe rust data were generated at Toluca, Mexico, in 2017 and in Mianyang, Ezhou, and Gansu, China, in 2019. Inclusive complete interval mapping (ICIM) was used to create a genetic map and identify significant resistance quantitative trait loci (QTL) with 2,350 polymorphic markers from a 15K wheat single-nucleotide polymorphism (SNP) array and simple-sequence repeats (SSRs). The pleiotropic multipathogen resistance gene Lr46/Yr29 and four QTL were identified, including two new loci, QLr.hzau-3BL and QYr.hzau-5AL, which explained 3 to 16% of the phenotypic variation in resistance to leaf rust and 7 to 14% of that to stripe rust. The flanking SNP markers for the two loci were converted to Kompetitive Allele-Specific PCR (KASP) markers and used to genotype a collection of 153 wheat lines, indicating the Chinese origin of the loci. Our results suggest that Neimai 836, which has been used as a parent for many wheat varieties in China, could be a useful source of high-level resistance to both leaf rust and stripe rust.

Obesity and related metabolic disorders are associated with intestinal microbiota dysbiosis, disrupted intestinal barrier and chronic inflammation. Shen-Yan-Fang-Shuai formula (SYFSF) is a traditional Chinese herbal formula composed of Astragali Radix, Radix Angelicae Sinensis, Rheum Officinale Baill, and four other herbs. In this study, we identified that SYFSF treatment prevented weight gain, low-grade inflammation and insulin resistance in high-fat diet (HFD)-fed mice. SYFSF also substantially improved gut barrier function, reduced metabolic endotoxemia, as well as systemic inflammation. Sequencing of 16S rRNA genes obtained from fecal samples demonstrated that SYFSF attenuated HFD-induced gut dysbiosis, seen an decreased Firmicutes to Bacteroidetes ratios. Microbial richness and diversity were also higher in the SYFSF-treated HFD group. Furthermore, similar therapeutic effects and changes in gut microbiota profile caused by SYFSF could be replicated by fecal microbiota transfer (FMT). Taken together, our study highlights the efficacy of SYFSF in preventing obesity and related metabolic disorders. Its therapeutic effect is associated with the modulation of gut microbiota, as a prebiotic.

Major et al. claimed that the patterns of proton transfer (Re- vs Si-face) and methyl transfer (C12 or C13) in our recent work [Wang et al. ACS Catal. 2017, 7, 5841−5846] on biocatalysis in trichodiene synthase (FSTS) contradict the so-called “well-established” spectrometric data and make “incorrect statements” on their previous work [Major et al. ACS Catal. 2017, 7, 812−818]. This response aims to clarify that the proton/methyl transfer styles are not yet validated experimentally, at least from their citations in the rebuttal paper [Major et al. DOI: 10.1021/acscatal.7b02823] and other studies we have found. Furthermore, the main conclusion (we proposed a general rule) in our previous work indeed is not dependent on those two reaction steps. In addition, we also compare the different views on reaction energetics, chemo-selectivity, and theoretical modeling for FSTS between Major’s and our work, which can serve as a framework for citation by other research groups and academic discussion in the future.

The development of novel isoform/class-selective inhibitors is still of great biological and medical significance to conquer the continuously reported side effects for the histone deacetylase (HDAC) drugs. The first potent HDAC allosteric inhibitor was discovered last year, and this allosteric inhibitor design is thought to be a promising strategy to overcome the current challenges in HDAC inhibitor design. However, the detailed allosteric mechanism and its remote regulatory effects on the catalytic/inhibitor activity of HDAC are still unclear. In this work, on the basis of microsecond-time-scale all-atom molecular dynamics (MD) simulations and picosecond-time-scale density functional theory/molecular mechanics MD simulations on HDAC8, we propose that the allostery is achieved by the intrinsic conformational flexibility of the binding rail (constituted by a highly conserved X-D residue dyad), which steers the loop-loop motion and creates the diverse shapes of the allosteric sites in different HDAC isoforms. Additionally, the rotatability of the binding rail is an inherent structural feature that regulates the hydrophobicity of the linker binding channel and thus further affects the HDAC enzyme inhibitory/catalytic activity by utilizing the promiscuity of X-D dyad. Since the plastic X residue is different among class I HDACs, these new findings provide a deeper understanding of the allostery, which is guidable for the design of new allosteric inhibitors toward the allosteric site and structure modifications on the conventional inhibitors binding into the active pocket by exploiting the intrinsic dynamic features of the conserved X-D dyad.

The folding mode of substrate FPP in sesquiterpene cyclases/synthases is key to the chemo- and stereoselectivity of the ultimate sesquiterpene products. However, the precise substrate folding modes in most sesquiterpene cyclases are still elusive, and it is challenging for theoretical simulations due to the high flexibility of FPP. Herein, by DFT/MM MD simulations, we obtain the optimal folding mode of FPP in the 1,6-closure trichodiene synthase and illuminate the whole catalytic mechanism for the biosynthesis of trichodiene. Furthermore, a simple and practical rule is proposed to decipher the relationship between the diverse FPP folding modes and chemical selectivity toward 1,6- and 1,10-ring closure, which are common pathways in all sesquiterpene cyclases.

Over the past several decades, natural products with poly-pharmacological profiles have demonstrated promise as novel therapeutics for various complex diseases, including cancer. Berberine (PubChem CID: 2353), a soliloquies quaternary alkaloid, has been validated to exert powerful effects in many cancers. However, the underlying molecular mechanism is not yet fully elucidated. In this study, we summarized the molecular effects of berberine against multiple cancers based on current available literatures. Furthermore, a systems pharmacology infrastructure was developed to discover new cancer indications of berberine and explore their molecular mechanisms. Specifically, we incorporated 289 high-quality protein targets of berberine by integrating experimental drug–target interactions (DTIs) extracted from literatures and computationally predicted DTIs inferred by network-based inference approach. Statistical network models were developed for identification of new cancer indications of berberine through integration of DTIs and curated cancer significantly mutated genes (SMGs). High accuracy was yielded for our statistical models. We further discussed three typical cancer indications (hepatocarcinoma, lung adenocarcinoma, and bladder carcinoma) of berberine with new mechanisms of actions (MOAs) based on our systems pharmacology framework. In summary, this study systematically provides a powerful strategy to identify potential anti-cancer effects of berberine with novel mechanisms from a systems pharmacology perspective.

Staphylopine is a newly identified broad-spectrum metallophore for metal acquisition, and it plays important roles in the survival and virulence of Staphylococcus aureus and other pathogens in the metal-scarce environment in hosts. CntK catalyzes the first step of staphylopine synthesis by converting L-histidine to D-histidine to provide an essential building block of staphylopine. Herein, the crystal structures of S. aureus CntK (SaCntK) and its C72S variant are determined at 1.82 and 1.58 A resolution, respectively. SaCntK forms a homodimer and each subunit contains a two-domain α/β structure. Its overall structure resembles diaminopimelate epimerase, although their sequence identities are lower than 22%. SaCntK is specific for histidine, whereas other proteinogenic amino acids, with the exception of arginine, do not show any binding with SaCntK. Structural modeling suggested that residues Asn16, Glu46, Gln47 and Glu208 are responsible for specific substrate binding, and their substitutions significantly reduced the binding of histidine to SaCntK. Structural modeling suggested SaCntK uses a two-base catalytic mechanism, which has been observed in many cofactor-independent racemases. Our study provides critical insights into the structure and functions of CntK in staphylopine synthesis, which makes it helpful for developing potential antibiotics targeting the staphylopine-mediated metal acquisition process in bacteria.

Histone Deacetylases (HDACs) are promising anticancer targets and several selective inhibitors have been created based on the architectural differences of foot-pockets among HDACs. However, the "gate-keeper" of foot-pockets is still controversial. Herein, it is for the first time revealed that a conserved R-E salt bridge plays a critical role in keeping foot-pockets closed in class-II HDACs by computational simulations. This finding is further substantiated by our mutagenesis experiments.

Geranyl pyrophosphate synthase (GPPS) is responsible for the formation of geranyl pyrophosphate (GPP), a key intermediate which has the potential to derive numerous functionally and structurally diverse groups of terpenoid natural products via the head-to-tail assembly of two isoprenoid building blocks (dimethylallyl diphosphate, DMAPP; isopentenyl diphosphate, IPP) in the initial step of carbon-chain elongation during isoprenoid biosynthesis. Elucidating the detailed catalytic mechanism in GPPS is of significant interests as it will stimulate the development of new technology in generating novel natural productlike scaffolds. It has been known that the catalytic reaction involves three sequential steps, namely “ionization–condensation–elimination”, but the exact catalytic mechanism has remained controversial since the 1970s. By employing Born–Oppenheimer density functional quantum mechanics (B3LYP/6-31(+)G*)/molecular mechanics dynamics simulations, here we suggest that GPPS adopts a protonation-induced ...

Single-gene mutants tolerant or sensitive to salt stress are ideal materials for identifying and cloning genes related to salt tolerance in rice (Oryza sativa L.). In the present study, a salt-sensitive mutant was obtained from the ethyl methanesulfonate (EMS)-induced Nipponbare bank. The mutant, designated rice salt sensitive 4 (rss4), showed a significant increase in salt sensitivity at the seedling stage and accumulated high levels of Na⁺ in shoots, particularly in the blades of old leaves, under conditions of NaCl stress. Genetic analysis indicated that the mutation was controlled by a single recessive gene. Quantitative trait locus (QTL) analysis for shoot Na⁺ content was performed using an F₂ population derived from a cross between the rss4 mutant and the indica cultivar Zhaiyeqing 8 (ZYQ8). Three QTLs were identified and one located on the long arm of chromosome 6 was determined to be the candidate locus of the rss4 gene based on comparison and analysis, which explained 40.5% of the phenotypic variance in the shoot Na⁺ content of the F₂ population. Further analysis of recombination events in 165 mutant individuals of an enlarged mapping population of rss4/ZYQ8 defined the rss4 locus to an interval of 230.5 kb bracketed by markers RM20566 and IM28706 on chromosome 6.

Development of isoform-selective histone deacetylase (HDAC) inhibitors is of great biological and medical interest. Among 11 zinc-dependent HDAC isoforms, it is particularly challenging to achieve isoform inhibition selectivity between HDAC1 and HDAC2 due to their very high structural similarities. In this work, by developing and applying a novel de novo reaction-mechanism-based inhibitor design strategy to exploit the reactivity difference, we have discovered the first HDAC2-selective inhibitor, β-hydroxymethyl chalcone. Our bioassay experiments show that this new compound has a unique time-dependent selective inhibition on HDAC2, leading to about 20-fold isoform-selectivity against HDAC1. Furthermore, our ab initio QM/MM molecular dynamics simulations, a state-of-the-art approach to study reactions in biological systems, have elucidated how the β-hydroxymethyl chalcone can achieve the distinct time-dependent inhibition toward HDAC2.

Background Xian-Fang-Huo-Ming-Yin (XFHM), a traditional herbal formula, has been used to treat sores and carbuncles for hundreds of years in Asia. Nowadays, its clinical effects in treatment of rheumatoid arthritis (RA) have been validated. In this study, we want to study its possible molecular mechanisms of regulating the differentiation of lymphocytes and production of pro-inflammatory cytokines in collagen-induced arthritis (CIA) mice for RA treatment. Methods A high performance liquid chromatography-electrospray ionization/mass spectrometer (HPLC-ESI/MSn) system was used to analyze the constituents of XFHM granules. An arthritics mouse model was induced by collagen and leflunomide (LEF) was used as a positive control medicine. Pathological changes at the metatarsophalangeal joint were studied through Safranin O and immunohistochemical staining. The differentiation of T, B and NK cells was examined by flow cytometry and pro-inflammatory cytokines were assayed using an Inflammation Antibody Array assay. The expression of key molecules of the nuclear factor κB (NF-κB) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways in spleen were studied by western-blot analysis. Results In our study. 21 different dominant chemical constituents were identified in XFHM. Treatment with XFHM suppressed the pathological changes in arthrosis of CIA. Additionally, XFHM down-regulated the proliferation and differentiation of CD3+ T cells and CD3−CD19+ B cells significantly. However, XFHM had no significant effect on CD3−NK1.1+ NK cells. Further study showed that the production of pro-inflammatory cytokines had been suppressed by inhibiting the activation of NF-κB and JAK/STAT signaling. Conclusions XFHM can regulate and maintain the immunologic balance of lymphocytic immunity and inhibit the production of pro-inflammatory cytokines, thus suppressing the pathological changes of RA. Therefore, XFHM may be used as an application of traditional medicine against RA in modern complementary and alternative therapeutics. Electronic supplementary material The online version of this article (doi:10.1186/s12906-016-1526-x) contains supplementary material, which is available to authorized users.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and satisfactory therapeutic strategies have not yet been established. The Shen-Yan-Fang-Shuai Formula (SYFSF) is a traditional Chinese formula composed of Astragali radix, Radixangelicae sinensis, Rheum officinale Baill, and four other herbs. It has been widely used as an effective treatment for DKD patients in China. However, little is known about the molecular mechanisms underlying SYFSF’s renoprotection. In this study, we compared the protective effect of SYFSF to irbesartan on the histology and renal cells in type 2 DKD rat model and high-glucose (HG) cultured mesangial cells, respectively. We found that SYFSF could significantly decrease urinary albumin, cholesterol, and triglyceride. And a decrease in serum creatinine was also found in SYFSF-treated group compared with irbesartan-treated rats. In addition, SYFSF inhibited the interstitial expansion and glomerulosclerosis in diabetic rats. Notably, SYFSF markedly downregulated the expression of MCP-1, TGF-β1, collagen IV, and fibronectin in diabetic rat models and HG-induced mesangial cell models. The renoprotection was closely associated with a reduced expression of TNF-α and phosphorylated NF-κBp65. Our study suggests that SYFSF may ameliorate diabetic kidney injury. The observed renoprotection is probably attributable to an inhibition of inflammatory response and extracellular matrix (ECM) accumulation mediated by TNF-α/NF-κBp65 signaling pathway.

A salt-sensitive mutant designated rice salt sensitive 2 (rss2) was isolated from the M2 generation of the rice cultivar Nipponbare mutagenized with ethyl methanesulfonate (EMS). This mutant exhibited a greater decrease in salt tolerance with a significant increase in Na(+) content in its shoots. Genetic analysis indicated that the increase in Na(+) in rss2 was controlled by a single recessive gene. Further genome-wide analysis of the linkage map constructed from the F2 population of rss2/Zhaiyeqing 8 (ZYQ8) showed that two quantitative trait loci (QTLs) on chromosomes 1 and 6 were responsible for the Na(+) concentration in shoots, which explained 14.5% and 53.3%, respectively, of the phenotypic variance. The locus on chromosome 1, but not that on chromosome 6, was also detected in the F2 population of Nipponbare/ZYQ8, suggesting that the QTL on chromosome 6 was responsible for the salt sensitivity in rss2. By analyzing the recombination events in 220 mutant individuals of an enlarged mapping population of rss2/ZYQ8, the rss2 locus was precisely mapped to an interval of 605.3 kb between insertion/deletion (InDel) markers IM21962 and IM22567. This finding will facilitate the cloning of the rss2 locus and provide insight into the physiological mechanisms of salt sensitivity in rice.

Three soil bacterial strains were identified as Chryseobacterium sp. TFB on the basis of their 16S rRNA gene sequences. Conidia of Arthrobotrys oligospora produced a few mycelial traps (MT) and conidial traps (CT) when cultured with bacterial cells that they did not produce when cultured with a bacterial cell-free culture filtrate. However, co-culture of A. oligospora with bacterial cells and bacteria-free filtrate simultaneously induced MT and CT in large amounts. With the increased concentration of bacteria-free filtrate, the number of typical CT increased, but conidial germination was progressively inhibited. Scanning electron microscopy of A. oligospora co-cultured with bacteria revealed that bacterial attachment to hyphae was a prerequisite to trap formation and that bacteria-free filtrate facilitated bacterial attachments to hyphae. The results that the addition of nutrients in co-culture medium decreased the number of traps suggest that this type of trap formation may be favoured at a low nutrient status. Eight fungi tested were able to form MT and CT when co-cultured with bacterial cells and bacteria-free culture filtrate, but the abilities varied among species. This study provides novel evidence that under laboratory conditions, soil bacteria attaching to hyphae could induce traps in nematode-trapping fungi.

Chlorogenic acid (CGA) and luteolin (Lut) are the predominant constituents of Caulis Lonicerae, which is usually used in the treatment for rheumatoid arthritis (RA).In this study, we investigated whether CGA and Lut could synergistically inhibit the proliferation of fibroblast-like synoviocytes (FLSs) in RA synovial tissues.Rat FLS cells (RSC-364) induced by interleukin (IL)-1β were treated by CGA, Lut or both of them. The apoptosis rates were detected by flow cytometer. Protein expression of key molecules of NF-κB and JAK/STAT signaling pathways were detected by Western blot.Treatment with CGA and Lut inhibited the proliferation of RSC-364 cells stimulated by IL-1β significantly and induced cell apoptosis notably. The ratio of apoptosis in RSC-364 cells induced with IL-1β accompanied by both CGA and Lut increased approximately 7-fold compared with those incubated with IL-1β alone. The results of immunoblot analysis revealed that the key molecules involved in the NF-κB and JAK/STAT-signaling pathways, including NF-κB p50, p100, IKKα/β, gp103, JAK1 and STAT3, were decreased significantly in RSC-364 cells treated by IL-1β plus CAG and Lut compared with those incubated with IL-1β alone. Additionally, the amounts of phospho-IKKα/β and phospho-STAT3 were also decreased significantly in cells treated with CGA and Lut. Furthermore, the synergistic effect of CGA and Lut was superior to the effect of one of these two ingredients.Our finding suggested that the combination of CGA and Lut may be a potential therapeutic treatment for the inflammatory proliferation of synoviocytes in patients with RA.

The role of the Mas receptor in the activity of valsartan against intimal hyperplasia is unclear. Herein, we investigated the role of the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis on the activity of valsartan against intimal hyperplasiain balloon-injured rat aortic arteries. Wistar rats were randomized equally into the sham control group, injured group, and injured plus valsartan (20 mg/kg/d)-treated group. Valsartan significantly attenuated the vascular smooth muscle cell proliferation and intimal and medial thickening on days 14 and 28 after injury. The angiotensin-(1-7) levels as well as ACE2 and Mas receptor mRNA/protein expression were significantly decreased in the injured rats, compared to the uninjured rats; meanwhile, the angiotensin II level as well as the ACE and AT1 receptor mRNA/protein expression were increased (all P

Chlorogenic acid (CGA) is the primary constituent of Caulis Lonicerae, a Chinese herb used for the treatment of rheumatoid arthritis (RA). The present study aimed to investigate whether CGA was able to inhibit the proliferation of the fibroblast-like synoviocyte cell line (RSC-364), stimulated by interleukin (IL)-6, through inducing apoptosis. Following incubation with IL-6 or IL-6 and CGA, the cellular proliferation of RSC-364 cells was detected by MTT assay. The ratio of apoptosed cells were detected by flow cytometry. Western blot analysis was performed to observe protein expression levels of key molecules involved in the Janus-activated kinase/signal transducer and activator of transcription 3 (JAK/STAT) signaling pathway [phosphorylated (p)-STAT3, JAK1 and gp130] and the nuclear factor κB (NF-κB) signaling pathway [phosphorylated (p)-inhibitor of κB kinase subunit α/β and NF-κB p50). It was revealed that CGA was able to inhibit the inflammatory proliferation of RSC-364 cells mediated by IL-6 through inducing apoptosis. CGA was also able to suppress the expression levels of key molecules in the JAK/STAT and NF-κB signaling pathways, and inhibit the activation of these signaling pathways in the inflammatory response through IL-6-mediated signaling, thereby resulting in the inhibition of the inflammatory proliferation of synoviocytes. The present results indicated that CGA may have potential as a novel therapeutic agent for inhibiting inflammatory hyperplasia of the synovium through inducing synoviocyte apoptosis in patients with RA.

Discovery of the isoform-selective histone deacetylases (HDACs) inhibitors is of great medical importance and still a challenge. The comparison studies on the structure-function relationship of the conserved residues, which are located in the linker binding channel among class I HDACs (including 4 isoforms: HDAC1/2/3/8), have been carried out by using ab initio QM/MM MD simulations, a state-of-the-art approach to simulate metallo-enzymes. We found that the conserved tyrosine (Y303/308/286/306 in HDAC1/2/3/8, respectively) could modulate the zinc-inhibitor chelation among all class I HDACs with different regulatory mechanisms. For HDAC1/2/3 selective-inhibitor benzamide, the conserved tyrosine could modulate the coordinative ability of the central atom (Zn(2+)), while for pan-inhibitor SAHA, the conserved tyrosine could increase the chelating ability of the ligand (SAHA). Moreover, it is first found that the conserved tyrosine is correlated with the intertransformation of π-π stacking styles (parallel shift vs T-shaped) by the aromatic ring in benzamide and the two conserved phenylalanine residues of HDACs. In addition, the catalytic roles of the conserved tyrosine in stabilizing the transition state and intermediate are further revealed. These findings provide useful molecular basis knowledge for further isoform-selective inhibitor design among class I HDACs.

Chrysanolide A, a novel guaianolide-type sesquiterpenoid trimer (3), along with its biogenetically related monomer (Chrysanolide B, 1) and dimer (Chrysanolide C, 2), were simultaneously isolated from Chrysanthemum indicum L flowers. Their structures and absolute configurations were elucidated via spectroscopic and computational methods. All isolated compounds were evaluated for their anti-HBV activities.