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Background: Icaritin is an aglycone of flavonoid glycosides from Herba Epimedii. It has good performance in the treatment of hepatocellular carcinoma in clinical trials. However, the natural icaritin content of Herba Epimedii is very low. At present, the icaritin is mainly prepared from flavonoid glycosides by α-L-rhamnosidases and β-glucosidases in two-step catalysis process. However, one-pot icaritin production required reported enzymes to be immobilized or bifunctional enzymes to hydrolyze substrate with long reaction time, which caused complicated operations and high costs. To improve the production efficiency and reduce costs, we explored α-L-rhamnosidase SPRHA2 and β-glucosidase PBGL to directly hydrolyze icariin to icaritin in one-pot, and developed the whole-cell catalytic method for efficient icaritin production., Results: The SPRHA2 and PBGL were expressed in Escherichia coli, respectively. One-pot production of icaritin was achieved by co-catalysis of SPRHA2 and PBGL. Moreover, whole-cell catalysis was developed for icariin hydrolysis. The mixture of SPRHA2 cells and PBGL cells transformed 200 g/L icariin into 103.69 g/L icaritin (yield 95.23%) in 4 h in whole-cell catalysis under the optimized reaction conditions. In order to further increase the production efficiency and simplify operations, we also constructed recombinant E. coli strains that co-expressed SPRHA2 and PBGL. Crude icariin extracts were also efficiently hydrolyzed by the whole-cell catalytic system., Conclusions: Compared to previous reports on icaritin production, in this study, whole-cell catalysis showed higher production efficiency of icaritin. This study provides promising approach for industrial production of icaritin in the future., (© 2023. The Author(s).)

Chinese herbal medicines (CHM) are frequently used to treat different types of inflammatory diseases and 15-Lipoxygenase (15-LOX) is a critical target enzyme for treating various inflammatory diseases. In this study, natural 15-LOX inhibitors were identified in CHM using an approach of virtual screening combined with the biological assays. First, an in-house Chinese medicine database containing 360 compounds was screened using a virtual screening approach based on pharmacophore and molecular docking to uncover several novel potential 15-LOX inhibitors. Secondly, the inhibitory effect of virtual screening hits against the 15-LOX enzyme was validated in an in vitro enzyme inhibition assay. Then, a tumor necrosis factor-α (TNF-α) release assay was carried out to explore the anti-inflammatory response of the active compounds. Furthermore, molecular dynamics (MD) simulation and binding free energy calculation were applied to analyze the process of inhibitors binding and also compared the mode of binding of the inhibitors by using the Molecular Mechanics-Generalized Born Surface Area (MM/GBSA) method. Finally, licochalcone B and eriodictyol were confirmed as inhibitors of the 15-LOX enzyme with IC 50 values of 9.67 and 18.99 μM, respectively. In vitro cell-based assay showed that licochalcone B and eriodictyol inhibited the release of TNF-α factor in RAW264.7 cells stimulated by lipopolysaccharides (LPS) in a dose-dependent manner. Molecular dynamics and binding free energy analysis showed that the two 15-LOX-ligand systems immediately attained equilibrium with almost 1 Å fluctuation, the calculated binding free energies were found around -18.89 and -12.96 kcal/mol for licochalcone B and eriodictyol, respectively. Thr412, Arg415, Val420, Thr429, Ile602 and Trp606 were the main amino acid residues for the inhibition of 15-LOX enzyme activity. The current study confirms that licochalcone B and eriodictyol are 15-LOX inhibitors and can suppress the release of the TNF-α factor in RAW264.7 cells stimulated by LPS, thus providing a basis for the follow-up research and development for 15-LOX inhibitors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: HuoXue JieDu Formula (HXJDF) originates from classical formulas and was formed based on clinical experience. It is composed of Euonymus alatus (Thunb.) Siebold, Panax notoginseng (Burkill) F.H. Chen, the roots of Anguina kirilowii (Maxim.) Kuntze, and Coptis omeiensis (C. Chen) C.Y.Cheng. HXJDF prevents the deterioration of diabetic retinopathy., Aim of the Study: To evaluate the effects of HXJDF on diabetic retinopathy in rats and investigate the roles of miRNAs in the effects of HXJDF., Materials and Methods: A single intraperitoneal injection of streptozotocin (STZ) (65 mg/kg) was used to induce diabetes in rats. Rats were divided into three groups: normal, diabetic, and diabetic + HXJDF. Rats were treated with HXJDF (15.4 g/kg) or water by oral gavage for twelve weeks. At the end of the treatment, rats were anaesthetized, and retinal haemodynamic changes were measured. Then, the retinas were removed and examined by haematoxylin and eosin (HE) staining and TUNEL assays. In addition, miRNA expression profiling was performed using miRNA microarrays and further validated by quantitative real-time PCR (qRT-PCR)., Results: Diabetes reduced peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MV) and central retinal vein velocity (CRV) but increased the resistance index (RI) and pulsatility index (PI). In addition, in the diabetic group, retinal cell arrangement was disordered and loosely arranged, the retinal thickness and retinal ganglion cell (RGC) number decreased, and retinal cell apoptosis increased. In addition, 11 miRNAs were upregulated and 4 miRNAs were downregulated. After treatment, HXJDF improved retinal haemodynamics and morphologic changes, restored retinal thickness and RGC number and decreased retinal cell apoptosis. Furthermore, the changes in miRNA expression were significantly abolished by HXJDF., Conclusion: HXJDF may prevent DR by regulating the expression of miRNAs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Norwogonin is a natural flavone with three phenolic hydroxyl groups in skeletal structure and has excellent antioxidant activity. However, the neuroprotective effect of norwogonin remains unclear. Here, we investigated the protective capacity of norwogonin against oxidative damage elicited by hypoxia in PC12 cells., Methods: The cell viability and apoptosis were examined by MTT assay and Annexin V-FITC/PI staining, respectively. Reactive oxygen species (ROS) content was measured using DCFH-DA assay. Lactate dehydrogenase (LDH), malondialdehyde (MDA) and antioxidant enzyme levels were determined using commercial kits. The expression of related genes and proteins was measured by real-time quantitative PCR and Western blotting, respectively., Results: We found that norwogonin alleviated hypoxia-induced injury in PC12 cells by increasing the cell viability, reducing LDH release, and ameliorating the changes of cell morphology. Norwogonin also acted as an antioxidant by scavenging ROS, reducing MDA production, maintaining the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and decreasing the expression levels of HIF-1α and VEGF. In addition, norwogonin prevented cell apoptosis via inhibiting the expression levels of caspase-3, cytochrome c and Bax, while increasing the expression levels of Bcl-2 and the ratio of Bcl-2/Bax., Conclusions: Norwogonin attenuates hypoxia-induced injury in PC12 cells by quenching ROS, maintaining the activities of antioxidant enzymes, and inhibiting mitochondrial apoptosis pathway.

The available scientific literature regarding tanshinones is very abundant, and after its review, it is noticeable that most of the articles focus on the properties of tanshinone I, cryptotanshinone, tanshinone IIA, sodium tanshinone IIA sulfonate and the dried root extract of Salvia miltiorrhiza (Tan- Shen). However, although these products have demonstrated important biological properties in both in vitro and in vivo models, their poor solubility and bioavailability have limited their clinical applications. For these reasons, many studies have focused on the search for new pharmaceutical formulations for tanshinones, as well as the synthesis of new derivatives that improve their biological properties. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2015) on tanshinones in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we offer an update on the last five years of new research on these quinones, focusing on their synthesis, biological activity on noncommunicable diseases and drug delivery systems, to support future research on its clinical applications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Deoxypodophyllotoxin, isolated from the Traditional Chinese Medicine Anthriscus sylvestris, is well-known because of its significant anti-tumor activity with strong toxicity in vitro and in vivo., Objective: In this article, a series of deoxypodophyllotoxin derivatives were synthesized and their anti-tumor effectiveness was evaluated., Methods: The anti-tumor activity of deoxypodophyllotoxin derivatives was investigated by the MTT assay method. Apoptosis percentage was measured by flow cytometer analysis using Annexin-V-FITC., Results: The derivatives revealed obvious cytotoxicity in the MTT assay by decreasing the number of late cancer cells. The decrease of Bcl-2/Bax could be observed in MCF-7, HepG2, HT-29, and MG-63 using Annexin V-FITC. The ratio of Bcl-2/Bax in the administration group was decreased, which was determined by the ELISA kit., Conclusion: The derivatives of deoxypodophyllotoxin could induce apoptosis in tumor cell lines by influencing Bcl-2/Bax., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Ethnopharmacological Relevance: The Yimusake tablet (YMSK-T) is a type of Xinjiang Uygur Medicine, which affects curing diseases of impotence and premature ejaculation. It has remarkable pharmacological effects that mainly involve improving the number and shape of smooth muscle cells in the corpus cavernosum and enhancing the relaxation and contraction function of corpus cavernosum smooth muscle., Aim of the Study: The YMSK-T prescription, which consists of 11 traditional herbs, has significant pharmacological effects, however the evaluation of toxicology and quality control of the preparation has not yet been reported. Therefore, in this study, we evaluated the toxicology and quality control of YMSK-T to ensure its safety and effectiveness in clinical applications., Materials and Methods: Male rats were divided into three groups and were given continuous gavage administration of high, medium and low concentrations of YMSK-T. To determine hematopoietic parameters, orbital blood was collected at regular intervals. At termination of the experiment, rats were dissected for histopathological examination. According to the function of the prescription medicinal materials, seven active components were selected for content determination under the same chromatographic condition of using 0.2% aqueous phosphoric acid (solvent A) and acetonitrile (solvent B) with a 40 min post time: 0-13 min, 20% →30% B; 13-26 min, 30% →72% B; 26-38 min, 72% →92% B; 38-40 min, 92% →96% B. The column was maintained at 25 °C and the total sample injection was 10 μL., Results: Our data showed that using a large dose (400X the dosage used in humans) of YMSK-T resulted in myocardium and liver damage, and eventually death of the rats. At sub-chronic toxicity, no significant differences were observed among indexes about relative organ weight, hematology, serum biochemistry and histopathological examination, and rats behaved normally. Our results also demonstrated that the YMSK-T dosage used was not toxic in the normal range. The linearity of each component was sufficient (correlation coefficients>0.9997). Moreover, the relative standard deviations of precision, repeatability, stability, and recovery were less than 2.0%, which showed that the method for determination of content was stable and reliable., Conclusions: YMSK-T has been found to be relatively safe in a rat model, and the method of content determination can be used for quality control of YMSK-T. Toxicology and quality control studies indicated that, the drug is safe and effective for clinical application., (Copyright © 2018. Published by Elsevier B.V.)

Context: The Chinese medicinal materials originate from animals, plants, or minerals must undergo appropriate treatment before use as decoction pieces. Processing of Chinese medicines with liquid excipients is a pharmaceutical technique that transforms medicinal raw materials into decoction pieces which are significantly different from the original form. During processing, significant changes occur in chemical constituents, which inevitably affects clinical efficacy. At present, the liquid materials in processing mainly involve wine, vinegar, honey, saline water, ginger juice, herbal juice, etc. Objective: This review introduces the typical methods of liquid excipients processing, summarizes the influence on chemical composition, pharmacological efficacy, and expounds the ways and mechanisms of liquid excipients to change the properties of drugs, enhance the efficacy, eliminate or reduce toxicity and adverse reaction. Methods: English and Chinese literature from 1986 to 2020 was collected from databases including Web of Science, PubMed, Elsevier, Chinese Pharmacopoeia 2015, and CNKI (Chinese). Liquid excipients, processing, pharmacological effects, synergism, chemical constitution, traditional Chinese medicine (TCM) were used as the key words. Results: Liquid excipients play a key role in the application of TCM. Processing with proper liquid excipients can change the content of toxic or active components by physical or chemical transformation, decrease or increase drug dissolution, alter drug pharmacokinetics, or exert their own pharmacological effects. Thus, processing with liquid excipients is essential to ensure the safety and efficacy of TCM in clinic. Conclusion: This article could be helpful for researchers who are interested in traditional Chinese herbs processed with liquid excipients.

Objective: To elucidate the mechanisms underlying the treatment of Alzheimer's disease (AD) with Traditional Chinese Medicine (TCM), by examining the active components, potential targets and synthetic pathways of Bulao Elixir (BLE)., Methods: The Absorption, Distribution, Metabolism, Excretion (ADME) / Toxicology (T) calculation was used to screen the active components of Bulao Elixir. Based on the TCM Systems Pharmacology Analysis Platform (TCMSP database) and a text mining tool (GoPubMed database), we predicted and screened the active components of Bulao Elixir and its therapeutic targets for AD. Using the Database for Annotation, Visualization and Integrated Discovery (DAVID), we obtained the targets for AD. Cytoscape software was used to establish a network map of the active component-target and target-pathway of Bulao Elixir. Gene function, related biological processes and signaling pathways were analyzed using the DAVID database., Results: Twelve active components were selected from 196 components of Bulao Elixir. Among 2209 targets, 102 effective targets were selected, and 30 important targets were identified via matching with the disease targets. After further analysis, 14 core targets were identified. Enrichment analysis revealed that most of these important targets were involved in multiple biological processes, including apoptosis, inflammatory reactions, and cell regulation cycles. The synthetic pathways for AD treatment were identified after analyzing and confirming the relevant pathways, providing potentially useful information for diagnosis and treatment methods for AD., Conclusion: The current study elucidated the potential treatment mechanisms of Bulao Elixir in AD using network pharmacology, providing a foundation for further clarification of its treatment targets.

To achieve improved drug delivery efficiency to hepatocellular carcinoma (HCC), biodegradable poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NP), surface-modified with SP94 peptide, were designed for the efficient delivery of cryptotanshinone to the tumor for the treatment of HCC. Cryptotanshinone NP and SP94-NP were prepared by using nanoprecipitation. The physicochemical and pharmaceutical properties of the NP and SP94-NP were characterized, and the release kinetics suggested that both NP and SP94-NP provided continuous, slow release of cryptotanshinone for 48 h. The in vitro cellular experiment demonstrated that SP94-NP significantly enhanced the cellular uptake of cryptotanshinone and induced high cytotoxicity and cellular apoptosis of hepatocellular carcinoma (HepG2) cells. The in vivo detecting results of targeting effect using the Cy5.5 probe evidenced that SP94-NP showed an accumulation in tumor more efficiently than that of unconjugated ones. Meanwhile, SP94-NP exhibited the smallest tumor size than other groups and showed no toxicity to body. The results of this study provide a promising nanoplatform for the targeting of HCC.

Chinese herbal medicine (CHM) addresses complex diseases through polypharmacological interactions. However, systematic studies of herbal medicine pharmacology remain challenging due to the complexity of CHM ingredients and their interactions with various targets. In this study, we aim to address this challenge with computational approaches. We investigated the herb-target-disease associations of 197 commonly prescribed CHMs using the similarity ensemble approach and DisGeNET database. We demonstrated that this method can be applied to associate herbs with their putative targets. In the case study of three well-known herbs, Radix Glycyrrhizae, Flos Lonicerae, and Rhizoma Coptidis, approximately 70% of the predicted targets were supported by scientific literature. By linking 406 targets to 2439 annotated diseases, we further analyzed the pharmacological functions of 197 herbs. Finally, we proposed a strategy of target-oriented herbal formula design and illustrated the target profiles for four common chronic diseases, namely, Alzheimer's disease, depressive disorder, hypertensive disease, and non-insulin-dependent diabetes mellitus. This computational approach holds great potential in the target identification of herbs, understanding the molecular mechanisms of CHM, and designing novel herbal formulas.

Paeonol, 2-hydroxy-4-methoxy acetophenone, is one of the main active ingredients of traditional Chinese medicine such as Cynanchum paniculatum, Paeonia suffruticosa Andr and Paeonia lactiflora Pall. Modern medical research has shown that paeonol has a wide range of pharmacological activities. In recent years, a large number of studies have been carried out on the structure modification of paeonol and the mechanism of action of paeonol derivatives has been studied. Some paeonol derivatives exhibit good pharmacological activities in terms of antibacterial, anti-inflammatory, antipyretic analgesic, antioxidant and other pharmacological effects. Herein, the research progress on paeonol derivatives and their pharmacological activities were systematically reviewed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Natural products play an important role in drug discovery. This work employed a natural product 1-methylhydantoin as the lead compound to develop novel dual-active drugs. 1-Methylhydantoin was isolated from Oviductus Ranae , which is a traditional Chinese medicine that has been used for tussive and inflammation treatment for a long time. An in silico study screened the more active 1-methylhydantoin derivatives. Antitussive assessment indicated that the newly synthesized agent had similar bioactivity with the natural product. An anti-inflammatory model used xylene induced ear edema model. At the same dosage (100 mg/Kg), the newly prepared agent had an inhibition rate 53.18% which was much higher than that of the lead compound (22.69%). The results might be ascribed to the cyclooxygenases-1 (COX-1) and cyclooxygenases-2 (COX-2) selectivity, and the fitness of the compound, and the binding pocket. The anti-particulate matter (PM 2.5) acute pneumonia was evaluated through an in vivo model constructed by nasal instillation with PM 2.5 suspension. The results of the above models suggested that this novel agent had remarkable antitussive, anti-inflammatory, and anti-PM 2.5 acute pneumonia activities.

Here we show that the efficacy of the chitosan interaction with diglycidyl ethers of glycols significantly depends on pH and the nature of acid used to dissolve chitosan. In solutions of hydrochloric acid, cross-linking with diglycidyl ethers of ethylene glycol (EGDGE) and polyethylene glycol (PEGDGE) at room and subzero temperatures yields mechanically stable chitosan gels and cryogels, while in acetic acid solutions only weak chitosan gels can be formed under the same conditions. A combination of elemental analysis, FT-IR spectroscopy, and solid state 13 C and 15 N NMR spectroscopy was used to elucidate possible differences in the mechanism of chitosan cross-linking in alkaline and acidic media at room and subzero temperatures. We have proved that in acidic media diglycidyl ethers of glycols interacted with chitosan mainly via hydroxyl groups at the C6 position of the glucosamine unit. Besides, not only cross-linkages but also grafts were formed at room temperature. The cryo-concentration effect facilitates cross-linkages formation at -10 °C and, despite lower modification degrees compared to those of gels obtained at room temperature, supermacroporous chitosan cryogels with Young's moduli up to 90 kPa can be fabricated in one step. Investigations of chitosan cryogels biocompatibility in a mouse model have shown that a moderate inflammatory reaction around the implants is accompanied by formation of a normal granulation tissue. No toxic, immunosuppressive, and sensitizing effects on the recipient's tissues have been observed.

BRM270 is the most leading phytochemical extract that possesses potent anticancer properties. A major challenge associated with this drug is its low bioavailability and thus requires high dosages for cancer treatment. Here, we report the novel nano-synthesis of phyto-composite, BRM270 for the first time by mechanical milling method with specific modifications for enhanced cytotoxicity against HepG2 human hepatoma cancer cells. Unlike free BRM270 and other phytomedicines, BRM270 nanoparticles (BRM270 NPs) are well-dispersed and small sized (23 to 70 nm) which is believed to greatly enhanced cellular uptake. Furthermore, the acidic tumor microenvironment attracts BRM270 NPs enhancing targeted therapy while leaving normal cells less affected. The comparative cytotoxicity analysis using MTT assay among the three treatment groups, such as free BRM270, BRM270 NPs, and doxorubicin demonstrated that BRM270 NPs induced greater cytotoxicity against HepG2 cells with an effective drug concentration of 12 μg/ml. From FACS analysis, we observed an apoptotic cell death of 44.4% at BRM270 NPs treated cells while only 12.5% found in the free BRM270 treated cells. Further, the comparative relative expression profiling of the candidate genes were showed significant (p < 0.05) down-regulation of IL6, BCL2, p53, and MMP9 in the BRM270 NPs treated cells, compared to the free BRM270 and doxorubicin. Indeed, the genes, CASPASE 9 and BAX have shown significant (p < 0.05) upregulation in cells treated with BRM270 NPs as compared to counter treatment groups. The investigation of the signal pathways and protein-protein network associations were also carried out to elucidate the functional insights underlying anti-cancer potential of BRM270 NPs in HepG2 cells. Taken together, our findings demonstrated that these uniquely engineered BRM270 NPs effectively enter into the cancer cells due to its acidic microenvironment thereby inducing apoptosis and regulate the cell-proliferation in-vitro at extremely low dosages., (Copyright © 2018. Published by Elsevier B.V.)

Background: Both Chuanxiong (Ligusticum chuanxiong Hort) and Tianma (Gastrodia elata Blume) have the effects of vasorelaxation and antihypertension. However, the effects of Tianshu Capsule (TSC, composed of Chuanxiong and Tianma in the mass ratio of 4:1) on antihypertensive activity have not been explored. This study aimed to investigate the eff ;ects of TSC on vascular tension and blood pressure in rats and to explore the underlying mechanisms., Methods: The vasorelaxant effect of TSC was explored on thoracic aortic rings (both intact endothelium and denuded) preincubated with phenylephrine (Phe) or potassium chloride (KCL). The mechanism was investigated in the presence of antagonists or blockers on aorta isolated from normotensive rats. The in vivo antihypertensive effect was assessed using a tail-cuff method on spontaneously hypertensive rats (SHRs)., Results: TSC (0.125-4 mg/mL) produced a concentration-dependent vasorelaxation on aortic rings preincubated with Phe (1 μM) or KCL (60 mM). Removal of aorta endothelium markedly attenuated the TSC activity. Pretreatment of aortic rings with β-adrenoceptor blocker propranolol (1 μM), muscarinic receptor antagonist atropine (1 μM), cyclooxygenase inhibitor indomethacin (IDO, 1 μM), adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 μM), K + channel blockers 4-aminopyridine(4-AP, 1 mM) or barium chloride(BaCl 2 , 1 mM) followed by addition of Phe (1 μM) prior to TSC did not influence the TSC-induced relaxation. In contrast, the vasorelaxant effects of TSC were markedly inhibited by the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 10 μM), guanylyl cyclase inhibitor 1H- [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 μM), K + channel blockers, glibenclamide (100 μM) and clotrimazole (5 mM). Moreover, TSC (2 mg/mL, 4 mg/mL) inhibited CaCl 2 -induced contractions and caused a concentration-dependent rightward shift of the response curves. Additionally, TSC (2 mg/mL, 4 mg/mL) depressed the constriction caused by Phe (1 μM) in the absence of extracellular Ca 2+ . Furthermore, TSC (2.15 g/kg) lowered the systolic blood pressure (SBP), with no alteration in heart rate (HR) in SHRs., Conclusions: These findings demonstrated that TSC induced vasorelaxant effects via both endothelium-dependent and endothelium-independent pathways. The NO/sGC/cGMP pathway, ATP-sensitive K + channels, Ca 2+ -activated K + channels, inhibition of extracellular Ca 2+ influx and intracellular Ca2 + release were probably involved in this relaxation. The vasorelaxant effects of TSC may make the greatest contribution to the reduction in high blood pressure., (Copyright © 2018. Published by Elsevier Masson SAS.)

Diosbulbin B (DBB) and 8-epidiosbulbin E acetate (EEA), belonging to furan-containing diterpenoid lactones, are the primary components of Dioscorea bulbifera L. (DB), a traditional Chinese medicine herb. Our earlier studies indicated that consumption of DBB or EEA induced acute hepatotoxicities. Both DBB and EEA were bioactivated by P450 3A4 to generate the corresponding cis-enedial reactive metabolites which are associated with the hepatotoxicities. It has been proposed that the electrophilic intermediates attack cellular nucleophiles such as protein or DNA, thought to be a mechanism of triggering toxicities. The purposes of our present study were to define the interaction of the electrophilic reactive metabolites originating from DBB and EEA with 2'-deoxyguanosine (dGuo), 2'-deoxycytidine (dCyd), and 2'-deoxyadenosine (dAdo) and to characterize DNA adducts arising from the reactive metabolites of DBB and EEA. The reactive metabolites of DBB and EEA were found to covalently bind to the exocyclic and endocyclic nitrogens of dCyd, dGuo, and dAdo to generate oxadiazabicyclo[3.3.0]octaimine adducts. The reactive metabolites of DBB and EEA also attacked dGuo, dAdo, and dCyd of calf thymus DNA. The DNA adducts possibly contribute to the toxicologies of DBB and EEA.

P-glycoprotein (P-gp)-mediated multi-drug resistance (MDR) is a well-documented and predominant phenotype hampering patients' response to cancer chemotherapy. Although the past several decades have witnessed the development of three generations of P-gp inhibitors, they have not lived up to the high expectations owing to their drawbacks, as exemplified by limited efficacy, drug-drug interactions (DDIs) and severe untoward reactions. The discovery of artemisinin is a testimony of the importance of traditional Chinese medicine (TCM) in innovative drug discovery. In search for a new generation of chemo-sensitizers, P-gp modulators originated from TCM have attracted increasing concern in the research community. In addition to identify TCM monomers or their synthetic intermediates as P-gp modulators, massive medicinal chemistry efforts have been made in discovering promising structural analogs and derivatives of them. Among these, compounds with dual role both as P-gp inhibitor and cytotoxic agent have continuously emerged. Hence, in this article, we will mainly enumerate the representative work conducted in the discovery of TCM monomers and their synthetic intermediates, analogs or derivatives as reversers of P-gp-mediated MDR., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

In clinic, both synthetic drugs and Shenzhu Capsule (SZC), one kind of traditional Chinese medicines (TCMs), are used to treat ulcerative colitis (UC). In our study, a systems pharmacology approach was employed to elucidate the chemical and mechanism differences between SZC and synthetic drugs in treating UC. First, the compound databases were constructed for SZC and synthetic drugs. Then, the targets of SZC were predicted with on-line tools and validated using molecular docking method. Finally, chemical space, targets, and pathways of SZC and synthetic drugs were compared. Results showed that atractylenolide I, atractylone, kaempferol, etc., were bioactive compounds of SZC. Comparison of SZC and synthetic drugs showed that (1) in chemical space, the area of SZC encompasses the area of synthetic drugs; (2) SZC can act on more targets and pathways than synthetic drugs; (3) SZC can not only regulate immune and inflammatory reactions but also act on ulcerative colitis complications (bloody diarrhea) and prevent UC to develop into colorectal cancer whereas synthetic drugs mainly regulate immune and inflammatory reactions. Our study could help us to understand the compound and mechanism differences between TCM and synthetic drugs.

Selenium nanoparticles (SeNPs) have attracted increasing interest over the last decades because of their activities on redox balance in human body. However, the SeNPs tend to aggregate into large clusters, resulting in lower bioactivity, bioavailability and biocompatibility. Surface-capping agents on SeNPs play crucial roles in its stabilization and biological activity. Here, a green synthesis method for the preparation of Lycium barbarum polysaccharides capped SeNPs using green tea extracts as reductants under mild conditions, at room temperature, is reported. The structure, size, morphology and thermal behaviour were analyzed by various characterization techniques. The functionalized nanoparticles demonstrated high antioxidant activity, including DPPH and ABTS free radical scavenging. Moreover, the SeNPs significantly protected the H 2 O 2 -induced PC-12 cell death. Taken together, these results evidence the possible application of these SeNPs as antioxidants food supplement or ingredient and neuroprotective agent.

Panaxatriol, a triterpene bearing a steroid-like structure similar to cardiac glycosides, was presumed to share the same bioactivity with cardiac glycosides, and may be a potential Na + , K + -ATPase inhibitor. In this paper, a series of panaxatriol derivatives were synthesized and evaluated for Na + , K + -ATPase inhibitory activities. The results of biological tests showed that more than half of the synthesized derivatives presented increased inhibitory activities compared with panaxatriol. Of these compounds, 13a with a 3, 4-seco skeleton showed the most potent inhibitory activity, which was equal to that of the standard drug digoxin. To understand the binding mode of the most active compound, molecular docking study of 13a with Na + , K + -ATPase was conducted. Therefore, 13a may serve as a new lead compound for the development of novel Na + , K + -ATPase inhibitors., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Malaria, one of the World's biggest billers' is on the schedule for biomedical research and public health policies. The introduction of the artemisinin, a Chinese traditional drug from Artemisia annua is a revolution in the treatment of malaria. Artemisinin-based combination treatment (ACT) is considered to be the best strategy for uncomplicated Falciparum malaria. The presence of 1,2,4-trioxane system in artemisinin is responsible for its antimalarial activity., Methods: In this study, twenty-nine analogues of artemisinin were taken into account for QSAR studies along with artemisinin. The most active analogue of artemisinin 21 was energy minimized. All the structures were prepared from the active conformer 21 and energy was minimized to the stable state using MMFF94 force field using ChemBioDraw-12. Genetic Algorithm is used to decide the descriptors best required for the model generation. The test set and training set division were done by using hierarchal clustering module available with NCSS statistical software., Results and Conclusion: The antimalarial activity of the artemisinin and its substituted analogues has been analyzed through the multiple linear regression (MLR) using various physiochemical and structural descriptors obtained from PADEL software. The models were prepared using the Sigma Plot version 11. The calculated 2D autocorrelation descriptors and the MLR model suggest that artemisinin and its analogues hold the scope in the optimization of antimalarial activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Luteolin (LUT) and luteoloside (LUS) belong to flavonoids with high anticancer potential and were loaded into biodegradable diblock copolymer micelles of methoxy polyethylene glycol-polycaprolactone (mPEG 5K -PCL 10K ), methoxy polyethylene glycol-polylactide-co-glycolide (mPEG 5K -PLGA 10K ), and methoxy polyethylene glycol-polylactide (mPEG 5K -PDLLA 10K ) by a self-assembly method, creating water-soluble LUT and LUS copolymer micelles, respectively. The solubilization formulations of the copolymer micelles were optimized with response surface methodology (RSM). The obtained drug micelles are torispherical under transmission electron microscope (TEM) with an average diameter of about 70 nm. The mPEG 5K -PLGA 10K exhibited higher loading capacity for LUS which was 4.33%, and LUT- (or LUS)-loaded mPEG 5K -PCL 10K exhibited a better stability and encapsulation efficiency which was 65.1 and 55.8%, respectively. The in vitro drug release study showed above 47% of LUT was released from micelles at pH 7.4 PBS; however, no more than 35% of LUT was released at pH 6.4 PBS within 24 h. Meanwhile, no more than 30% of LUS was released from micelles whether at pH 6.4 or 7.4 PBS solution within 24 h.

Hericium erinaceus is typically used in traditional Chinese medicine for mucosal protection, healing of gastric ulcers, and treatment of gastritis. We purified from the cultured mycelia of H. erinaceus a polysaccharide with anti-gastric ulcer and antigastritis activity, but its effects on gastric malignancy have not been elucidated. We examined the differential effects of this purified polysaccharide, named EP-1, on the human gastric (GES-1) cell line and a precancerous cell line (MC) that was transformed from GES-1 using N-methyl-N'-nitro-N-nitrosoguanidine. We observed that the polysaccharide potently induced cell apoptosis and cell cycle arrest at the G0/G1 phase in the MC cell line but did not have any effect on the GES-1 cell line at the same doses. Further mechanistic studies revealed that the polysaccharide exerted its activity through an apoptosis-associated pathway by modulating the expression of Bax, Bcl-2, and caspase-3. Differential effects of the polysaccharide on the GES-1 and MC cell lines indicate that the polysaccharide was effective in preventing gastric cancer progression.

Tanshinone IIA is a valuable bioactive natural product isolated from the well-known Chinese herb Danshen. Structural manipulation of the A-ring of tanshinone IIA is rather limited. In this study, a substrate tautomerization-induced catalyst-free benzylic sp 3 C-H acyloxylation approach is reported that allows the direct introduction of various acyloxy groups at the A-ring benzylic methylene of various tanshinone IIA substrates, thus avoiding the use of expensive transition metal catalysts and the production of harmful byproducts. This approach features a unique acid-induced reversible enolization/oxa-conjugate addition process followed by oxidation to exclusively give a series of diverse 1-acyloxylated derivatives under simple conditions in a regioselective manner. Compared with the literature procedures, this protocol demonstrates a higher efficiency, a more robust functional-group tolerance, atom economy, and lower cost.

The first and asymmetric total synthesis of hedyosumins A, B, and C was accomplished in 13-14 steps from simple starting materials. The essential tools that allow us to access the tetracyclic skeleton include an organocatalytic [4 + 3] cycloaddition reaction, an intramolecular aldol condensation, and an intramolecular carboxymercuration/demercuration enabled lactonization. A CBS-catalyzed asymmetric reduction was employed to boost the ee of the synthetic natural products to an excellent level. This synthesis established the absolute configurations of hedyosumins A, B, and C.

Lancolide E (1) featuring a complex tetracyclo[5.4.0.0(2,4).0(3,7)]undecane-bridged system that is constructed by an eight-, a three-, and two five-membered carbon rings in a sterically congested region was obtained in trace amounts from a "talented" schinortriterpenoid producer Schisandra lancifolia. Its structure was fully characterized by combining 2D NMR spectroscopy, theoretical calculations, and X-ray diffraction analysis. The biogenetic pathway of 1 was proposed to involve a Prins cyclization.

The (anaphylactoid) hypersensibility mechanism of ″imprinting templates″ characteristics of traditional Chinese medicine (TCM) injection supramolecules was clarified to lay the foundation to build safety evaluation method. Based on the previous publication on special impact of Chinese medicine theories on supramolcular chemistry, combined with the natural origination of (anaphylactoid) hypersensitized special rules as well as the sensitization phenomenon of cordate houttuynia injection, the impact of the structure characteristics of ″imprinting templates″ in TCM injection supramolecules on its (anaphylactoid) hypersensibility was clarified. In Chinese medicine injections, the supramolecular structures can independently be generated, showing overall apparent (anaphylactoid) hypersensibility nature, and their structure characteristics were dependent on the strength. In addition, (anaphylactoid) hypersensitive critical supramolecular structure was present. When it was administrated by ″injection″, it's structure was not easy to be destroyed, often showing apparent immunogenicity, whereas if it was administrated by ″oral″, the structure would be destroyed by the gastrointestinal tract, showing weaker or no apparent immunogenicity. Therefore, there are differences in (anaphylactoid) hypersensibility between ″injection″ and ″oral″ administration of TCM. TCM injections would produce the supramolecules between ″molecular society″ by independent reaction of supramolecular ″imprinting template″ (chemical determinants), showing apparent immune process of recognition, copying, and storage. Single molecule is a special example for this. The screening of anaphylactoid (sensitinogen) includes the single ingredients and their forming supramolecules for TCM injection. This is the unique feature for safety evaluation of Chinese medicine injection., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Mushroom cultivation benefits humankind as it deliberately encourages wild mushrooms to be commercially propagated while recycling agricultural wastes. Ganoderma neo-japonicum is a rare polypore mushroom found growing on decaying Schizostachyum brachycladium (a tropical bamboo) clumps in Malaysia. The Malaysian indigenous tribes including the Temuans and Temiars use the basidiocarps of G. neo-japonicum to treat various ailments including diabetes. In this study, the domestication of G. neo-japonicum in artificial logs of different agricultural residues was investigated. Sawdust promoted the mycelia spawn colonisation in the shortest period of 38 ± 0.5 days. However, only sawdust and bamboo dust supported the primodia formation. Complex medium supported mycelium growth in submerged cultures and 27.11 ± 0.43 g/L of mycelia was obtained after 2 weeks of cultivation at 28 °C and 200 rpm. Antioxidant potential in mushroom may be influenced by different cultivation and extraction methods. The different extracts from the wild and cultivated basidiocarps as well as mycelia were then tested for their antioxidant properties. Aqueous and ethanol extracts of mycelia and basidiocarps tested had varying levels of antioxidant activities. To conclude, domestication of wild G. neo-japonicum using agroresidues may ensure a continuous supply of G. neo-japonicum for its medicinal use while ensuring the conservation of this rare species.

Stemona alkaloids, featuring polycyclic structures and interesting bioactivities, constitute a distinct class from the Stemonaceae family. In this review, recent advances in the synthesis of these unique alkaloids are briefly discussed, highlighting the application of novel synthetic strategies to access the core structures, as well as creative solutions to the installation of multiple stereogenic centers. The literature reviewed in this article covers the publications from 2010 to November 2014, a period that witnessed the prosperity of the synthesis of Stemona alkaloids.

We have previously reported that the danshensu-cysteine conjugate N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC) is a potent anti-oxidative and anti-apoptotic agent. Herein, we further design and asymmetrically synthesize two diastereoisomers of DSC and explore their potential bioactivities. Our results show that DSC and its two diastereoisomers exert similar protective effects in hydrogen peroxide (H2O2)-induced cellular injury in SH-SY5Y cells, as evidenced by the increase of cell viability, superoxide dismutase (SOD), and reduced glutathione (GSH) activity, and glutathione peroxidase (GPx) expression, and the decrease of cellular morphological changes and nuclear condensation, lactate dehydrogenase (LDH) release, and malondialdehyde (MDA) production. In H2O2-stimulated human umbilical vein endothelial cells (HUVEC), DSC concentration-dependently attenuates H2O2-induced cell death, LDH release, mitochondrial membrane potential collapse, and modulates the expression of apoptosis-related proteins (Bcl-2, Bax, caspase-3, and caspase-9). Our results provide strong evidence that DSC and its two diastereoisomers have similar anti-oxidative activity and that DSC exerts significant vascular-protective effects, at least in part, through inhibition of apoptosis and modulation of endogenous antioxidant enzymes.

Components previously reported from Cyclocarya paliurus include the oleananes cyclocaric acids A and B, with cyclocaric acid A possessing an oxetane ring. Isolation of cyclocaric acid A from the plant extract and comparison to the literature report show that the compound originally reported as cyclocaric acid A is, in fact, hederagenin. This was confirmed by independent synthesis of the oxetane and indicates that cyclocaric acid A may not actually be a natural product.

A series of 6-deoxymollugins were prepared five steps from benzaldehyde and its derivatives via phenylboronic acid-catalyzed chromenylation as a key step. Their inhibitory activities against tyrosinase from mushroom were evaluated to show that the parent, methyl 2,2-dimethyl-2H-benzo[h]chromene-5-carboxylate (9a) showed best and promising inhibitory activity at IC50 = 18.3 μM.

For the establishment of chemical library of protoberberines provided for the bio-activity screening, the target compounds were synthesized by thermal degradation and nucleophilic substitution reactions with the bio-active alkaloid, palmatine (1), as the raw material, and their structures were identified and conformed by 1H-NMR and MS spectra. Among them, 13 compounds were new.

1,2,3,4-Tetrahydro-β-carbolines (THβCs) are a pharmacologically important group of compounds belonging to the indole alkaloids. C1-Substituted optically active THβCs have been the target of extensive synthetic efforts due to the presence of the scaffold in numerous natural products and synthetic targets. This review briefly summarizes the methods to obtain the C1 stereocenter and concentrates on evaluating the pharmacological importance of optically active C1-substituted THβCs, including their PDE5-inhibitory, antimalarial, antiviral and antitumor activities.

Huperzine A, huperzine B, and huperzine U are congeners isolated from the Chinese herb Huperzia serrata (= Lycopodium serratum ) in minuscule amounts. The most efficient total synthesis of huperzine A, the first asymmetric total syntheses of huperzine B, and the first total synthesis of huperzine U have been achieved efficiently in overall yields of 17%, 10%, and 9%, respectively, each spanning 10-13 steps from (R)-pulegone. The featured steps include palladium-catalyzed Buchwald-Hartwig coupling and Heck cyclization reactions and an Ir-catalyzed olefin isomerization reaction. This work has established the absolute configurations of huperzine B and huperzine U and revealed that natural huperzine A, huperzine B, and huperzine U possess the same set of absolute stereochemistries, thus providing support for the potential role of huperzine B and huperzine U in the biosynthesis of huperzine A.

Ten lupeol dicarboxylic acid monoester derivatives as new potent antitumor agents were synthesized and evaluated for in vitro antitumor activities against A549, LAC, HepG2 and HeLa cell lines. Among them, compounds 1-5 showed excellent antitumor activities against all tested tumor cell lines and compounds 6-10 exhibited high activities against A549, HepG2 and HeLa cells, exceeded lupeol, lupanol and doxorubicin. Compound 2 displayed the highest potent antitumor activities with IC50 values of 5.78 μM against A549 cell, 2.38 μM against LAC cell, 6.14 μM against HepG2 cell and 0.00842 μM against HeLa cell.

Aim: In a search for new cardiovascular drug candidates, a series of novel oxime ethers derived from a natural isochroman-4-one were synthesized., Method: Compounds 3 and 6, derived from the natural antihypertensive compound 7, 8-dihydroxy-3-methyl-isochroman-4-one (XJP), were designed and synthesized. Subsequently, a series of novel isochroman-4-one oxime ether hybrids were prepared by hybridizing various N-substituted isopropanolamine functionalities to isochroman-4-one oxime. Furthermore, β1-adrenergic blocking activities of the synthesized compounds were assayed using the isolated rat left atria., Results: Twenty target compounds were obtained, and the preliminary structure-activity relationships were deduced. The most promising compound Ic exhibited β1-adrenoceptor blocking activity (inhibition: 52.2%) at 10(-7) mol·L(-1), which was superior to that of propranolol (inhibition: 49.7%)., Conclusion: The results suggested that natural product XJP/isopropanolamine moiety hybrids may provide a promising approach for the discovery of novel cardiovascular drug candidates., (Copyright © 2013 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

The total synthesis of a methylated analogue of (+)-Salvianolic acid C has been achieved. Key aspects of the synthetic route include an economical Cu(I) acetylide coupling, unique carboxyl activation conditions via microwave irradiation and a novel lipase catalysed kinetic resolution of a racemic mixture of secondary alcohol Danshensu. The preparation of this methylated analogue will not only improve the bioavailability, but also enable access to new and wider bioactivity applications for (+)-Salvianolic acid C.

Oh my goch: The total syntheses of ainsliadimer B and gochnatiolides A and B from α-santonin have been accomplished in 25 steps with approximately 1 % overall yield. A Diels-Alder reaction of natural dehydrozaluzanin C with a monomeric guaianolide derivative allows stereoselective assembly of a dimeric gochnatiolide-type skeleton with the required stereochemistry and preinstalled functionalities for the synthesis of dimeric ainsliadimer B and gochnatiolides A and B (see scheme)., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Three sodium salts of (2E)-3-(4'-halophenyl)prop-2-enoyl sulfachloropyrazine (CCSCP) were synthesized and their structures were determined by (1)H and (13)C NMR, LC-MS and IR. The binding properties between CCSCPs and bovine serum albumin (BSA) were studied using fluorescence spectroscopy in combination with UV-vis absorbance spectroscopy. The results indicate that the fluorescence quenching mechanisms between BSA and CCSCPs were static quenching at low concentrations of CCSCPs or combined quenching (static and dynamic) at higher CCSCP concentrations of 298, 303 and 308 K. The binding constants, binding sites and corresponding thermodynamic parameters (ΔH, ΔS, ΔG) were calculated at different temperatures. All ΔG values were negative, which revealed that the binding processes were spontaneous. Although all CCSCPs had negative ΔH and positive ΔS, the contributions of ΔH and ΔS to ΔG values were different. When the 4'-substituent was fluorine or chlorine, van der Waals interactions and hydrogen bonds were the main interaction forces. However, when the halogen was bromine, ionic interaction and proton transfer controlled the overall energetics. The binding distances between CCSCPs and BSA were determined using the Förster non-radiation energy transfer theory and the effects of CCSCPs on the conformation of BSA were analyzed by synchronous fluorescence spectroscopy., (Copyright © 2012 John Wiley & Sons, Ltd.)

Bisbenzylisoquinoline alkaloid, nelumboferine which was recently isolated from the embryo of Nelumbo nucifera, and stereoisomers of neferine, which is a major alkaloid of the embryo of N. nucifera, were stereoselectively synthesized. Pharmacological activity of nelumboferine, stereoisomers of neferine, liensinine, isoliensinine, and O-methylneferine were evaluated.

The spirocyclic pyrrole alkaloid, acortatarin A, which had been isolated from a Chinese medicinal plant, was synthesized from a known olefinic compound by a concise six-step sequence involving N-alkylation of a pyrrole derivative with an α-bromo ketone intermediate as the key step.

The development of dry powder inhalation (DPI) products of traditional Chinese medicine (TCM) remains to be a challenge due to chemical complexity and batch-to-batch variations in constituent composition. This study was to investigate the feasibility of using spray-dried corrugated particles to improve the aerodynamic performance of a TCM, Shuang-Huang-Lian (SHL), in carrier-based DPI. Particles with different surface roughness were spray-dried by the addition of leucine and concomitant manipulation of spray-drying parameters. The surface roughness was determined by atomic force microscopy, whilst the aerodynamic performance of drug particle-mannitol/lactose blends was evaluated using a next-generation pharmaceutical impactor through a Cyclohaler. Although the emission efficiency for corrugated particle-based DPI was ~10% lower than that for smooth SHL, the fine particle fractions (FPF(<4.4 μm)) of 32.4-36.8% for the former were significantly higher than those of 14.7-16.2% for the latter. In particular, the FPF and fraction of drug detached from the carrier appeared not to be significantly affected by the variation in constituent composition of SHL. This study demonstrates that the use of corrugated particles in carrier-based DPI improved aerosol performance by facilitating drug detachment from the carrier, independent of variation in constituent composition, and such particles were potentially applicable to the development of SHL DPI products.

Objective: To study synthesis of baicalin-copper and baicalin-aluminium complex and its antimicrobial, anti-tumor activity and anti-tumor effect against macrophages., Method: Baicalin was reacted with metallic salt under a weak base condition to produce baicalin-copper and baicalin-aluminium complex. Baicalin and its synthesized complex were detected for antimicrobial activity against Staphylococcus aureus, Hay bacillus, Escherichia coli, Salmonella and Candida albicans by twofold broth dilution technique. Their anti-tumor activity against A549 and IC50 of HepG2 cells and anti-tumor effect against macrophages were detected by the MTT. And their phagocytic effect on macrophages was determined by the neutral red assay., Result: The yields of baicalin-copper and baicalin-aluminium complex were 73.93% and 91.08%, respectively. The minimum inhibitory concentration (MIC) value against Staphylococcus aureus, Hay bacillus, Escherichia coli, Salmonella and Candida albicans was 0.0004, 0.0009, 0.0004, 0.0009, 0.000 4 mol x L(-1) for baicalin-copper complex and 0.0011, 0.0011, 0.0011, 0.0011, 0.0005 mol x L(-1) for baicalin-aluminium complex. The IC50 values against A549 and HepG2 cells were 89.6, 22.6 micromol x L(-1) for baicalin-copper complex, and 138.8, 97.2 micromol x L(-1) for baicalin-aluminium complex. The inhibitory ratio of macrophage on A549 cell was 43.52%, 80.89%, 52.66%, respectively, after the macrophages were stimulated by baicalin, baicalin-copper and baicalin-aluminium complex at a concentration of 160 micromol x L(-1)., Conclusion: The acute toxicity test in mice showed that the complex was nontoxic to mice. Baicalin-copper complex showed the highest antimicrobial, anti-tumor activity, and the strongest effect on the anti-tumor activity of macrophage, while baicalin showed the lowest activities compared with baicalin-copper and baicalin-aluminium complex.

Dimethyl lithosermate B (DLB) is a highly potent natural antioxidant and antidiabetic polyphenol with unknown mode of action. To determine its cellular targets, a photochemical and fluorescent dimethyl lithopermate B probe was designed and efficiently synthesized. The dual-labeled chemical probe for biological application was evaluated by UV and fluorescence to determine its electrochemical absorption and emission properties. This probe could be valuable for investigating ligand-protein interactions and subcellular localization., (© 2011 by the authors; licensee MDPI, Basel, Switzerland.)

Aberrations in cyclic adenosine monophosphate (cAMP) signaling cascade has been linked to the allergic responses that associate with the risks of stroke or cardiovascular diseases. Phosphodiesterase 4D (PDE4D) has been shown to be highly involved in cAMP regulation and is hence implied to be a potential drug target in stroke prevention. To identify potential PDE4D inhibitors from traditional Chinese medicine (TCM), we employed machine learning modeling techniques to screen a comprehensive TCM database. The multiple linear regression (MLR) and support vector machine (SVM) models constructed have correlation coefficients of 0.8234 and 0.7854 respectively. Three candidates from the ginger family were identified based on the prediction models. Molecular dynamics simulation further validated the binding stabilities of each candidate in comparison to the control inhibitor L-454560. The intermolecular distances suggested that the candidates could hinder PDE4D from binding to cAMP. Furthermore, the HypoGen validation suggested that top2, top3, and the control L-454560 mapped with the predicted pharmacophores. The results suggested that the 3 compounds identified from the ginger family were capable in inhibiting cAMP binding and hydrolysis by PDE4D. We further identified and characterized the ligand binding properties that are associated with the inhibition of PDE4D.

An effective two step transformation of oridonin to 15,16-seco-ent-kaurane skeleton is reported. We also achieved the conversion of one intermediate to natural product rubescensin S and revised its structure as a 13S configuration although 13R is reported in the literature.

In continuation of our program aimed at the discovery and development of natural products-based insecticidal agents, twelve 28-acyloxy derivatives of toosendanin (2a-l) were semisynthesized and preliminarily evaluated their activity against the pre-third-instar larvae of Mythimna separata Walker in vivo at the concentration of 1mg/mL. Some compounds exhibited the potent insecticidal activity. Especially compounds 2c and 2j displayed the more promising insecticidal activity than their natural precursor, toosendanin, a commercial insecticide derived from Melia azedarach at 1mg/mL. In general, it indicated that the butanoyloxy or phenylacryloyloxy moiety at the 28-position of toosendanin was essential for the insecticidal activity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)