Pre-treatment of rapamycin transformed M2 microglia alleviates traumatic cervical spinal cord injury via AIM2 signaling pathway in vitro and in vivo.

BACKGROUND: Traumatic spinal cord injury (SCI) is still devastating. It was suggested that the inhibition of mTOR may alleviate neuronal inflammatory injury but its underlying mechanism remained to be elucidated. AIM2 (absent in melanoma 2) recruits ASC (apoptosis-associated speck-like protein containing a CARD) and caspase-1 to form the AIM2 inflammasome, activate caspase-1, and elicit inflammatory responses. We designed this study to elucidate whether pre-treatments of rapamycin could suppress SCI induced neuronal inflammatory injury via AIM2 signaling pathway in vitro and in vivo. METHODS: We performed oxygen and glucose deprivation / re-oxygenation (OGD) treatment and rats clipping model to mimic neuronal injury after SCI in vitro and in vivo. Morphologic changes of injured spinal cord were detected by hematoxylin and eosin staining. The expression of mTOR, p-mTOR, AIM2, ASC, Caspase-1 and et al were analyzed by fluorescent staining, western blotting or qPCR. The polarization phenotype of microglia was identified by flow cytometry or fluorescent staining. RESULTS: We found BV-2 microglia without any pre-treatment cannot alleviate primary cultured neuronal OGD injury. However, pre-treated rapamycin in BV-2 cells could transform microglia to M2 phenotype and protects against neuronal OGD injury via AIM2 signaling pathway. Similarly, pre-treatment of rapamycin could improve the outcome of cervical SCI rats through AIM2 signaling pathway. CONCLUSIONS: It was suggested that resting state microglia pre-treated by rapamycin could protect against neuronal injury via AIM2 signaling pathway in vitro and in vivo. Pre-inhibition of mTOR pathway may improve neuronal protection after SCI.

Synthesis-accessibility-oriented design of c-Jun N-terminal kinase 1 inhibitor.

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disease with poor prognosis and limited treatment options. The c-Jun N-Terminal Kinase 1 (JNK1), a key component of the MAPK pathway, has been implicated in the pathogenesis of IPF and represents a potential therapeutic target. However, the development of JNK1 inhibitors has been slowed, partly due to synthetic complexity in medicinal chemistry modification. Here, we report a synthesis-accessibility-oriented strategy for designing JNK1 inhibitors based on computational prediction of synthetic feasibility and fragment-based molecule generation. This strategy led to the discovery of several potent JNK1 inhibitors, such as compound C6 (IC50 = 33.5 nM), which exhibited comparable activity to the clinical candidate CC-90001 (IC50 = 24.4 nM). The anti-fibrotic effect of C6 was further confirmed in animal model of pulmonary fibrosis. Moreover, compound C6 could be synthesized in only two steps, compared to nine steps for CC-90001. Our findings suggest that compound C6 is a promising lead for further optimization and development as a novel anti-fibrotic agent targeting JNK1. In addition, the discovery of C6 also demonstrates the feasibility of synthesis-accessibility-oriented strategy in lead discovery.

Ambient Temperature NO Adsorber Derived from Pyrolysis of Co-MOF(ZIF-67).

Co-, Ni-, and Zn-containing MOFs are prepared and then pyrolyzed to generate materials for ambient temperature NO adsorption. Materials containing Co are much more efficient for NO adsorption than those containing Ni and Zn; therefore, Co is identified as the active phase. The best performing material studied here achieves 100% low concentration (10 ppm) NO adsorption for more than 15 h under a weight hourly space velocity of 120 000 mL g-1 h-1. Powder X-ray diffraction, X-ray photoelectron spectroscopy, Fourier transform infrared, and Raman spectroscopies, along with scanning electron microscopy and TEM, are used to probe the physicochemical properties of the materials, particularly the Co active phase, and chemistries involved in NO adsorption-desorption. NO adsorbs on oxygen-covered Co nanoparticle surfaces in the form of nitrates and desorbs as NO at higher temperatures as a result of surface nitrate decomposition. NO storage capacity decreases gradually upon repeated NO adsorption-desorption cycles, likely because of Co3O4 formation during these processes.

Lemon yellow #15 a new highly stable, water soluble food colorant from the peel of Citrus limon.

To provide stable and low-cost naturally derived yellow pigments, a variety of food byproducts were evaluated and the constituents of lemon peel have emerged yielding a highly promising natural product with applications as a food dye. Here we report a new, highly stable and water soluble food dye called yellow #15 from the ethanol extract of the zest of Citrus limon. The structure of lemon yellow #15 was carefully assigned on the basis of spectroscopic data, including 1D and 2D NMR spectroscopy, and the absolute configuration was established by comparison of the experimental CD with calculated electronic circular dichroism (ECD) spectral data. CIELAB values and Delta CIELAB were measured and revealed this new water-soluble pigment has superior light stability relative to other natural products used as food dyes.

Unequivocal determination of caulamidines A and B: application and validation of new tools in the structure elucidation tool box.

Ambiguities and errors in the structural assignment of organic molecules hinder both drug discovery and total synthesis efforts. Newly described NMR experimental approaches can provide valuable structural details and a complementary means of structure verification. The caulamidines are trihalogenated alkaloids from a marine bryozoan with an unprecedented structural scaffold. Their unique carbon and nitrogen framework was deduced by conventional NMR methods supplemented by new experiments that define 2-bond heteronuclear connectivities, reveal very long-range connectivity data, or visualize the 35,37Cl isotopic effect on chlorinated carbons. Computer-assisted structural elucidation (CASE) analysis of the spectroscopic data for caulamidine A provided only one viable structural alternative. Anisotropic NMR parameters, specifically residual dipolar coupling and residual chemical shift anisotropy data, were measured for caulamidine A and compared to DFT-calculated values for the proposed structure, the CASE-derived alternative structure, and two energetically feasible stereoisomers. Anisotropy-based NMR experiments provide a global, orthogonal means to verify complex structures free from investigator bias. The anisotropic NMR data were fully consistent with the assigned structure and configuration of caulamidine A. Caulamidine B has the same heterocyclic scaffold as A but a different composition and pattern of halogen substitution. Caulamidines A and B inhibited both wild-type and drug-resistant strains of the malaria parasite Plasmodium falciparum at low micromolar concentrations, yet were nontoxic to human cells.

Hepatoprotective Dibenzocyclooctadiene and Tetrahydrobenzocyclooctabenzofuranone Lignans from Kadsura longipedunculata.

Five new dibenzocyclooctadiene lignans, longipedlignans A-E (1-5), five new tetrahydrobenzocyclooctabenzofuranones (6-10), and 18 known analogues (11-28) were isolated from the roots of Kadsura longipedunculata. Compounds 6-10 are new spirobenzofuranoid-dibenzocyclooctadiene-type lignans. Their structures and absolute configurations were established using a combination of MS, NMR, and electronic circular dichroism data. Spirobenzofuranoids 6 and 15 showed moderate hepatoprotective activity against N-acetyl- p-aminophenol-induced toxicity in HepG2 cells with cell survival rates at 10 µM of 52.2% and 50.2%, respectively.

Interactions of Desmethoxyyangonin, a Secondary Metabolite from Renealmia alpinia, with Human Monoamine Oxidase-A and Oxidase-B.

Renealmia alpinia (Zingiberaceae), a medicinal plant of tropical rainforests, is used to treat snakebites and other injuries and also as a febrifuge, analgesic, antiemetic, antiulcer, and anticonvulsant. The dichloromethane extract of R. alpinia leaves showed potent inhibition of human monoamine oxidases- (MAOs-) A and B. Phytochemical studies yielded six known compounds, including pinostrobin 1, 4'-methyl ether sakuranetin 2, sakuranetin 3, pinostrobin chalcone 4, yashabushidiol A 5, and desmethoxyyangonin 6. Compound 6 displayed about 30-fold higher affinity for MAO-B than MAO-A, with Ki values of 31 and 922 nM, respectively. Kinetic analysis of inhibition and equilibrium-dialysis dissociation assay of the enzyme-inhibitor complex showed reversible binding of desmethoxyyangonin 6 with MAO-A and MAO-B. The binding interactions of compound 6 in the active site of the MAO-A and MAO-B isoenzymes, investigated through molecular modeling algorithms, confirmed preferential binding of desmethoxyyangonin 6 with MAO-B compared to MAO-A. Selective reversible inhibitors of MAO-B, like desmethoxyyangonin 6, may have important therapeutic significance for the treatment of neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease.

Flavonoids from the roots of Artocarpus heterophyllus.

Four new flavonoids, artoheteroids A-D (1-4), together with six known ones (5-10), were isolated from the roots of Artocarpus heterophyllus. Their structures were elucidated by spectroscopic methods, including 1D and 2D NMR, UV, IR, CD, and HR-ESI-MS. All isolated compounds were screened for their inhibitory abilities against cathepsin K (CatK). Among them, compounds 1-2, 4-6, and 10 were found to have suppression capabilities against CatK with IC50 values ranging from 1.4 to 93.9µM.

Methemoglobinemia Hemotoxicity of Some Antimalarial 8-Aminoquinoline Analogues and Their Hydroxylated Derivatives: Density Functional Theory Computation of Ionization Potentials.

The administration of primaquine (PQ), an essential drug for the treatment and radical cure of malaria, can lead to methemoglobin formation and life-threatening hemolysis for glucose-6-phosphate dehydrogenase deficient patients. The ionization potential (IP, a quantitative measure of the ability to lose an electron) of the metabolites generated by antimalarial 8-aminoquinoline (8-AQ) drugs like PQ has been believed to be correlated in part to this methemoglobinemia hemotoxicity: the lower the IP of an 8-AQ derivative, the higher the concentration of methemoglobin generated. In this work, demethoxylated primaquine (AQ02) was employed as a model, by intensive computation at the B3LYP-SCRF(PCM)/6-311++G**//B3LYP/6-31G** level in water, to study the effects of hydroxylation at various positions on the ionization potential. Compared to the parent AQ02, the IPs of AQ02's metabolites hydroxylated at N1', C5, and C7 were lower by 61, 30, and 19 kJ/mol, respectively, while differences in the IP relative to PQ were small for hydroxylation at all other positions. The C6 position, at which the IP of the hydroxylated metabolite was greater than that of AQ02, by 2 kJ/mol, was found to be unique. Several literature and proposed 8-AQ analogues were studied to evaluate substituent effects on their potential to generate methemoglobin, with the finding that hydroxylations at N1' and C5 contribute the most to the potential hemotoxicity of PQ-based antimalarials, whereas hydroxylation at C7 has little effect. Phenoxylation at C5 in PQ-based 8-AQs can block the hydroxylation at C5 and reduce the potential for methemoglobin generation, while -CF3 and chlorines attached to the phenolic ring can further reduce the risk. The H-shift at N1' during the cationization of hydroxylated metabolites of 8-AQs sharply decreased their IPs, but this effect can be significantly reduced by the introduction of an electron-withdrawing group to the quinoline core. The results and this approach may be utilized for the design of safer antimalarial 8-AQ analogues.

Meroterpenoids with Antiproliferative Activity from a Hawaiian-Plant Associated Fungus Peyronellaea coffeae-arabicae FT238.

Three unusual polyketide-sesquiterpene metabolites peyronellins A-C (1-3), along with the new epoxyphomalin analog 11-dehydroxy epoxyphomalin A (4), have been isolated from the endophytic fungus Peyronellaea coffeae-arabicae FT238, which was isolated from the native Hawaiian plant Pritchardia lowreyana. The structures of compounds 1-4 were characterized based on NMR and MS spectroscopic analysis. The absolute configuration (AC) of the compounds was determined by electronic circular dichroism (ECD). Compound 4 showed antiproliferative activity with an IC50 of 0.5 µM against OVCAR3, and it also strongly inhibited Stat3 at 5 µM.

Eremophilane sesquiterpenes from Hawaiian endophytic fungus Chaetoconis sp. FT087.

Seven sesquiterpene derivatives, including chaetopenoids A-F and dendryphiellin A1, and 6-methyl-(2E, 4E, 6S) octadienoic acid were isolated from the culture broth of Chaetoconis sp. FT087. Their structures were determined through the analysis of HRMS and NMR spectroscopic data. The absolute configurations of chaetopenoids A-D were elucidated by comparison of their CD and optical rotation data with those in the literature. Chaetopenoids A-C and E belong to the eremophilane type of sesquiterpenoids, while chaetopenoids D and F and dendryphiellin A1 have a trinor-eremophilane skeleton. All compounds were tested against A2780 and cisplatin resistant A2780CisR cell lines, and dendryphiellin A1 was moderately active with IC50 values of 6.6 and 9.1 µg/mL, respectively.

A New Metabolite with a Unique 4-Pyranone-γ-Lactam-1,4-Thiazine Moiety from a Hawaiian-Plant Associated Fungus.

An endophytic fungus Paraphaeosphaeria neglecta FT462 isolated from the Hawaiian-plant Lycopodiella cernua (L.) Pic. Serm produced one unusual compound (1, paraphaeosphaeride A) with the 4-pyranone-γ-lactam-1,4-thiazine moiety, along with two new compounds (2 and 3, paraphaeosphaerides B and C, respectively) and the known compound (4). Compounds 1-3 were characterized by NMR and MS spectroscopic analysis. The absolute configuration of the 3-position of compound 1 was determined as S by electronic circular dichroism (ECD) calculations. Compound 3 also showed STAT3 inhibition at 10 µM.

Polycyclic Polyprenylated Acylphloroglucinol Congeners Possessing Diverse Structures from Hypericum henryi.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of hybrid natural products sharing the mevalonate/methylerythritol phosphate and polyketide biosynthetic pathways and showing considerable structural and bioactive diversity. In a systematic phytochemical investigation of Hypericum henryi, 40 PPAP-type derivatives, including the new compounds hyphenrones G-Q, were obtained. These compounds represent 12 different structural types, including four unusual skeletons exemplified by 5, 8, 10, and 17. The 12 different core structures found are explicable in terms of their biosynthetic origin. The structure of a known PPAP, perforatumone, was revised to hyphenrone A (5) by NMR spectroscopic and biomimetic synthesis methods. Several compounds exhibited inhibitory activities against acetylcholinesterase and human tumor cell lines. This study deals with the structural diversity, function, and biogenesis of natural PPAPs.

Sulfated steroid-amino acid conjugates from the Irish marine sponge Polymastia boletiformis.

Antifungal bioactivity-guided fractionation of the organic extract of the sponge Polymastia boletiformis, collected from the west coast of Ireland, led to the isolation of two new sulfated steroid-amino acid conjugates (1 and 2). Extensive 1D and 2D NMR analyses in combination with quantum mechanical calculations of the electronic circular dichroism (ECD) spectra, optical rotation, and 13C chemical shifts were used to establish the chemical structures of 1 and 2. Both compounds exhibited moderate antifungal activity against Cladosporium cucumerinum, while compound 2 was also active against Candida albicans. Marine natural products containing steroidal and amino acid constituents are extremely rare in nature.

Computational Study on the Effect of Exocyclic Substituents on the Ionization Potential of Primaquine: Insights into the Design of Primaquine-Based Antimalarial Drugs with Less Methemoglobin Generation.

The effect of an exocyclic substituent on the ionization potential of primaquine, an important antimalarial drug, was investigated using density functional theory methods. It was found that an electron-donating group (EDG) makes the ionization potential decrease. In contrast, an electron-withdrawing group (EWG) makes the ionization potential increase. Among all the exocyclic positions, a substituent at the 5- or 7-position has the largest effect. This can be explained by the contribution of the atomic orbitals at those positions to the highest occupied molecular orbital (HOMO). In addition, a substituent at the N8-position has a considerably large effect on the ionization potential because this atom makes the second largest contribution to the HOMO. These findings have potential implications for the design of less hemotoxic antimalarial drugs. We suggest that it is worth considering placement of an EWG at the 5-, 7-, or N8-positions of primaquine in future drug discovery attempts.

[Traditional Chinese medicine inheritance system analysis of professor Ding Yuanqing in treating tic disorder medication based on experience].

In recent years, the incidence of tic disorders has increased, and it is not uncommon for the patients to treat the disease. The pathogenesis and pathogenesis of Western medicine are not yet clear, the clinical commonly used western medicine has many adverse reactions, traditional Chinese medicine (TCM) research is increasingly valued. Based on the software of TCM inheritance assistant system, this paper discusses Ding Yuanqing's experience in treating tic disorder with Professor. Collect yuan Qing Ding professor in treating tic disorder of medical records by association rules Apriori algorithm, complex system entropy clustering without supervision and data mining method, carries on the analysis to the selected 800 prescriptions, to determine the frequency of use of prescription drugs, the association rules between the drug and digging out the 12 core combination and the first six new prescription, medication transferred to the liver and extinguish wind, cooling blood and relieving convulsion, Qingxin soothe the nerves, with the card cut, flexible application, strict compatibility.

Hydroxylated derivatives of NPC1161: theoretical insights into their potential toxicity and the feasibility and regioselectivity of their formation.

For antimalarial 8-aminoquinoline (8-AQ) drugs, the ionization potential (energy required to remove an electron) of their putative metabolites has been proposed to be correlated in part to their hemotoxicity potential. NPC1161 is a developmental candidate as an 8-AQ antimalarial drug. In this work, the ionization potentials (IPs) of the S-NPC1161 (NPC1161a) hydroxylated derivatives, which are possible metabolites derived from action of endogenous cytochrome P450 (CYP450) enzymes, were calculated at the B3LYP-SCRF(PCM)/6-311++G**//B3LYP/6-31G** level in water. The derivative hydroxylated at N1' (8-amino) was found to have the smallest IP of ∼ 430 kJ/mol, predicting that it would be the most hemotoxic. The calculated IPs of the derivatives hydroxylated at the C2 and C7 positions were ∼ 475 and ∼ 478 kJ/mol, respectively, whereas the calculated IPs of those hydroxylated at all other possible positions were between 480 and 490 kJ/mol. The homolytic bond dissociation energies (HBDEs) of all C-H/N-H bonds in NPC1161a were also calculated. The smaller HBDEs of the C-H/N-H bonds on the 8-amino side chain suggest that these positions are more easily hydroxylated compared to other sites. Molecular orbital analysis implies that the N1' position should be the most reactive center when NPC1161 approaches the heme in CYP450.

New acylphloroglucinol derivatives with diverse architectures from Hypericum henryi.

Hyphenrones A-F (1-6), six polycyclic polyprenylated acylphloroglucinol derivatives with four architectures including three unprecedented cores as exemplified by 1, 3, and 4, were isolated from Hypericum henryi. Compounds 3 and 4 possess two unique 5/8/5 and 6/6/5/8/5 fused ring systems, respectively. Their absolute configurations were defined by experimental and calculated ECD of 4 and X-ray diffractions of 5 and 6, coupled with their putative biosynthetic origins. Three compounds exhibited interesting AChE inhibitory activities.

Effect of antimalarial drug primaquine and its derivatives on the ionization potential of hemoglobin: A QM/MM study.

We used quantum mechanics/molecular mechanics calculations to test if antimalarial primaquine (PQ) and its derivatives aid the conversion of hemoglobin to methemoglobin by binding to hemoglobin and merely lowering hemoglobin's ionization potential (IP). Our results showed that PQ and its derivatives do not significantly lower the hemoglobin IP, disproving the hypothesis.

Antidiabetic ellagitannins from pomegranate flowers: inhibition of α-glucosidase and lipogenic gene expression.

Two new ellagitannins containing a rare 3-oxo-1,3,3a,8b-tetrahydrofuro[3,4-b]benzofuran moiety, namely punicatannins A (1) and B (2), were isolated from pomegranate (Punica granatum) flowers. Their structures with absolute configuration were determined by detailed analysis of spectroscopic data, electronic circular dichroism (ECD) calculation, and chemical hydrolysis. A plausible biogenetic route involving a key enzymatic 1,4-Michael addition is proposed. Punicatannin A showed potent inhibition of α-glucosidase and lipogenic gene expression.