Total Synthesis and Assignment of the Absolute Configuration of (+)-Omphalic Acid.

Omphalane diterpenoids usually contain a cyclohexane-fused bicyclo[3.2.1]octane scaffold embedded with two continuous quaternary carbon centers, which pose considerable challenges to synthetic chemists. Herein, we reported the first total synthesis of omphalic acid with high stereochemical control, featuring an intermolecular Diels-Alder cycloaddition, ring reorganization through Criegee oxidative cleavage and programmed aldol condensations, conformationally controlled hydrogenation, and Pd-catalyzed carboxylation. The absolute configuration of omphalic acid was defined for the first time via the asymmetric total synthesis facilitated by a derivatization resolution protocol.

[Effect of warm needle moxibustion on morphological changes of cartilage and subchondral bone in knee osteoarthritis rabbits].

OBJECTIVE: To observe the effect of warm needle with moxibustion (WNM) on morphological changes of articular cartilage and subchondral bone tissues in knee osteoarthritis (KOA) rabbits, so as to explore whether WNM intervention can delay the development of KOA. METHODS: Forty male New Zealand rabbits were randomly divided into blank control, model, WNM and medication (Alendronate sodium) groups, with 10 rabbits in each group. A KOA model was established by immobilizing the right hind limb of rabbits with orthopedic casting tape for 6 weeks. The rabbits of the WNM group received WNM stimulation at "Neixiyan"(EX-LE4) "Waixiyan"(ST35) and "Heding"(EX-LE2) for 15 min, once a day for 4 weeks and those of the medication group received gavage of Alendronate sodium (150 µg·kg-1·d-1) once a day for 4 weeks. X-ray examination and magnetic resonance imaging (MRI) scanning were performed to observe the structure of the knee joints. Outcomes of X-ray examination were used to assess the degree of bone hyperplasia and joint space stenosis which were scaled according to Kellgren and Lawrence (K-L) standards, and those of MRI used to evaluate the degree of cartilage damage and bone marrow edema degrees which were respectively scored according to Recht scaling standards and semi-quantitative whole-organ MRI score (WORMS). Histopathological changes (degeneration degrees) of the articular cartilage were observed after H.E. staining, and given Mankin score. The ultrastructure of the cartilage surface and chondrocytes was observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM), respectively. RESULTS: Compared with the blank control group, the K-L grade, Recht grade, WORMS and Mankin score of the model group were significantly increased (P<0.05,P<0.01). After the intervention and in comparison with the model group, the K-L grade, Recht grade, WORMS and Mankin score of both WNM and medication groups were significantly decreased (P<0.05,P<0.01). Results of SEM showed severe defect, bulge and uneven surface of the cartilage with irregular growth and regeneration, and those of TEM showed degeneration and swelling of chondrocytes, margination of endonuclear chromatin, reduction in the number of organelles with disordered arrangement, extreme expansion of endoplasmic reticulum with detachment of the ribosome, unclear mitochondria, and disordered distribution of collagen fibers in the extracellular matrix in the model group, which was relatively milder in both the WNM and medication groups. Compared with the medication group, the Mankin score in the WNM group was evidently lower (P<0.05). CONCLUSION: WNM can effectively slow down the degeneration of cartilage and subchondral bone of KOA rabbits, delay the development of KOA.

Conformational Design Principles in Total Synthesis.

Conformation is one of the most fundamental concepts in organic chemistry for chemists to visualize a molecule as a three-dimensional object in addition to its constitution and configuration. Conformational factors significantly affect the physical properties, chemical reactivities, and biological activities of a molecule. The significance of conformational design has been generally recognized since its successful application in the total synthesis of complex natural products, such as vitamin B12 and erythronolide. Conformational analysis, especially intentional control of conformational preferences by conformational design, could play a critical role in the synthesis of complex organic molecules by guiding the formation of bonds, stereocenters, or rings. This Minireview highlights selected examples of conformational design in natural-product synthesis, with particular emphasis on the applications and new insights advanced in the last 20 years. The examples discussed herein are divided into three categories by structural features of the substrates: open-chain type, cyclohexane type, and medium- and large-ring type.

Recent progress in the total synthesis of marine brominated sesquiterpene aplydactone.

Aplydactone is a brominated sesquiterpene isolated from the sea hare Aplysia dactylomela. Structurally, it features a complex cage-like skeleton containing a highly strained tricyclic-[4.2.0.03,8]-4-decanone system. Its unique structural features have fascinated many synthetic chemists. In this review, the synthetic efforts towards aplydactone in the last five years are summarized in two categories including nonbiomimetic synthesis and biomimetic synthesis based on the core synthetic strategy. These syntheses set a classical and instructive example for the syntheses of other marine natural products.

Nesteretal A, A Novel Class of Cage-Like Polyketide from Marine-Derived Actinomycete Nesterenkonia halobia.

An intriguing cage-like polyhemiketal, nesteretal A (1), was isolated from the coral-derived actinomycete Nesterenkonia halobia. Its structure was established by extensive spectroscopic and computational methods. Nesteretal A is a highly oxygenated compound featuring an unprecedented 5/5/5/5 tetracyclic scaffold. A possible biosynthetic pathway of 1 from naturally occurring diacetyl was proposed. Compound 1 showed a weak retinoid X receptor-α (RXRα) transcriptional activation effect.

Integration of Preferences in Decomposition Multiobjective Optimization.

Rather than a whole Pareto-optimal front, which demands too many points (especially in a high-dimensional space), the decision maker (DM) may only be interested in a partial region, called the region of interest (ROI). In this case, solutions outside this region can be noisy to the decision-making procedure. Even worse, there is no guarantee that we can find the preferred solutions when tackling problems with complicated properties or many objectives. In this paper, we develop a systematic way to incorporate the DM's preference information into the decomposition-based evolutionary multiobjective optimization methods. Generally speaking, our basic idea is a nonuniform mapping scheme by which the originally evenly distributed reference points on a canonical simplex can be mapped to new positions close to the aspiration-level vector supplied by the DM. By this means, we are able to steer the search process toward the ROI either directly or interactively and also handle many objectives. Meanwhile, solutions lying on the boundary can be approximated as well given the DM's requirements. Furthermore, the extent of the ROI is intuitively understandable and controllable in a closed form. Extensive experiments on a variety of benchmark problems with 2 to 10 objectives, fully demonstrate the effectiveness of our proposed method for approximating the preferred solutions in the ROI.

Asymmetric Total Synthesis of (+)-Majusculoic Acid via a Dimerization-Dedimerization Strategy and Absolute Configuration Assignment.

The first total synthesis of (+)-majusculoic acid, the enantiomer of naturally occurring antifungal cyclopropane fatty acid (-)-majusculoic acid, was accomplished in 13 steps, leading to the assignment of the absolute configuration of the natural product. The synthesis featured a ring closing metathesis dimerization, a conformationally controlled cyclopropanation, a dedimerization, and a bromoolefination.

Total Synthesis of Aplydactone by a Conformationally Controlled C-H Functionalization.

A concise, protecting-group-free total synthesis of the unusual brominated sesquiterpene aplydactone is described. Our synthesis features a [2+2] photocycloaddition, a Wolff ring contraction, an unusual remote C-H functionalization to establish the highly strained tetracyclic core, and a hydrogen-atom transfer (HAT) reaction to access the bromine-containing stereocenter. A finely tuned conformation of the α-diazoketone precursor is the key for the success of the late-stage transannular C-H insertion to deliver a bridged six-membered ring and a quaternary stereocenter (C6) between two quaternary carbon atoms (C1 and C7).

[Expression of Serotonin Receptor and Transporter Related Genes of CD4+ T Lymphocytes in Patients with Asthma and Depression].

OBJECTIVE: To explore the comorbidity mechanism of asthma and depression. METHODS: A self-developed questionnaire, which also contained Asthma Control Test (ACT), Asthma Quality of Life Questionnaire (AQLQ) and Hamilton Rating Scale for depression ( HRSD), was administered in 41 participants with asthma (AS), asthma and depression (AD), or none any of these conditions (health control, HC). Lung function and blood levels of eosnophils and IgE were also detected in those in the AS and AD groups. Blood CD4+ T cells were isolated in all of the participants to extract RNA for reverse transcription to cDNA. Real-time polymerase chain reaction (RT-PCR) was performed using cDNA as a template to detected the expression levels of HTR1A, HTR2A, HTR7, SLC6A4, and B2M genes. RESULTS: Participants with AS and AD had lower expression level of SLC6A4 than the healthy controls (P = 0.000). The expression level of HTR2A in participants with AS was lower than that in the healthy controls (P = 0.021) and marginally lower than that in participants with AD (P = 0.077). Participants with AD had lower AQLQ scores than participants with AS (P = 0.004). CONCLUSION: Asthma and depression is correlated at gene level. Decreased expression of SLC6A4 gene may be one of the possible comorbidity mechanisms of asthma and depression.

Th1/Th2/Th17 cells imbalance in patients with asthma with and without psychological symptoms.

BACKGROUND: The prevalence of psychological symptoms such as anxiety and depression among patients with asthma is high. Both asthma and psychological symptoms are characterized by immune inflammation in which CD4+ T cells play a role. OBJECTIVE: To investigate whether T-helper (Th) 1, Th2, and Th17 cells imbalance exists in patients with asthma and with and in patients without psychological symptoms. METHODS: The messenger RNA (mRNA) expression of T-box 21 (T-bet), GATA binding protein 3 (GATA-3), and RAR-related orphan receptor C (RORC) in peripheral CD4+ T cells of 20 patients with asthma and with psychological symptoms, 30 patients with asthma and without psychological symptoms, and 30 healthy subjects were detected by real-time polymerase chain reaction. A Luminex-based approach quantified the levels of interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin (IL) 4, and IL-17A cytokines in serum. RESULTS: The mRNA expressions of T-bet, GATA-3 and RORC were significantly different among the three groups. Significant elevations of the expressions of T-bet, GATA-3, and RORC mRNA were found in patients with asthma and with psychological symptoms than in healthy subjects, along with the higher levels of IFN-γ, TNF-α, and IL-17A. Increased expressions of T-bet mRNA were found in patients with asthma and with psychological symptoms but not in those without psychological symptoms. However, the ratio of T-bet to GATA-3 was in balance in patients with asthma and with psychological symptoms. CONCLUSION: Analysis of our data revealed Th1 and Th2 cells activated in balance in the peripheral blood of patients with asthma and with psychological symptoms, along with activated Th17 cells. This finding provided an improved understanding of the immune-inflammation responses in patients with asthma and with psychological symptoms, and offered information for new targeted therapy to patients with asthma and with psychological symptoms.

Association between interleukin-17a gene polymorphisms and asthma risk: a meta-analysis.

BACKGROUND: Interleukin-17A (IL-17A), a proinflammatory cytokine, plays an important role in the pathogenesis of asthma. Considerable research has assessed the association between IL-17A polymorphisms and asthma risk, but the results are inconsistent. OBJECTIVE: This meta-analysis was carried out to make a more precise estimation of the relationship between IL-17A polymorphisms and asthma risk. METHODS: The PUBMED, MEDLINE, EMBASE, Chinese National Knowledge Infrastructure and Wan Fang databases were searched systemically on December 12, 2014 and data were extracted from eligible studies by two independent reviewers. Meta-analysis, sub-group analysis, sensitivity analysis and publication bias assessments were all done using Stata 12.1 software. RESULTS: The IL-17A -737C/T polymorphism and IL-17A -197G/A polymorphism were included in the analysis with seven case-control studies. Asthma patients (n = 2882) and healthy controls (n = 2093) were included. The IL17A -737C/T polymorphism was found to have a significantly protective effect on asthma in the allele model (OR = 0.86, 95% CI 0.78-0.96, P = 0.007), dominant model (OR = 0.76, 95% CI 0.65-0.88, P <0.001) and heterozygous model (OR = 0.75, 95% CI 0.64-0.88, P < 0.001) in the overall analysis. Stratified by ethnicity and age, the effects were also significant in the Asian population and in children. However, for IL-17A -197G/A, no significant association was revealed either in the overall analysis in the ethnicity-special subgroup analysis. CONCLUSIONS: The IL-17A -737C/T polymorphism is likely to contribute to protection against asthma, while the IL-17A -197G/A polymorphism may not be associated with asthma susceptibility.

Total Synthesis of (+)-Fusarisetin A Driven by a One-Pot Four-Reaction Process.

A concise, asymmetric total synthesis of (+)-fusarisetin A, a hybrid natural product, has been achieved. A one-pot four-reaction process efficiently delivered the tetracycle 2 which served as a key intermediate for the synthesis of the title natural product and its analogues through amino acid incorporation.