Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines.

Herein, we report a visible-light-mediated palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines, affording unsaturated γ- and ε-amino acid derivatives with diverse structures. In this methodology, the diazo compound readily transforms into a hybrid α-ester alkylpalladium radical with the release of dinitrogen. The radical intermediate selectively adds to the double bond of a 1,3-diene or allene, followed by the allylpalladium radical-polar crossover path and selective allylic substitution with the amine substrate, thereby leading to a single unsaturated γ- or ε-amino acid derivative. This approach proceeds under mild and simple reaction conditions and shows high functional group tolerance, especially in the incorporation of various bioactive molecules. The studies on scale-up reactions and diverse derivatizations highlight the practical utility of this multicomponent reaction protocol.

Photoredox-Catalyzed Carbonyl Alkylative Amination with Diazo Compounds: A Three-Component Reaction for the Construction of γ-Amino Acid Derivatives.

A photoredox-catalyzed reaction of secondary amines, aldehydes, diazo compounds, and Hantzsch ester is reported, affording biologically active γ-amino acid derivatives in high yields. This one-pot process tolerates a broad range of functional groups and various drug molecules and biologically active compounds. Remarkably, a gram-scale reaction and diverse transformations of γ-amino acid derivatives were successfully performed, and the utility of the products is demonstrated in the synthesis of therapeutic agent pregabalin.

Polymer Topology Reinforced Synergistic Interactions among Nanoscale Molecular Clusters for Impact Resistance with Facile Processability and Recoverability.

The intrinsic conflicts between mechanical performances and processability are main challenges to develop cost-effective impact-resistant materials from polymers and their composites. Herein, polyhedral oligomeric silsesquioxanes (POSSs) are integrated as side chains to the polymer backbones. The one-dimension (1D) rigid topology imposes strong space confinements to realize synergistic interactions among POSS units, reinforcing the correlations among polymer chains. The afforded composites demonstrate unprecedented mechanical properties with ultra-stretchability, high rate-dependent strength, superior impact-resistant capacity as well as feasible processability/recoverability. The hierarchical structures of the hybrid polymers enable the co-existence of multiple dynamic relaxations that are responsible for fast energy dissipation and high mechanical strengths. The effective synergistic correlation strategy paves a new pathway for the design of advanced cluster-based materials.

Unexpected Elasticity in Assemblies of Glassy Supra-Nanoparticle Clusters.

Granular materials, composed of densely packed particles, are known to possess unique mechanical properties that are highly dependent on the surface structure of the particles. A microscopic understanding of the structure-property relationship in these systems remains unclear. Here, supra-nanoparticle clusters (SNPCs) with precise structures are developed as model systems to elucidate the unexpected elastic behaviors. SNPCs are prepared by coordination-driven assembly of polyhedral oligomeric silsesquioxane (POSS) with metal-organic polyhedron (MOP). Due to the disparity in sizes, the POSS-MOP assemblies, like their classic nanoparticles counterparts, ordering is suppressed, and the POSS-MOP mixtures will vitrify or jam as a function of decreasing temperature. An unexpected elasticity is observed for the SNPC assemblies with a high modulus that is maintained at temperatures far beyond the glass transition temperature. From studies on the dynamics of the hierarchical structures of SNPCs and molecular dynamic simulation, the elasticity has its origins in the interpenetration of POSS-ended arms. The physical molecular interpenetration and inter-locking phenomenon favors the convenient solution or pressing processing of the novel cluster-based elastomers.

Lasso Proteins: Modular Design, Cellular Synthesis, and Topological Transformation.

Entangled proteins have attracted significant research interest. Herein, we report the first rationally designed lasso proteins, or protein [1]rotaxanes, by using a p53dim-entwined dimer for intramolecular entanglement and a SpyTag-SpyCatcher reaction for side-chain ring closure. The lasso structures were confirmed by proteolytic digestion, mutation, NMR spectrometry, and controlled ligation. Their dynamic properties were probed by experiments such as end-capping, proteolytic digestion, and heating/cooling. As a versatile topological intermediate, a lasso protein could be converted to a rotaxane, a heterocatenane, and a "slide-ring" network. Being entirely genetically encoded, this robust and modular lasso-protein motif is a valuable addition to the topological protein repertoire and a promising candidate for protein-based biomaterials.

Radical-Mediated Strategies for the Functionalization of Alkenes with Diazo Compounds.

One of the most common reactions of diazo compounds with alkenes is cyclopropanation, which occurs through metal carbene or free carbene intermediates. Alternative functionalization of alkenes with diazo compounds is limited, and a methodology for the addition of the elements of Z-CHR2 (with Z = H or heteroatom, and CHR2 originates from N2═CR2) across a carbon-carbon double bond has not been reported. Here we report a novel reaction of diazo compounds utilizing a radical-mediated addition strategy to achieve difunctionalization of diverse alkenes. Diazo compounds are transformed to carbon radicals with a photocatalyst or an iron catalyst through PCET processes. The carbon radical selectively adds to diverse alkenes, delivering new carbon radical species, and then forms products through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT), or forms azidoalkylation products through an iron catalytic cycle. These two processes are highly complementary, proceed under mild reaction conditions, and show high functional group tolerance. Furthermore, both transformations are successfully performed on a gram-scale, and diverse γ-amino esters, γ-amino alcohols, and complex spirolactams are easily prepared with commercially available reagents. Mechanistic studies reveal the plausible pathways that link the two processes and explain the unique advantages of each.

Relationship between Tissue Distributions of Modified Wuzi Yanzong Prescription () in Rats and Meridian Tropism Theory.

OBJECTIVE: To investigate the relationship between tissue distributions of modified Wuzi Yanzong prescription (, MWP) in rats and meridian tropism theory. METHODS: A high-performance liquid chromatography with Fourier transform-mass spectrometry (HPLC-FT) method was used to identify the metabolites of MWP in different tissues of rats after continued oral administration of MWP for 7 days. The relationship between MWP and meridian tropism theory was studied according to the tissue distributions of the metabolites of MWP in rats and the relevant literature. RESULTS: Nineteen metabolites, mainly flavanoid compounds, were detected in the different rat tissues and classified to each herb in MWP. Further, it was able to establish that the tissue distributions of the metabolites of MWP were consistent with the descriptions of meridian tropism of MWP available in literature, this result might be useful in clarifying the mechanism of MWP on meridian tropism. In the long run, these data might provide scientific evidence of the meridian tropism theory to further promote the reasonable, effective utilization, and modernization of Chinese medicine. CONCLUSION: The tissue distributions of MWP in vivo were consistent with the descriptions of meridian tropism of MWP.

[Study of effect of Humifuse Euphorbia Herb on alleviating insulin resistance in type 2 diabetic model KK-Ay mice].

[To explore the effect of Humifuse Euphorbia Herb ( HEH) on alleviating insulin resistance in type 2 diabetic KK-Ay mice. Totally 40 KK-Ay mice fed with high-fat diet were divided into four groups: the metformin group, the model group, the HEH low-dose group and the HEH high-dose group, and orally administrated with metformin hydrochloride (250 mg x kg(-1)), distilled water, humifuse euphorbia herb 1 g x kg(-1) and 2 g x kg(-1). Besides, C57BL/6J mice with ordinary feed were taken as the normal control group and orally administrated with equal distilled water. The oral administration for the five groups lasted for eight weeks. Before and after the experiment, weight, fasting glucose and insulin tolerance were determined. The morphological changes in pancreas were observed through hematoxylin-eosin (HE) staining on pancreatic tissue sections. The serum insulin, TNF-α, IL-6, adiponectin (ADPN) and leptin (LEP) were detected by ELISA. The results showed that HEH could reduce weight and fasting glucose in KK-Ay mice, alleviate hyperinsulinemia, reduce blood glucose-time AUC, increase 30-min blood glucose decline rate, relieve insulin resistance, significantly ameliorate the pathomorphological changes in pancreas in each group, decrease serum TNF-α, IL-6 and leptin levels in KK-Ay mice and rise serum ADPN level. This study proved that humifuse euphorbia herb can ameliorate the insulin resistance in KK-Ay mice, and its mechanism may be related to the effect on inflammatory factors and adipocytokines.

Schisandrin B exerts anti-neuroinflammatory activity by inhibiting the Toll-like receptor 4-dependent MyD88/IKK/NF-κB signaling pathway in lipopolysaccharide-induced microglia.

Microglial-mediated neuroinflammation is now considered to be central to the pathogenesis of various neurodegenerative processes, including Alzheimer's disease and Parkinson's disease. Therefore, rational modulation of microglia function to obtain neuroprotective effects is important for the development of safe and effective anti-inflammatory and neuroprotective agents. Here, we investigated the anti-inflammatory and neuroprotective effects, and potential molecular mechanism of action of Schisandrin B (Sch B); which is isolated from the Schizandra fruit (Schisandra chinesnesis). Sch B exerted significant neuroprotective effects against microglial-mediated inflammatory injury in microglia-neuron co-cultures. In addition, Sch B significantly downregulated pro-inflammatory cytokines, including nitrite oxide (NO), tumor necrosis factor (TNF)-α, prostaglandin E(2) (PGE(2)), interleukin (IL)-1ß and IL-6. Additionally, Sch B inhibited the interaction of Toll-like receptor 4 with the Toll adapter proteins MyD88, IRAK-1 and TRAF-6 resulting in an inhibition of the IKK/nuclear transcription factor (NF)-κB inflammatory signaling pathway. Furthermore, Sch B inhibited the production of reactive oxygen species (ROS) and NADPH oxidase activity in microglia. In summary, Sch B may exert neuroprotective activity by attenuating the microglial-mediated neuroinflammatory response by inhibiting the TLR4-dependent MyD88/IKK/NF-κB signaling pathway.

Aluminum maltolate induces primary rat astrocyte apoptosis via overactivation of the class III PI3K/Beclin 1-dependent autophagy signal.

Aluminum-induced neuronal cell apoptosis has been implicated in various neurodegenerative disorders. However, whether autophagy, a vital lysosomal degradation pathway, is involved in this pathogenesis still remains unknown. Our present findings demonstrated that aluminum significantly increased rat astrocyte apoptosis and autophagy levels in a dose-dependent manner. Examination of the associated mechanisms revealed that aluminum at low levels (400µM) did not increase apoptosis protein expressions (cleaved caspase-3 and cleaved PARP), but markedly up-regulated autophagy-related protein Beclin 1 expression. This indicates that the autophagy process occurs earlier than neuronal apoptosis. Moreover, aluminum at high levels (1600µM) significantly induced autophagy-related protein (Beclin 1 and LC3II) and apoptosis-related protein expressions, showing that both autophagy and apoptosis processes are activated under high levels of aluminum exposure. We used 3-methyladenine, an inhibitor of class III phosphatidylinositol-3 kinase, to treat astrocytes and found that the apoptosis rate in the 3-MA/aluminum co-treated group was markedly down-regulated compared with aluminum alone-treated astrocytes. The apoptosis protein and autophagy-related protein expressions were also decreased. These observations showed that the mild autophagy process may precede apoptosis in low dose aluminum-insulted astrocytes, and high dose aluminum-induced serious autophagy may result in cell apoptosis via the Beclin 1-dependent autophagy signal pathway.

Modified Wu-Zi-Yan-Zong prescription, a traditional Chinese polyherbal formula, suppresses lipopolysaccharide-induced neuroinflammatory processes in rat astrocytes via NF-κB and JNK/p38 MAPK signaling pathways.

Neuroinflammation plays an important role in several neurodegenerative diseases. In this study, we investigated the anti-inflammatory properties of modified Wu-Zi-Yan-Zong prescription (MWP), a traditional Chinese polyherbal formula, in primary cultured rat astrocytes treated with lipopolysaccharide (LPS). The results showed that MWP significantly inhibited release of nitric oxide (NO) and prostaglandin E (PGE), as well as expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 in LPS-induced rat astrocytes. Mechanism study indicated that MWP significantly inhibited nuclear factor-kappa B (NF-κB) inflammatory signaling pathway through attenuating inhibitor of nuclear factor-κB (IκB) degradation and down-regulating IκB kinases (IKKs) phosphorylation level. Moreover, MWP also decreased c-Jun NH(2)-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) phosphorylation, which play an important role in the induction of proinflammatory gene expressions. At last, MWP protected neurons from LPS-activated astrocytes in neuron-astrocyte co-culture system. Taken together, our results suggest that MWP may act to suppress neuroinflammatory response in LPS-stimulated rat astrocytes via NF-κB and JNK/p38 MAPK signaling cascades, and MWP may be a useful agent for prevention and treatment of neuroinflammatory disease.

A randomized double-blind placebo-controlled study of Pu'er tea extract on the regulation of metabolic syndrome.

OBJECTIVE: To explore the regulative efficacy of Pu'er tea () extract on metabolic syndrome. METHODS: Ninety patients with metabolic syndrome were randomly divided into two groups, the intervention group administered with Pu'er tea extract, and the placebo group with placebo capsules. After 3 months' treatment, body mass index, waist hip ratio, blood lipids, blood sugar, immune and inflammatory index, and oxidation index of the patients with metabolic syndrome were tested and analyzed. RESULTS: In the intervention group, the body mass index, waist-hip ratio, fasting and 2 h postprandial blood glucose, serum total cholesterol, triglycerides, low density lipoprotein and apolipoprotein B-100 all decreased in the patients with metabolic syndrome, and also the high-density lipoprotein level increased and apolipoprotein A-1 showed the tendency to increase. Serum C-reactive protein, tumor necrosis factor-α, and interleukin-6 were decreased in the intervention group. Interleukin-10 level was increased, MDA was decreased and superoxide dismutase was increased. Compared with before treatment and the placebo group, there were significant differences (P<0.05, P<0.01). CONCLUSIONS: Pu'er tea demonstrated excellent potential in improving central obesity, adjusting blood lipid, lowering blood sugar, regulating immunity and resisting oxidation. It can adjust the metabolic syndrome of different clinical phenotypes to different degrees, and is ideally fit for early prevention of metabolic syndrome.

Icariin attenuates lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting TAK1/IKK/NF-kappaB and JNK/p38 MAPK pathways.

Microglia in the central nervous system (CNS) play an important role in the initiation of neuroinflammatory response. Icariin, a compound from Epimedium brevicornum Maxim, has been reported to have anti-inflammatory effect on the macrophage cell line RAW264.7. However, it is currently unknown what anti-inflammatory role icariin may play in the CNS. Here, we reported the discovery that icariin significantly inhibited the release of nitric oxide (NO), prostaglandin E (PGE)-2, reactive oxygen species (ROS) and mRNA expression of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in lipopolysaccharide (LPS)-activated microglia. Icariin also inhibited the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 in a dose-dependent manner. Further mechanism studies revealed that icariin blocked TAK1/IKK/NF-kappaB and JNK/p38 MAPK pathways. It was also found that icariin reduced the degeneration of cortical neurons induced by LPS-activated microglia in neuron-microglia co-culture system. Taken together these findings provide mechanistic insights into the suppressive effect of icariin on LPS-induced neuroinflammatory response in microglia, and emphasize the neuroprotective effect and therapeutic potential of icariin in neuroinflammatory diseases.

Protective effects of Wu-Zi-Yan-Zong-Fang on amyloid beta-induced damage in vivo and in vitro.

This study was designed to determine the effects of Wu-Zi-Yan-Zong-Fang on amyloid-beta(25-35)-induced cognitive deficits in rats and neurotoxicity in pheochromocytoma cells and the possible mechanism of action. In vivo studies showed that Wu-Zi-Yan-Zong-Fang significantly ameliorated the spatial memory and retention deficits, decreased acetylcholinesterase activity, and increased acetylcholine content caused by intracerebroventricular injection of amyloid-beta(25-35). In vitro results showed that Wu-Zi-Yan-Zong-Fang increased cell viability and the activity of superoxide dismutase and catalase and decreased the release of lactate dehydrogenase and the level of malondialdehyde. Wu-Zi-Yan-Zong-Fang also significantly reduced the percentage of apoptotic cells and blocked the increase in the intracellular concentration of Ca(2+). These data suggest that Wu-Zi-Yan-Zong-Fang has potent protective effects for the treatment of Alzheimer's disease in future.

[Study on anti-tumor effect of dry and fresh Gekko swinhonis freeze-dried powders on mice sarcoma S180 and acute toxicity testing of two powders].

OBJECTIVE: To investigate the anti-tumor activity of dry Gekko swinhonis freeze-dried powder (DGFP) and fresh G. swinhonis freeze-dried powder (FGFP) on mice sarcoma S180 and acute toxicity testing of the two powders. METHOD: Mice xenotransplant model of sarcoma S180 was established. Eighty mice were randomly divided into 8 groups. Control group were orally administrated by saline, another intraperitoneally injected with 5-Fu, the other six groups were orally administrated by DGFP and FGFP, each at three different doses (low, moderate and high). Rate of restraining tumor, index of thymus and spleen were calculated after 10 days' treatment. Acute toxicity testing tried to figure out LDs and LD, of DGFP and FGFP. RESULT: The restraining tumor rates of DGFP and FGFP each at three doses were 31.4%, 50.8%, 37.7% and 14.8%, 19.1%, 54.7%. DGFP and FGFP elevated the thymic weight and thymic index of the mice to different extent. There were no significant differences among the eight groups in their spleen weight and spleen index. Acute toxicity testing did not figure out LD50 of DGFP and FGFP. In LD0 test, the administrating dosages of DGFP and FGFP given to the mice were both more than 2000 times than those given to patients on clinic. The result showed nothing abnormal in DGFP group. Compared with the DGFP and control group there was only a significant body weight decrease (P < 0.01) in the FGFP group in the first three days. However, on the fifth day and the seventh day there was no significant difference. CONCLUSION: DGFP and FGFP have conspicuous anti-tumor effects in vivo. The mechanism may be related to the elevated cellular immune function. Acute toxicity testing reveals that DGFP and FGFP are quite safe for conventional oral use on clinic.

Effect of modified wuzi yanzong granule on patients with mild cognitive impairment from oxidative damage aspect.

OBJECTIVE: To observe the effects of modified Wuzi Yanzong Granule (WYG) on memory function and the activity of serum superoxide dismutase (SOD), malondialdehyde (MDA) levels, leukocyte mitochondrial DNA (mtDNA) deletion rate and beta-amyloid protein(1-28) (A beta(1-28)) in patients with mild cognitive impairment (MCI). METHODS: Thirty-six patients with MCI were selected based on the internationally recognized Petersen's criteria, and equally and randomly assigned to two groups. The treated group was treated with WYG and the control group was treated with placebo for 3 months. In addition, 20 healthy subjects were included in the study as the normal control group. Changes of memory function, SOD activity, MDA content, leukocyte mtDNA deletion rate and A beta(1-28) content were observed before and after treatment. RESULTS: Compared with the normal control group, the memory quotient and SOD activity in patients with MCI decreased significantly (P < 0.01), while MDA, A beta(1-28) levels and the leukocyte mtDNA deletion rate increased significantly (P < 0.01). After treatment, levels of memory quotient and serum SOD activity increased while the serum MDA level, leukocyte mtDNA deletion rate and A beta(1-28) level decreased in the treated group compared with those before treatment (P<0.01, P<0.05). Meanwhile, leukocyte mtDNA deletion rate and A beta(1-28) content in the treated group were all lower than those in the control group (P<0.05). CONCLUSION: WYG could improve memory function in patients with MCI and the therapeutic mechanism is possibly related to the increased activity of anti-oxidase, the improved free radical metabolism and the alleviation of leukocyte mtDNA oxidation damage. WYG shows clinical significance in delaying the progression of MCI.

[Effects of modified Wuzi Yanzong Granule on memory ability and volume of hippocampus measured by MRI in patients with mild cognitive impairment].

OBJECTIVE: To observe the effect of modified Wuzi Yanzong Granule (WYG) on memory ability and volume of hippocampus measured by magnetic resonance imaging (MRI) in patients with mild cognitive impairment (MCI). METHODS: According to the international accepted diagnostic criteria, 36 MCI patients were selected and randomly assigned to two groups equally, the treated group treated with WYG and the control group with placebo, with a course of 3 months for both groups. Besides, 20 healthy subjects were selected as the normal group. The changes of memory ability were observed and the volume of hippocampus was detected by MRI before and after treatment. RESULTS: Memory quotient (MQ) was significantly lower in MCI patients than in healthy subjects (P < 0.01), after treatment it increased in the treated group as compared with that before treatment (P < 0.01), and the increment was higher than that in the control group (P < 0.05); the volume of hippocampus, total or that of either side, as well as the increment of the total volume of hippocampus in the treated group were all higher than those in the control group (P < 0.05). CONCLUSION: WYG could improve memory ability in MCI patients and could prevent and treat the hippocampal atrophy to certain degree.

[Clinical study on treatment of mild cognitive impairment by modified wuzi yanzong granule].

OBJECTIVE: To observe the clinical efficacy and safety of modified Wuzi Yanzong Granule (MWYG) in treating mild cognitive impairment (MCI), and to explore its mechanism. METHODS: Forty-four MCI patients were selected referring to the international recognized Peterson's criteria and randomly divided into two groups, the treated group treated with MWYG and the control group treated with Ginkgo leaf extraction, with the course of 3 months for both groups. Changes of memorial quotient (MQ), superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, mitochondrial DNA (mtDNA) deletion rate and acetylcholinesterase (AchE) before and after treatment were observed. RESULTS: After treatment, levels of MQ, serum SOD activity increased and serum MDA content, mtDNA deletion rate and AchE decreased in both groups (P < 0.01), but the difference between the two groups was insignificant. No adverse reaction was found in two groups. CONCLUSION: Both MWYG and Ginkgo leaf capsule can effectively improve the memorial function of patients with MCI, the therapeutic mechanism is possibly related with the actions in reducing AchE activity, improving free radical metabolism, and alleviating mitochondrial DNA oxidation damage.

[Effect of wuzi yanzong Pill on mitochondrial DNA deletion and respiratory chain enzyme complex activity in peripheral leukocyte of aged male with kidney deficiency syndrome].

OBJECTIVE: To investigate the effect of Wuzi Yanzong Pill (WZYZP) on mitochondrial DNA (mtDNA) deletion and respiratory chain enzyme complex (RCZC) in peripheral blood leukocyte of aged male with Kidney Deficiency Syndrome (KDS). METHODS: Single-blinded study was conducted in 38 aged male with KDS, who were randomly divided into 2 groups treated with WZYZP and placebo respectively for 3 months. Levels of mtDNA deletion and RCZC were determined by polymerase chain reaction (PCR) and enzyme kinetics technique respectively. RESULTS: WZYZP could reduce the mtDNA deletion and raise the activity of mitochondrial RCZC I, IV in peripheral blood leukocyte of aged male with KDS (P < 0.05, P < 0.01). CONCLUSION: WZYZP has protective effect on mtDNA from oxidative damage in leukocyte of aged male with KDS.