[Research progress in drugs targeting 5-lipoxygenase for age-related diseases].

With the acceleration of aging society, delaying aging or promoting healthy aging has become a major demand for human health. 5-Lipoxygenase (5-LOX) is a key enzyme catalyzing arachidonic acid into leukotrienes (LTs), which is a potent mediator of the inflammatory response. Previous studies showed that abnormal activation of 5-LOX and overproduction of LTs are closely related to the occurrence and development of aging-related inflammatory diseases. Therefore, inhibiting 5-LOX activation is a possibly potential strategy for treating age-related diseases. In this paper, the latest research progress in 5-LOX activation, 5-LOX in mediating aging-related diseases and its small molecule inhibitors is briefly reviewed to provide scientific theoretical basis and new ideas for the prevention and treatment of aging-related inflammatory diseases.

MCL Plays an Anti-Inflammatory Role in Mycobacterium tuberculosis-Induced Immune Response by Inhibiting NF-κB and NLRP3 Inflammasome Activation.

Mycobacterium tuberculosis (Mtb) remains a significant menace to global health as it induces granulomatous lung lesions and systemic inflammatory responses during active tuberculosis (TB). Micheliolide (MCL), a sesquiterpene lactone, was recently reported to have a function of relieving LPS-induced inflammatory response, but the regulative role of MCL on the immunopathology of TB still remains unknown. In this experiment, we examined the inhibitory effect of MCL on Mtb-induced inflammatory response in mouse macrophage-like cell line Raw264.7 by downregulating the activation of nuclear factor kappa B (NF-κB) and NLRP3 inflammasome. Evidences showed that MCL decreased the secretion of Mtb-induced inflammatory cytokines (IL-1ß and TNF-α) in a dose-dependent manner. Meanwhile, MCL dramatically suppressed Mtb-induced activation of iNOS and COX2 as well as subsequent production of NO. Furthermore, MCL inhibited Mtb-induced phosphorylation of Akt (Ser 473) in Raw264.7. According to our results, MCL plays an important role in modulating Mtb-induced inflammatory response through PI3K/Akt/NF-κB pathway and subsequently downregulating the activation of NLRP3 inflammasome. Therefore, MCL may represent as a potential drug candidate in the adjuvant treatment of TB by regulating host immune response.

Highly Regio- and Diastereoselective Synthesis of 6,7-Dihydro-4H-furo[3,4-c]pyran Derivatives through Pd-Catalyzed Formal (3 + 3) Allylic Cycloaddition of 2-Butene-1,4-diols with 2-(1-Alkynyl)-2-alken-1-ones.

A highly efficient synthesis of 7-vinyl-6,7-dihydro-4H-furo[3,4-c]pyran derivatives from 2-butene-1,4-diols and 2-(1-alkynyl)-2-alken-1-ones has been achieved with high regio- and diastereoselectivity (dr > 20:1) by Pd-catalyzed tandem heterocyclization/cross-coupling. The π-allyl palladium species Int II generated from 2-butene-1,4-diol by direct cleavage of the C-OH bond is the key to the success in this formal (3 + 3) cycloaddition reaction.

Dehydrozaluzanin C- derivative protects septic mice by alleviating over-activated inflammatory response and promoting the phagocytosis of macrophages.

Host-directed therapy (HDT) is a new adjuvant strategy that interfere with host cell factors that are required by a pathogen for replication or persistence. In this study, we assessed the effect of dehydrozaluzanin C-derivative (DHZD), a modified compound from dehydrozaluzanin C (DHZC), as a potential HDT agent for severe infection. LPS-induced septic mouse model and Carbapenem resistant Klebsiella pneumoniae (CRKP) infection mouse model was used for testing in vivo. RAW264.7 cells, mouse primary macrophages, and DCs were used for in vitro experiments. Dexamethasone (DXM) was used as a positive control agent. DHZD ameliorated tissue damage (lung, kidney, and liver) and excessive inflammatory response induced by LPS or CRKP infection in mice. Also, DHZD improved the hypothermic symptoms of acute peritonitis induced by CRKP, inhibited heat-killed CRKP (HK-CRKP)-induced inflammatory response in macrophages, and upregulated the proportions of phagocytic cell types in lungs. In vitro data suggested that DHZD decreases LPS-stimulated expression of IL-6, TNF-α and MCP-1 via PI3K/Akt/p70S6K signaling pathway in macrophages. Interestingly, the combined treatment group of DXM and DHZD had a higher survival rate and lower level of IL-6 than those of the DXM-treated group; the combination of DHZD and DXM played a synergistic role in decreasing IL-6 secretion in sera. Moreover, the phagocytic receptor CD36 was increased by DHZD in macrophages, which was accompanied by increased bacterial phagocytosis in a clathrin- and actin-dependent manner. This data suggests that DHZD may be a potential drug candidate for treating bacterial infections.

Micheliolide attenuates neuroinflammation to improve cognitive impairment of Alzheimer's disease by inhibiting NF-κB and PI3K/Akt signaling pathways.

Inflammatory reaction in the brain activates glial cells, and over-activated glial cells secrete inflammatory mediators, which aggravates the inflammatory response in the brain and accelerates the development of Alzheimer's disease (AD) in turn. Numerous natural compounds from herbs can alleviate inflammation, and it is very promising to find anti-neuroinflammatory natural compounds. Micheliolide (MCL) is an asesquiterpene lactone. Studies have proved that MCL showed an obvious anti-inflammatory property. Nevertheless, whether MCL can treat AD has not been determined. In this research, AD model mice were fed with a diet supplemented MCL for 3 months, the cognitive ability and inflammatory state of mice were detected. We found that MCL raised the frequency of touching novel objects, cut down the escape latency, raised the number of crossing platform, inhibited the infiltration of inflammatory cells and the secretion of interleukin-1α (IL-1α), IL-12p40, IL-13, IL-17A, tumor necrosis factor-α (TNF-α), granulocyte colony stimulating factor (G-CSF), macrophage inflammatory protein-1α (MIP-1α) and monocyte chemotactic protein-1 (MCP-1) in peripheral blood samples, inhibited the hyperplasia of glial cells and the production of IL-1α, IL-4, G-CSF, granulocyte-macrophage colony stimulating factor (GM-CSF), MIP-1α and MIP-1ß, and reduced the deposition of Aß peptides in the brain of AD mice. We also concluded that MCL dropped the expression of IL-1ß, TNF-α, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and the phosphorylation of IκB, p65 and Akt in BV-2 cells. In conclusion, MCL alleviates the intensity of systemic inflammatory reaction via inhibiting nuclear transcription factor κ gene binding (NF-κB) and phosphoinositide-3-kinase/serine/threonine kinase (PI3K/Akt) pathways in glial cells, and improves the cognitive impairment of AD mice. Therefore, MCL could be a therapeutic candidate for AD.

Exercise in cold: Friend than foe to cardiovascular health.

Exercise has been proven to benefit human health comprehensively regardless of the intensity, time, or environment. Recent studies have found that combined exercise with a cold environment displays a synergistical beneficial effect on cardiovascular system compared to exercise in thermoneutral environment. Cold environment leads to an increase in body heat loss, and has been considered a notorious factor for cardiovascular system. Exercise in cold increases the stress of cardiovascular system and risks of cardiovascular diseases, but increases the body tolerance to detrimental insults and benefits cardiovascular health. The biological effects and its underlying mechanisms of exercise in cold are complex and not well studied. Evidence has shown that exercise in cold exerts more noticeable effects on sympathetic nervous activation, bioenergetics, anti-oxidative capacity, and immune response compared to exercise in thermoneutral environment. It also increases the secretion of a series of exerkines, including irisin and fibroblast growth factor 21, which may contribute to the cardiovascular benefits induced by exercise in cold. Further well-designed studies are needed to advance the biological effects of exercise in cold. Understanding the mechanisms underlying the benefits of exercise in cold will help prescribe cold exercise to those who can benefit from it.

Impact of Biochar on Rhizosphere Bacterial Diversity Restoration Following Chloropicrin Fumigation of Planted Soil.

Chloropicrin (CP) can effectively combat soil-borne diseases but has significant side effects on nontarget microorganisms. The rhizosphere microflora play a crucial role in promoting plant growth and protecting plants from infection by soil-borne pathogens. We conducted a laboratory pot experiment to evaluate the effect of CP on the rhizosphere soil bacterial flora and the effect of biochar amendments on the reconstruction of microbial communities. Our results show that CP fumigation and biochar additions promoted the growth of cucumber plants in the later stage of the pot experiment. CP significantly inhibited the rhizobacterial diversity and changed the community composition. Biochar amendments after CP fumigation shortened the time for the rhizobacterial diversity to recover to unfumigated levels. Biochar amendments promoted the transplantation of new populations to empty microbiome niches that were caused by CP and, in particular, stimulated many beneficial microorganisms to become the predominant flora. The relative abundances of many functional taxa related to plant-disease suppressiveness and pollutant bioremediation increased, including Pseudomonas, Stenotrophomonas, Bacillus, Massilia, Acinetobacter, Delftia, Micromonospora, Cytophagaceae, and Flavisolibacter. These changes stimulated by biochar amendments would promote multifunctionality in the soil rhizosphere and benefit plant growth and disease resistance.

Transition-metal-free approaches to 2,3-diarylated indenones from 2-alkynylbenzaldehydes and phenols with tunable selectivity.

The first transition-metal-free regioselective synthesis of 2,3-diarylindenones via tandem annulation of 2-alkynylbenzaldehydes with phenols is described. Two different modes of reaction controlled by electronic effects and temperature furnished either "non-rearranged" or "rearranged" indenones in high selectivity.

Design, synthesis and biological evaluation of novel nitric oxide donors with antioxidative activity.

Reactive oxygen species (ROS) are the primary cause of organic nitrate drug tolerance and endothelial dysfunction. In order to scavenge the ROS and maintain the therapeutic effect of nitrates, we designed and synthesized ten new types of dual-acting nitrate molecules by combining NIT-type nitroxides and 5-ISMN. These included two types of novel epimeric nitroxide-nitrate conjugates (15(S) and 15(R)), which had pharmacophore connections. We also synthesized 8 NIT radicals without 5-ISMN in order to compare the activities of these novel nitric oxide donors. Several dual-acting nitroxide-based nitrate conjugates showed the ability to release NO and cause anti-oxidant effects in human umbilical vein endothelial cells. Among these conjugates, 15(S) showed the most prominent pro-vasodilative effect. In angiotensin II infusion-induced hypertensive mice, 15(S) treatment for 4 weeks decreased both the systolic and diastolic blood pressures and ameliorated the vascular endothelial and smooth muscle functions of isolated thoracic aortas. In addition, the vascular structure of the mice was restored and their vascular oxidative stress was decreased. The results suggest that these novel nitric oxide donors can be used as potential drugs in the treatment of vascular diseases. Therefore, the strategy of using a combination of antioxidants and NO-donors can be a promising way to develop novel organic nitrate drugs for future use in combating disease.

Discovery of MAO-B Inhibitor with Machine Learning, Topomer CoMFA, Molecular Docking and Multi-Spectroscopy Approaches.

Alzheimer's disease (AD) is the most common type of dementia and is a serious disruption to normal life. Monoamine oxidase-B (MAO-B) is an important target for the treatment of AD. In this study, machine learning approaches were applied to investigate the identification model of MAO-B inhibitors. The results showed that the identification model for MAO-B inhibitors with　K-nearest neighbor(KNN) algorithm had a prediction accuracy of 94.1% and 88.0% for the 10-fold cross-validation test and the independent test set, respectively. Secondly, a quantitative activity prediction model for MAO-B was investigated with the Topomer CoMFA model. Two separate cutting mode approaches were used to predict the activity of MAO-B inhibitors. The results showed that the cut model with q2 = 0.612 (cross-validated correlation coefficient) and r2 = 0.824 (non-cross-validated correlation coefficient) were determined for the training and test sets, respectively. In addition, molecular docking was employed to analyze the interaction between MAO-B and inhibitors. Finally, based on our proposed prediction model, 1-(4-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)propan-1-one (LB) was predicted as a potential MAO-B inhibitor and was validated by a multi-spectroscopic approach including fluorescence spectra and ultraviolet spectrophotometry.

Palladium-catalyzed Ugi-type reaction of 2-iodoanilines with isocyanides and carboxylic acids affording N-acyl anthranilamides.

The first palladium-catalyzed Ugi-type multicomponent reaction for the synthesis of N-acyl anthranilamides from isocyanides, 2-iodoanilines and carboxylic acids has been developed. This method provides expeditious and highly efficient access to structurally diverse N-acyl anthranilamides from readily available starting materials with good functional group compatibility. The utility of this method has been demonstrated by the late stage functionalization of two commercial drugs: Flurbiprofen and Loxoprofen.

NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions.

BACKGROUND: Blood transfusion, a common basic supporting therapy, can lead to acute hemolytic transfusion reaction (AHTR). AHTR poses a great risk to patients through kidney function damage in a short time. Previous reports found that heme from destroyed red blood cells impaired kidney function, and NLR family pyrin domain containing 3 (NLRP3) inflammasome was augmented in case of kidney injury. However, the detailed mechanism regarding whether NLRP3 inflammasome is involved in kidney function injury in AHTR is not fully understood yet. METHODS: Hemolysis models were established by vein injection with human blood plasma or mouse heme from destroyed red blood cells. The injured renal tubular epithelial cells (RTECs) were evaluated by tubular damage markers staining in hemolysis models and in primary RTECs in vitro. The activation of NLRP3 inflammasome in RTECs by hemes was investigated by Western blot, ELISA, scanning electron microscopy, immunofluorescent staining, flow cytometry, and hemolysis models. NLRP3 gene knockout mice were employed to confirm these observations in vitro and in vivo. The binding between a novel inhibitor (66PR) and NLRP3 was affirmed by molecule docking and co-immunoprecipitation. The rescue of 66PR on kidney function impairment was explored in murine hemolysis models. RESULTS: We found that heme could activate NLRP3 inflammasome in RTECs to induce kidney function injury. NLRP3 gene knockout could prevent the damage of RTECs caused by hemes and recover kidney function in AHTR. Moreover, NLRP3 inflammasome chemical inhibitor, 66PR, could bind to NLRP3 protein and inhibit inflammasome activation in RTECs, which consequently relieved the injury of RTECs caused by hemes, and alleviated kidney function damage in the AHTR model. CONCLUSIONS: Hemes could activate NLRP3 inflammasome in RTECs, and a novel NLRP3 inflammasome inhibitor named 66PR relieved kidney function damage in AHTR. Our findings provided a new possible strategy to treat kidney function failure in AHTR.

Synthesis and application of a novel single-isomer mono-6-deoxy-6-((2S,3S)-(+)-2,3-O-isopropylidene-1,4-tetramethylenediamine)-ß-cyclodextrin as chiral selector in capillary electrophoresis.

A novel single isomer of positively charged ß-cyclodextrin, mono-6-deoxy-6-((2S,3S)-(+)-2,3-O-isopropylidene-1,4-tetramethylenediamine)-ß-CD (MIPTACD) was designed and synthesized in seven steps starting from commercially available (2R,3R)-tartaric acid. The chiral resolution abilities of the new cationic chiral selector were studied by capillary electrophoresis using 10 different dansyl (Dns)-amino acids and N-acetylphenylalanine (N-Ac-Phe) as model analytes. The effects of running buffer pH and chiral selector concentration on the separation selectivity, resolutions, and migration times of analytes were studied in detail. MIPTACD shows a very good chiral recognition ability even at very low concentrations at the investigated pH values, as shown by the very large values of selectivity and resolution towards amino acids enantiomers to be assessed.

Quantitative HPLC method and pharmacokinetic studies of ergosta-4,6,8(14),22-tetraen-3-one, a natural product with diuretic activity from Polyporus umbellatus.

A simple and specific HPLC method with dual wavelength UV detection for the determination of ergosta-4,6,8(14),22-tetraen-3-one (ergone) in rat plasma was developed and proved to be efficient. The method used ergosterol as internal standard (IS). Following a single-step protein precipitation, the analyte and IS were separated on an Inertsil ODS-3 column with a mobile phase containing methanol-water (99:1, v/v) at a flow rate of 1 mL/min. The analytes were detected by using UV detection at wavelength of 350 (ergone) and 283 (IS) nm, respectively. The calibration curve was linear over the range of 0.1-2.0 µg/mL and the lower limit of quantification was 0.1 µg/mL. The intra-day and inter-day precision studies showed good reproducibility with RSD less than 8.5%. The intra-day and inter-day accuracy ranged from 95.6 to 104%. Mean extraction recovery was above 95% at the low, medium and high concentrations. The present HPLC-UV method was simple and reliable. The method described herein had been successfully applied for the pharmacokinetic studies in male SD rats after administration of 20 mg/kg dose of solution of ergone.

Baicalin protects mice from infection with methicillin-resistant Staphylococcus aureus via alleviating inflammatory response.

Sepsis was redefined as life-threatening organ dysfunction caused by a dysregulated host response to infection in 2016. One of its most common causes is Staphylococcus aureus, especially methicillin-resistant Staphylococcus aureus (MRSA), which leads to a significant increase in morbidity and mortality. Therefore, innovative and effective approaches to combat MRSA infection are urgently needed. Recently, host-directed therapy (HDT) has become a new strategy in the treatment of infectious diseases, especially those caused by antibiotic-resistant bacteria. Baicalin (BAI) is the predominant flavonoid and bioactive compound isolated from the roots of Radix Scutellariae (Huang Qin), a kind of traditional Chinese medicine. It has been reported that BAI exhibits multiple biological properties such as anti-oxidant, antitumor, and anti-inflammatory activities. However, the therapeutic role of BAI in MRSA infection is still unknown. In this study, it is found that BAI treatment inhibited the production of IL-6, TNF-α, and other cytokines from MRSA- or bacterial mimics-stimulated Mϕs and dendritic cells (DCs). BAI played an anti-inflammatory role by inhibiting the activation of ERK, JNK MAPK, and NF-κB pathways. Moreover, the serum level of TNF-α was decreased, whereas IL-10 was increased, in mice injected with MRSA. Furthermore, the bacterial load in livers and kidneys were further decreased by the combination of BAI and vancomycin (VAN), which might account for the amelioration of tissue damage. BAI reduced the high mortality rate caused by MRSA infection. Collectively, the results suggested that BAI may be a viable candidate of HDT strategy against severe sepsis caused by antibiotic-resistant bacteria such as MRSA.

4,4,5,5-Tetra-methyl-2-[4-(2-pyrid-yl)phen-yl]-3,4-dihydro-imidazole-1-oxyl-3-oxide.

In the title compound, C(18)H(20)N(3)O(2), the pyridine and phenyl rings are coplanar [dihedral angle = 3.5 (3)°]. The phenyl ring makes a dihedral angle of 29.6 (1)° with the imidazole ring. The crystal structure is stabilized by inter-molecular C-H⋯O hydrogen bonds.

Aging effect on the mobility and bioavailability of copper in soil.

Aging effect on the mobility and bioavailability of copper (Cu) was investigated using a spiked soil with different incubation periods from 3 to 56 d. Wheat was planted and earthworms were cultured separately in the incubated soils. The mobility of Cu in soil was evaluated by a chemical fractionation scheme and the toxicity and bioavailability were assessed by measuring the biomass and Cu concentration in tissues. Results showed that aging had a significant effect on Cu fraction distribution, of which Cu tended to incorporate from the exchangeable into more stable fractions such as the reducible and oxidisable fractions. However, aging had little effect on Cu bioavailability to wheat and earthworm. Comparing the soil being incubated for 3 d and 56 d, Cu concentration in wheat roots decreased from 14.5 to 12.8 mg/kg, and no significant changes in Cu concentration were observed in both wheat shoots and earthworms. The Cu concentration was around 2.0 and 50 mg/kg for wheat shoots and earthworms, respectively, irrespective of soil incubation time. The CaCl2-extractable Cu had a linear relationship with Cu concentration in wheat roots (R2 = 0.65, P < 0.05), but no linear relationship can be found for wheat shoots and earthworms. Biological control may be more crucial for Cu accumulation in organism than the changes in soil Cu fraction caused by aging.

Mesenchymal Stromal Cells Directly Promote Inflammation by Canonical NLRP3 and Non-canonical Caspase-11 Inflammasomes.

Mesenchymal stromal cells (MSCs) based therapy is a promising approach to treat inflammatory disorders. However, therapeutic effect is not always achieved. Thus the mechanism involved in inflammation requires further elucidation. To explore the mechanisms by which MSCs respond to inflammatory stimuli, we investigated whether MSCs employed inflammasomes to participate in inflammation. Using in vitro and in vivo models, we found that canonical NLRP3 and non-canonical caspase-11 inflammasomes were activated in bone-associated MSCs (BA-MSCs) to promote the inflammatory response. The NLRP3 inflammasome was activated to mainly elicit IL-1ß/18 release, whereas the caspase-11 inflammasome managed pyroptosis. Furthermore, we sought a small molecule component (66PR) to inhibit the activation of inflammasomes in BA-MSCs, which consequently improved their survival and therapeutic potential in inflammation bowel diseases. These current findings indicated that MSCs themselves could directly promote the inflammatory response by an inflammasome-dependent pathway. Our observations suggested that inhibition of the proinflammatory property may improve MSCs utilization in inflammatory disorders.