Bioactive Species Research Articles

Cyanidin‐3‐O‐glucoside, cyanidin, and oxidation products of cyanidin protect neuronal function through alleviating inflammation and oxidative damage

Neurotoxicity seriously affects the normal function of the nervous system. Cyanidin-3-O-glucoside (C3G) is the most abundant anthocyanin widely distributed in plants. Using β-amyloid (Aβ) transgenic Caenorhabditis elegans and cell models, the neuroprotective effect of C3G was examined. The results showed that C3G remarkably suppressed Aβ aggregation, enhanced antioxidant capacity, improved the sensitive capacity towards chemical compounds, and boosted the memory ability of C. elegans. There was no significant difference between preventive and long-term treatment groups at the same dosage of C3G. Given the rapid metabolism and oxidation of C3G in vivo, the antioxidative and anti-inflammatory activities of C3G, the metabolite cyanidin (Cy), oxidation products of Cy (OP), as well as protocatechuic acid (PCA) at the corresponding level in OP were compared by using lipopolysaccharide (LPS)-stimulated BV2 microglia cell model. The results indicated that C3G, Cy, and OP could prevent BV2 cells against LPS-induced inflammation and oxidative damage. There was no significant difference on antioxidative and anti-inflammatory activities among C3G, Cy, and OP at the same level. Notably, PCA at the corresponding concentration in OP exhibited limited antioxidative and anti-inflammatory activities. The results suggested that C3G could exert neuroprotective function through the metabolite Cy and its oxidation products by inhibiting inflammation and oxidative damage, and PCA was not the primary bioactive species in OP. PRACTICAL APPLICATION: This study confirmed the neuroprotection of cyanidin-3-O-glucoside (C3G) in transgenic Caenorhabditis elegans. C3G, its metabolite cyanidin (Cy), and oxidation products of Cy (OP) alleviated both neuroinflammation and oxidative damage. It highlighted that C3G-rich foods could exert neuroprotective potential through their oxidation products, the constitution, and existence of OP in vivo need further study.

Covalent organic framework‐supported Pd nanoparticles: An efficient and reusable heterogeneous catalyst for Suzuki–Miyaura coupling reactions

AbstractA Schiff base hollow covalent organic framework (COF) was used for anchoring Pd(II) to synthesize the Pd@COF‐TB nanocatalyst. Then, the as‐synthesized Pd@COF‐TB catalyst has been meticulously characterized using several methods. Thereafter, the catalytic performance of the Pd@COF‐TB species regarding Suzuki–Miyaura coupling reactions was examined, and the corresponding products were obtained with good to excellent yields. Besides, the Pd@COF‐TB catalyst could be recovered conveniently and reused at least eight times without obvious decrease in activity and selectivity. More importantly, the leaching of Pd during the reaction process could be negligible, which is crucially important when preparing bioactive species.

Alkylgold(III) Complexes Undergo Unprecedented Photo-Induced β-Hydride Elimination and Reduction for Targeted Cancer Therapy.

Spatiotemporally controllable activation of prodrugs within tumors is highly desirable for cancer therapy to minimize toxic side effects. Herein we report that stable alkylgold(III) complexes can undergo unprecedented photo-induced β-hydride elimination, releasing alkyl ligands and forming gold(III)-hydride intermediates that could be quickly converted into bioactive [AuIII -S] adducts; meanwhile, the remaining alkylgold(III) complexes can photo-catalytically reduce [AuIII -S] into more bioactive AuI species. Such photo-reactivities make it possible to functionalize gold complexes on the auxiliary alkyl ligands without attenuating the metal-biomacromolecule interactions. As a result, the gold(III) complexes containing glucose-functionalized alkyl ligands displayed efficient and tumor-selective uptake; notably, after one- or two-photon activation, the complexes exhibited high thioredoxin reductase (TrxR) inhibition, potent cytotoxicity, and strong antiangiogenesis and antitumor activities in vivo.

Alkylgold(III) Complexes Undergo Unprecedented Photo‐Induced β‐Hydride Elimination and Reduction for Targeted Cancer Therapy

AbstractSpatiotemporally controllable activation of prodrugs within tumors is highly desirable for cancer therapy to minimize toxic side effects. Herein we report that stable alkylgold(III) complexes can undergo unprecedented photo‐induced β‐hydride elimination, releasing alkyl ligands and forming gold(III)‐hydride intermediates that could be quickly converted into bioactive [AuIII−S] adducts; meanwhile, the remaining alkylgold(III) complexes can photo‐catalytically reduce [AuIII−S] into more bioactive AuIspecies. Such photo‐reactivities make it possible to functionalize gold complexes on the auxiliary alkyl ligands without attenuating the metal–biomacromolecule interactions. As a result, the gold(III) complexes containing glucose‐functionalized alkyl ligands displayed efficient and tumor‐selective uptake; notably, after one‐ or two‐photon activation, the complexes exhibited high thioredoxin reductase (TrxR) inhibition, potent cytotoxicity, and strong antiangiogenesis and antitumor activities in vivo.

Inorganic nitrate and nitrite ameliorate kidney fibrosis by restoring lipid metabolism via dual regulation of AMP-activated protein kinase and the AKT-PGC1α pathway

BackgroundRenal fibrosis, associated with oxidative stress and nitric oxide (NO) deficiency, contributes to the development of chronic kidney disease and renal failure. As major energy source in maintaining renal physiological functions, tubular epithelial cells with decreased fatty acid oxidation play a key role in renal fibrosis development. Inorganic nitrate, found in high levels in certain vegetables, can increase the formation and signaling by bioactive nitrogen species, including NO, and dampen oxidative stress. In this study, we evaluated the therapeutic value of inorganic nitrate treatment on development of kidney fibrosis and investigated underlying mechanisms including regulation of lipid metabolism in tubular epithelial cells. MethodsInorganic nitrate was supplemented in a mouse model of complete unilateral ureteral obstruction (UUO)-induced fibrosis. Inorganic nitrite was applied in transforming growth factor β-induced pro-fibrotic cells in vitro. Metformin was administrated as a positive control. Fibrosis, oxidative stress and lipid metabolism were evaluated. ResultsNitrate treatment boosted the nitrate-nitrite-NO pathway, which ameliorated UUO-induced renal dysfunction and fibrosis in mice, represented by improved glomerular filtration and morphological structure and decreased renal collagen deposition, pro-fibrotic marker expression, and inflammation. In human proximal tubule epithelial cells (HK-2), inorganic nitrite treatment prevented transforming growth factor β-induced pro-fibrotic changes. Mechanistically, boosting the nitrate-nitrite-NO pathway promoted AMP-activated protein kinase (AMPK) phosphorylation, improved AKT-mediated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) activity and restored mitochondrial function. Accordingly, treatment with nitrate (in vivo) or nitrite (in vitro) decreased lipid accumulation, which was associated with dampened NADPH oxidase activity and mitochondria-derived oxidative stress. ConclusionsOur findings indicate that inorganic nitrate and nitrite treatment attenuates the development of kidney fibrosis by targeting oxidative stress and lipid metabolism. Underlying mechanisms include modulation of AMPK and AKT-PGC1α pathways.

The Biological Variability of Plasma Ceramides in Healthy Subjects.

Ceramides are bioactive lipid species that mediate numerous cell-signaling events. Elevated plasma ceramides concentration constitutes a risk factor for several pathologies. Multiple studies have affirmed the plasma concentrations of 4 specific ceramides (Cer16:0, Cer18:0, Cer24:0, and Cer24:1) can predict cardiovascular disease risk. Furthermore, these ceramides can be altered by many lipid-lowering therapies. Understanding the biological variability within an individual, and within a population, will further inform the clinical use of plasma ceramides as a biomarker. In this study, we aimed to define the intra- and interbiological variability of ceramides in a healthy reference population in a weekly and monthly manner. Fasting plasma from 24 healthy adults was collected daily (5 days), weekly (4 weeks), and monthly (7 months). Ceramide concentrations were measured with liquid chromatography-mass spectrometry (LC-MS). For analysis, we used random-effects regression models to estimate variance components. The analytical variability was smaller compared to the biological variability overall. The greatest variation reported was between-subject variation for all ceramide species. The critical difference-reference change value (RCV) for within-subject variations monthly were 0.07 mcmol/L (Cer16:0), 0.04 mcmol/L (Cer18:0), 1.09 mcmol/L (Cer24:0), and 0.27 mcmol/L (Cer24:1). The index of individuality (IOI) of ceramides were 0.82 (Cer16:0), 0.96 (Cer18:0), 1.06 (Cer24:0), and 0.89 (Cer24:1). The most consistent ceramide species was Cer18:0 with the lowest within- and between-subject critical differences in weekly and monthly measurements. Overall, this study demonstrates that the variability of ceramide concentrations at different time points is minimal within individuals, allowing a single draw to be sufficient at least in a yearly time frame.

Nitrogen–doped carbon quantum dots as fluorescent nanosensor for selective determination and cellular imaging of ClO−

The carbon nanomaterial based fluorescent probes have been widely applied in biological imaging. In the current research, we propose an interesting strategy for selective sensing of hypochlorite (ClO−) by a water–soluble and highly fluorescent nanosensor based on the N–doped carbon quantum dots (CDs) which was fabricated by a facile and environmental friendly hydrothermal approach from polyvinyl pyrrolidone, L–arginine and tryptophan. The structural characteristics of the probe were measured by multitudinous methods which proved the nanometer spherical structure of the probe and the successfully N–doping. Fluorescent investigation demonstrated that the probe is not only highly stable under interferences of pH, ionic strength, and irradiation, but also significantly selective toward ClO− amongst a variety of attractive bioactive species through the fluorescent quenching process which was correlative with the concentration of ClO− and linearly in the range of 0.1–50 μmol·L–1 with the sensitivity of 0.03 μmol·L–1. The probe can also be further illustrated in a prospective application for determination of ClO− in environmental water through both solution response and filer paper sensing. Moreover, the positive biocompatibility and ignorable cytotoxicity made the probe a promising effective agent for detection and visualizing ClO− in living cells which can facilitate the understanding the oxidative stress from the overexpressing ClO−.

Recent progress in small-molecule fluorescent probes for endoplasmic reticulum imaging in biological systems.

Endoplasmic reticulum (ER) is an indispensable organelle in eukaryotic cells involved in protein synthesis and processing, as well as calcium storage and release. Therefore, maintaining the quality of ER is of great importance for cellular homeostasis. Aberrant fluctuations of bioactive species in the ER will result in homeostasis disequilibrium and further cause ER stress, which has evolved to contribute to the pathogenesis of various diseases. Therefore, the real-time monitoring of various bioactive species in the ER is of high priority to ascertain the mysterious roles of ER, which will contribute to unveiling the corresponding mechanism of organism disturbances. Recently, fluorescence imaging has emerged as a robust technique for the direct visualization of molecular events due to its outstanding sensitivity, high temporal-spatial resolution and noninvasive nature. In this review, we comprehensively summarize the recent progress in design strategies, bioimaging applications, potential directions and challenges of ER-targetable small-molecular fluorescent probes.

Non-denaturing affinity purification of soluble oligomeric Aβ from human brain using a novel calcium-sensitive monoclonal antibody.

The soluble fraction of human AD brain extracts contains the most bioactive oligomeric forms of Aβ (oAβ), which are low in abundance. Few methods exist to enrich for oAβ from soluble brain extracts without denaturing them. Purification of natural, human oAβ would allow further structural and biochemical study of this truly disease-relevant species. A panel of anti-oAβ monoclonal antibodies was developed by immunizing Trianni mice with synthetic Aβ aggregates. Clones were screened for oAβ selectivity and protection against human oAβ-induced injury in an in vitro neuritic integrity assay and in mouse hippocampal slice LTP recordings. Four antibodies with selectivity for oAβ over monomeric Aβ and protective effects were chosen for further study. Quantitative immunoprecipitations (IP followed by guanidine denaturation and monomer-specific ELISA) were performed on soluble extracts obtained by soaking cortical fragments bits in TBS to enrich for bioactive diffusible oAβ species. One antibody, B24, could IP oAβ only from non-dialyzed extracts. Iterative IPs were used to identify calcium as the soluble, dialyzable factor required for B24 binding to oAβ. Differential Scanning Fluorimetry (nano-DSF), Octet biolayer interferometry (BLI), and immunohistochemistry were further used to characterize B24 calcium-dependence and reversibility of binding to oAβ. B24 showed complete dependence on calcium at low millimolar levels for binding to soluble human oAβ, plaques, and synthetic Aβ protofibrils. Calcium induced a conformational change in B24. Binding of human soluble brain extracts to B24, washing, and elution with EGTA resulted in enrichment of oAβ. The recovered oAβ accounted for 20-40% of the initial input oAβ, accompanied by >400-fold reduction in total protein content. The recovered oAβ required guanidine hydrochloride for denaturation and detection by Aβ monomer-specific ELISA, implying that the recovered oAβ had not been denatured during purification. Calcium did not affect the size distribution of oAβ from human brain extracts by size exclusion chromatography. B24 is protective against natural oAβ-induced neuronal injury and binds oAβ in a calcium-dependent manner. This unique characteristic allows affinity purification of bioactive oAβ from human brain extracts for further study and drug development.

Anti-depressive effects of Jiao-Tai-Wan on CORT-induced depression in mice by inhibiting inflammation and microglia activation

Ethnopharmacological relevanceJiao-Tai-Wan (JTW) is a very famous traditional Chinese medicine formula for the treatment of psychiatric disorders, especially in anxiety, insomnia and depression. However, its molecular mechanism of treatment remains indistinct. Aim of the studyWe aimed to reveal the action mechanism of JTW on anti-depression via inhibiting microglia activation and pro-inflammatory response both in vivo and in vitro. Material and methodsThe corticosterone (CORT)-induced depression mouse model was used to evaluate the therapeutic efficacy of JTW. Behavioral tests (open field, elevated plus maze, tail suspension and forced swim test) were conducted to evaluate the effect of JTW on depressive-like behaviors. The levels of inflammatory factors and the concentration of neurotransmitters were detected by RT-qPCR or ELISA assays. Then three hippocampal tissue samples per group (Control, CORT, and JTW group) were sent for RNA sequencing (RNA-seq). Transcriptomics data analysis was used to screen the key potential therapeutic targets and signaling pathways of JTW. Based on 8 bioactive species of JTW by our previous study using High-performance liquid chromatography (HPLC) analysis, molecular docking analyses were used to predict the interaction of JTW-derived compounds and depression targets. Finally, the results of transcriptome and molecular docking analyses were combined to verify the targets, key pathways, and efficacy of JTW treatment in vivo and vitro. ResultsJTW ameliorated CORT-induced depressive-like behaviors, neuronal damage and enhanced the levels of monoamine neurotransmitters in the serum of mice. JTW also inhibited CORT-induced inflammatory activation of microglia and decreased the serum levels of interleukin- 6(IL-6) and interleukin- 1β (IL-1β) in vivo. Transcriptomic data analysis showed there were 10 key driver analysis (KDA) genes with the strongest correlation which JTW regulated in depression mice. Molecular docking analysis displayed bioactive compound Magnoflorine had the strongest binding force to the key gene colony-stimulating factor 1 receptor (CSF1R), which is the signaling microglia dependent upon for their survival. Meanwhile, CSF1R staining showed it was consistent with inflammatory activation of microglia. Our vitro experiment also showed JTW and CSF1R inhibitor significantly reduced lipopolysaccharide (LPS)/interferon-gamma (IFNɣ)-induced inflammatory activation response in macrophage cells. ConclusionsOur study suggests that JTW might ameliorate CORT-induced neuronal damage in depression mice by inhibiting CSF1R mediated microglia activation and pro-inflammatory response.

Targeted Treatment of Ischemic Stroke by Bioactive Nanoparticle-Derived Reactive Oxygen Species Responsive and Inflammation-Resolving Nanotherapies.

Stroke is a primary cause of death and disability worldwide, while effective and safe drugs remain to be developed for its clinical treatment. Herein, we report bioactive nanoparticle-derived multifunctional nanotherapies for ischemic stroke, which are engineered from a pharmacologically active oligosaccharide material (termed as TPCD) prepared by covalently conjugating a radical-scavenging compound (Tempol) and a hydrogen-peroxide-eliminating moiety of phenylboronic acid pinacol ester (PBAP) on β-cyclodextrin. Of note, combined functional moieties of Tempol and PBAP on β-cyclodextrin contribute to antioxidative and anti-inflammatory activities of TPCD. Cellularly, TPCD nanoparticles (i.e., TPCD NPs) reduced oxygen-glucose deprivation-induced overproduction of oxidative mediators, increased antioxidant enzyme expression, and suppressed microglial-mediated inflammation, thereby inhibiting neuronal apoptosis. After intravenous (i.v.) delivery, TPCD NPs could efficiently accumulate at the cerebral ischemic injury site of mice with middle cerebral artery occlusion (MCAO), showing considerable distribution in cells relevant to the pathogenesis of stroke. Therapeutically, TPCD NPs significantly decreased infarct volume and accelerated recovery of neurological function in MCAO mice. Mechanistically, efficacy of TPCD NPs is achieved by its antioxidative, anti-inflammatory, and antiapoptotic effects. Furthermore, TPCD NPs can function as a reactive oxygen species labile nanovehicle to efficiently load and triggerably release an inflammation-resolving peptide Ac2-26, giving rise to an inflammation-resolving nanotherapy (i.e., ATPCD NP). Compared to TPCD NP, ATPCD NP demonstrated notably enhanced in vivo efficacies, largely resulting from its additional inflammation-resolving activity. Consequently, TPCD NP-derived nanomedicines can be further developed as promising targeted therapies for stroke and other inflammation-associated cerebrovascular diseases.

Recent advances in 1,8-naphthalimide-based small-molecule fluorescent probes for organelles imaging and tracking in living cells

• Small-molecule NI -based fluorescent probes for imaging and tracking organelles in living cells are systematically reviewed. • The organelle-targeting groups and possible molecular labeling mechanisms are comprehensively summarized. • A detailed introduction of NI -based fluorescent probe for monitoring these organelle dynamics, their microenvironments, bio-/chem-active species, and enzyme activities. • The challenges and perspectives of NI -based fluorescent probe in future biological applications and clinical diagnosis. The application of fluorescent probes for organelle imaging and tracking has been extensively explored in recent years due to their unique optical performance. This review focuses on 1,8-naphthalimide (NI) fluorophore highlighting the recent advances in imaging and tracking of individual or multiple organelles in living cells. Specifically, we emphasize their labeling mechanism, and summarize the applications by monitoring their dynamic microenvironment ( e.g. , viscosity, polarity, temperature, and pH), bioactive species ( e.g. , cations/anions, molecules, radicals), and the enzyme activities. We also point out the shortcomings of the reported NI-based organelle fluorescent probes and present our perspective on the future developments in this field. We hope this review can be used not only as a reference for beginners, but also as a compass of these fields, and contribute to solving more promising and meaningful topics for chemical and biological researchers.

Psychedelics, Sociality, and Human Evolution.

Our hominin ancestors inevitably encountered and likely ingested psychedelic mushrooms throughout their evolutionary history. This assertion is supported by current understanding of: early hominins’ paleodiet and paleoecology; primate phylogeny of mycophagical and self-medicative behaviors; and the biogeography of psilocybin-containing fungi. These lines of evidence indicate mushrooms (including bioactive species) have been a relevant resource since the Pliocene, when hominins intensified exploitation of forest floor foods. Psilocybin and similar psychedelics that primarily target the serotonin 2A receptor subtype stimulate an active coping strategy response that may provide an enhanced capacity for adaptive changes through a flexible and associative mode of cognition. Such psychedelics also alter emotional processing, self-regulation, and social behavior, often having enduring effects on individual and group well-being and sociality. A homeostatic and drug instrumentalization perspective suggests that incidental inclusion of psychedelics in the diet of hominins, and their eventual addition to rituals and institutions of early humans could have conferred selective advantages. Hominin evolution occurred in an ever-changing, and at times quickly changing, environmental landscape and entailed advancement into a socio-cognitive niche, i.e., the development of a socially interdependent lifeway based on reasoning, cooperative communication, and social learning. In this context, psychedelics’ effects in enhancing sociality, imagination, eloquence, and suggestibility may have increased adaptability and fitness. We present interdisciplinary evidence for a model of psychedelic instrumentalization focused on four interrelated instrumentalization goals: management of psychological distress and treatment of health problems; enhanced social interaction and interpersonal relations; facilitation of collective ritual and religious activities; and enhanced group decision-making. The socio-cognitive niche was simultaneously a selection pressure and an adaptive response, and was partially constructed by hominins through their activities and their choices. Therefore, the evolutionary scenario put forward suggests that integration of psilocybin into ancient diet, communal practice, and proto-religious activity may have enhanced hominin response to the socio-cognitive niche, while also aiding in its creation. In particular, the interpersonal and prosocial effects of psilocybin may have mediated the expansion of social bonding mechanisms such as laughter, music, storytelling, and religion, imposing a systematic bias on the selective environment that favored selection for prosociality in our lineage.

SOD2 in skeletal muscle: New insights from an inducible deletion model

Metabolic conditions such as obesity, insulin resistance and glucose intolerance are frequently associated with impairments in skeletal muscle function and metabolism. This is often linked to dysregulation of homeostatic pathways including an increase in reactive oxygen species (ROS) and oxidative stress. One of the main sites of ROS production is the mitochondria, where the flux of substrates through the electron transport chain (ETC) can result in the generation of oxygen free radicals. Fortunately, several mechanisms exist to buffer bursts of intracellular ROS and peroxide production, including the enzymes Catalase, Glutathione Peroxidase and Superoxide Dismutase (SOD). Of the latter, there are two intracellular isoforms; SOD1 which is mostly cytoplasmic, and SOD2 which is found exclusively in the mitochondria. Developmental and chronic loss of these enzymes has been linked to disease in several studies, however the temporal effects of these disturbances remain largely unexplored. Here, we induced a post-developmental (8-week old mice) deletion of SOD2 in skeletal muscle (SOD2-iMKO) and demonstrate that 16 weeks of SOD2 deletion leads to no major impairment in whole body metabolism, despite these mice displaying alterations in aspects of mitochondrial abundance and voluntary ambulatory movement. This is likely partly explained by the suggestive data that a compensatory response may exist from other redox enzymes, including catalase and glutathione peroxidases. Nevertheless, we demonstrated that inducible SOD2 deletion impacts on specific aspects of muscle lipid metabolism, including the abundance of phospholipids and phosphatidic acid (PA), the latter being a key intermediate in several cellular signaling pathways. Thus, our findings suggest that post-developmental deletion of SOD2 induces a more subtle phenotype than previous embryonic models have shown, allowing us to highlight a previously unrecognized link between SOD2, mitochondrial function and bioactive lipid species including PA.

Targeted Delivery of Zinc Pyrithione to Skin Epithelia.

Zinc pyrithione (ZnPT) is an anti-fungal drug delivered as a microparticle to skin epithelia. It is one of the most widely used ingredients worldwide in medicated shampoo for treating dandruff and seborrheic dermatitis (SD), a disorder with symptoms that include skin flaking, erythema and pruritus. SD is a multi-factorial disease driven by microbiol dysbiosis, primarily involving Malassezia yeast. Anti-fungal activity of ZnPT depends on the cutaneous availability of bioactive monomeric molecular species, occurring upon particle dissolution. The success of ZnPT as a topical therapeutic is underscored by the way it balances treatment efficacy with formulation safety. This review demonstrates how ZnPT achieves this balance, by integrating the current understanding of SD pathogenesis with an up-to-date analysis of ZnPT pharmacology, therapeutics and toxicology. ZnPT has anti-fungal activity with an average in vitro minimum inhibitory concentration of 10–15 ppm against the most abundant scalp skin Malassezia species (Malassezia globosa and Malassezia restrica). Efficacy is dependent on the targeted delivery of ZnPT to the skin sites where these yeasts reside, including the scalp surface and hair follicle infundibulum. Imaging and quantitative analysis tools have been fundamental for critically evaluating the therapeutic performance and safety of topical ZnPT formulations. Toxicologic investigations have focused on understanding the risk of local and systemic adverse effects following exposure from percutaneous penetration. Future research is expected to yield further advances in ZnPT formulations for SD and also include re-purposing towards a range of other dermatologic applications, which is likely to have significant clinical impact.

Hybrid functionalized coatings on Metallic Biomaterials for Tissue Engineering

The review encompasses state-of-the-art strategies for design and fabrication of smart biomaterials for tissue engineering. The focus of the work is mainly put on metallic biomaterials with hybrid coatings consisting of bioceramic and polymeric layers with hierarchical organization and drug-eluting capacity. Key technologies and steps to design hybrid smart and multifunctional coatings on metallic cores for bone regeneration implants and cardiovascular stents are outlined, including additive manufacturing of titanium and magnesium alloys for permanent and temporary implant applications. Three levels of hierarchical surface functionalization are described: i) in situ modification of the core material, incorporating bioactive inorganic species and phases by means of ceramic coatings via anodic electrochemical treatments ; ii) post-treatment application of polymer layers, monolithic or with specific porous breath figure topography; and iii) application of a cellular therapy component (single cell or cell sheet). Recent progress in incorporation of drug-eluting functionality into such materials via direct or nanocarrier-assisted loading is also highlighted. • Hybrid hierarchical design is needed for new permanent and temporary biomaterials. • Hybrid systems combine alloys with bioceramic and biodegradable polymer coatings. • Hybrid hierarchical coatings are versatile and successful drug-eluting systems. • Cell therapy could improve the final implantation success of the biomaterial

Nontargeted Metabolomics as a Screening Tool for Estimating Bioactive Metabolites in the Extracts of 50 Indigenous Korean Plants.

Many indigenous Korean plants have been used in medicinal preparations and health-promoting foods. These plant species contain beneficial metabolites with various bioactivities, such as antioxidant and anti-inflammatory activities. Herein, we suggest a new screening strategy using metabolomics to explore the bioactive compounds in 50 Korean plants. Secondary metabolites were analyzed using UHPLC-LTQ-Orbitrap-MS/MS. The plant extracts were subjected to antioxidant and anti-inflammatory assays. We identified metabolites that contributed to bioactivities according to the results of bioassays and multivariate analyses. Using Pearson’s correlation, phenolics (e.g., casuarictin, 3-O-methylellagic acid) showed positive correlation with antioxidant activity, while biflavonoids (e.g., amentoflavone, rosbustaflavone) were correlated with nitric oxide (NO) inhibition activity. To compensate for the limitation of this new strategy, we further validated these by investigating three parts (branches, fruits, leaves) of Platycladus orientalis which showed high activities on both bioassays. Unlike the above observation, we identified significantly different metabolites from different parts, which was not the results of bioassays. In these validation steps, interestingly, biflavonoids (e.g., robustaflavone, sciadopitysin) contributed to both activities in P. orientalis. The findings of this work suggest that new strategy could be more beneficial in the identification of bioactive plant species as well as that of their corresponding bioactive compounds that impart the bioactivity.

Utilization of Plant-Based Wastes for a Sustainable Preparation of Xanthophyll Esters via Acid Anhydrides Using β-Pinene as a Bio-Derived Solvent

A new valorization strategy for selected plant-based waste materials has been put forward. We have shown that avocado peels (fruit waste) and green leaves of Japanese knotweed (plant waste) are good sources of free xanthophylls such as antheraxanthin (9 mg/100 g dry weight) and lutein (106 mg/100 g dry weight), respectively, which can be converted into xanthophyll esters, a process inspired by nature to regulate the physicochemical properties of these bioactive species such as solubility and chemical stability. To this end, we developed the first environmentally friendly and economically viable synthetic platform and critically evaluated it by preparing 55 different xanthophyll esters (combining 5 model xanthophylls with 11 structurally and electronically distinct acid anhydrides). These esters were synthesized using β-pinene as a bio-derived solvent at ambient temperature and pressure with excellent selectivity (median 97%) and finally isolated in high yields (median 81%) and with high purities (median 97%). The integration of this technology with xanthophyll-containing wastes contributes to the zero-waste principle, and new valorization pathways for invasive alien plant species (such as Japanese knotweed) are particularly welcome as they help to control their rapid spread which causes great economic damage and loss of biodiversity around the globe.

Nitric oxide signalling in kidney regulation and cardiometabolic health.

The prevalence of cardiovascular and metabolic disease coupled with kidney dysfunction is increasing worldwide. This triad of disorders is associated with considerable morbidity and mortality as well as a substantial economic burden. Further understanding of the underlying pathophysiological mechanisms is important to develop novel preventive or therapeutic approaches. Among the proposed mechanisms, compromised nitric oxide (NO) bioactivity associated with oxidative stress is considered to be important. NO is a short-lived diatomic signalling molecule that exerts numerous effects on the kidneys, heart and vasculature as well as on peripheral metabolically active organs. The enzymatic l-arginine-dependent NO synthase (NOS) pathway is classically viewed as the main source of endogenous NO formation. However, the function of the NOS system is often compromised in various pathologies including kidney, cardiovascular and metabolic diseases. An alternative pathway, the nitrate–nitrite–NO pathway, enables endogenous or dietary-derived inorganic nitrate and nitrite to be recycled via serial reduction to form bioactive nitrogen species, including NO, independent of the NOS system. Signalling via these nitrogen species is linked with cGMP-dependent and independent mechanisms. Novel approaches to restoring NO homeostasis during NOS deficiency and oxidative stress have potential therapeutic applications in kidney, cardiovascular and metabolic disorders.

Decreased Cortical Nrf2 Gene Expression in Autism Spectrum Disorder and its Relationship to Thiol and Cobalamin status

Background The etiology of Autism spectrum disorder (ASD) is suspected to involve redox imbalances. In accordance with this, we previously published that sulfur metabolites in the methionine cycle and transsulfuration pathway were dysregulated in ASD frontal cortex. This was accompanied by disturbed vitamin B12 or cobalamin status. Cobalamin abundance and levels of the bioactive species methylcobalamin (MeCbl) were decreased, while levels of oxidized inert hydroxocobalamin (OHCbl) were increased in those tissues. Cellular cobalamin status is dependent on antioxidant availability. Reports have described decreased expression or activity of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in blood cells in ASD. Nrf2 is a transcription factor that promotes transcription of genes involved in maintaining antioxidant and detoxification status. We followed up on our postmortem study by performing real-time quantitative polymerase chain reaction (RT-qPCR) to investigate expression redox-linked genes. Genes included Nrf2 (NFE2L2), cystathionine beta synthase (CBS), cystathionine gamma-lyase (CTH), solute carrier family 1 member 1 (SLC1A1), glutathione synthetase (GSS), and glutathione reductase (GSR). We then searched for correlations among gene expression, thiols, and cobalamins to understand what factors may contribute to deranged sulfur and cobalamin metabolism in the brain in ASD. Methods RNA was isolated from control and ASD frontal cortex tissue using RNAqueous-4PCR kit manufactured by Ambion. Complementary DNA (cDNA) was synthesized with a Roche First Strand cDNA Synthesis kit. RT-qPCR was performed with a Roche LightCycler 480 model. Gene expression was normalized to glyceraldehyde 3-phosphate dehydrogenase. Bioinformatics searches were conducted with data downloaded from the consensus RNA dataset compiled by The Human Protein Atlas. Data were analyzed with Microsoft Excel and GraphPad Prism. Results NFE2L2, CBS, CTH, SLC1A1, and GSS RNA were decreased in ASD frontal cortex. Correlation analyses of pooled control and ASD data revealed strong associations between NFE2L2, cobalamin abundance, methionine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH). An association was also found with the transsulfuration metabolite cystathionine. Homocysteine (HCY) and OHCbl were inversely correlated with NFE2L2 expression. We decided to use a bioinformatics approach to further probe a general connection between Nrf2 and cobalamin status, utilizing cobalamin levels in various tissues published by Hsu et al. in 1966. Data obtained from The Human Protein Atlas revealed impressive associations between the expression of Nrf2-regulated genes, NFE2L2 expression, and tissue cobalamin abundance as described by Hsu et al. Conclusion Our RT-qPCR data support a role for decreased Nrf2 activity as an important feature of ASD. We further find that NFE2L2 expression is related to the metabolic patterns we characterized in ASD frontal cortex. Results of our bioinformatics inquiry suggest a potential causal role for Nrf2 that requires further investigation.