Optical substrates for drug-metabolizing enzymes : Recent advances and future perspectives

Drug-metabolizing enzymes (DMEs), a diverse group of enzymes responsible for the metabolic elimination of drugs and other xenobiotics, have been recognized as the critical determinants to drug safety and efficacy. Deciphering and understanding the key roles of individual DMEs in drug metabolism and toxicity, as well as characterizing the interactions of central DMEs with xenobiotics require reliable, practical and highly specific tools for sensing the activities of these enzymes in biological systems. In the last few decades, the scientists have developed a variety of optical substrates for sensing human DMEs, parts of them have been successfully used for studying target enzyme(s) in tissue preparations and living systems. Herein, molecular design principals and recent advances in the development and applications of optical substrates for human DMEs have been reviewed systematically. Furthermore, the challenges and future perspectives in this field are also highlighted. The presented information offers a group of practical approaches and imaging tools for sensing DMEs activities in complex biological systems, which strongly facilitates high-throughput screening the modulators of target DMEs and studies on drug/herb-drug interactions, as well as promotes the fundamental researches for exploring the relevance of DMEs to human diseases and drug treatment outcomes. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.Peer reviewe

An Essential Role for RIG-I in Toll-like Receptor-Stimulated Phagocytosis

SummaryRetinoic acid-inducible gene-I (RIG-I) plays an important role in antiviral response by recognizing double-stranded RNA. Here we demonstrate an unanticipated role of RIG-I in Toll-like receptor (TLR)-stimulated phagocytosis. Stimulation with lipopolysaccharide (LPS), a ligand of TLR4, induced the expression of RIG-I in macrophages. Depletion of RIG-I by RNAi or gene targeting inhibited the LPS-induced phagocytosis of bacteria. Cellular processes involved in phagocytosis, such as small GTPase Cdc42/Rac1 activation, actin polymerization, and actin-regulator Arp2/3 recruitment, were also impaired in RIG-I-deficient macrophages activated by LPS. Moreover, RIG-I−/− mice were found to be more susceptible to infection with Escherichia coli as compared to wild-type mice. Thus, the regulatory functions of RIG-I are strikingly broad, including a role not only in antiviral responses but in antibacterial responses as well

Involvement of Autophagy in Cardiac Remodeling in Transgenic Mice with Cardiac Specific Over-Expression of Human Programmed Cell Death 5

Programmed cell death 5 (PDCD5) is a cytosolic protein suppressing growth of multiple types of cancer cells through activating p53. We hypothesized that PDCD5 plays an essential role in cardiac remodeling and function. PDCD5 was significantly up-regulated in the hearts from mice subjected to angiotensin II treatment or transverse aortic constriction. Thus, we generated transgenic mice over-expressing human PDCD5 under the control of alpha myosin heavy chain promoter to examine the role of PDCD5 in cardiac remodeling. Transgenic founder died spontaneously displayed enlarged heart. The high PDCD5 over-expressing line (10-fold) showed reduced survival rate, increase in heart weight normalized to body weight. Real-Time RT-PCR analysis revealed fetal gene program was up-regulated. Echocardiography and histopathological examination showed characteristics of dilated cardiomyopathy and heart failure in transgenic mice. Western blot and immunohistochemistry analysis showed autophagy was dramatically increased in transgenic mice as compared to WT littermates control mice, while apoptosis remained unchanged. The enhanced autophagy in high over-expressing line was associated with significant increase in p53 activity and its downstream target damage-regulated autophagy modulator expression. The low over-expressing line (3.5-fold) appeared normal, but was more susceptible to angiotensin II-induced cardiac hypertrophy. This study is the first providing evidence that PDCD5 plays an important role in cardiac remodeling

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies

Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility

Synthèse et caractérisation de catalyseurs sans platine pour pile à combustible PEM

The proton exchange membrane fuel cell (PEMFC) is a crucial device for the development of the hydrogen energy economy. A large amount of platinum-based catalyst is required at the cathode to accelerate the oxygen reduction reaction, which limits the commercialization of the fuel cell on a large scale. Today, Fe-N-C material is regarded as a promising non-noble metal catalyst to replace platinum, but its lower activity and material transport with this type of catalyst remain problematic. In this manuscript, a series of Fe-N-C aerogel catalysts were synthesized by pyrolysis of resorcinol-melamine-formaldehyde (RMF) aerogels containing an Fe precursor. The highly porous structure of the aerogel facilitates the transport of material and its synthesis method allows to control its composition. The impacts of the nature of the Fe precursor and the melamine content on the properties of the active centers and the ORR activity of the catalysts have been studied and links between synthesis parameters and electrochemical performances have been established, in RDE as well as in single cell. Concerning the durability, a study of the addition of CeO2 as a peroxide scavenger has also been carried out.La pile à combustible à membrane échangeuse de protons (PEMFC) est un dispositif crucial pour le développement de l'économie basée sur l'hydrogène comme vecteur énergétique. Une grande quantité de catalyseur à base de platine est nécessaire à la cathode pour accélérer la réaction de réduction de l'oxygène, ce qui limite la commercialisation de la pile à combustible à grande échelle. Aujourd'hui, le matériau Fe-N-C est considéré comme un catalyseur prometteur à base de métal non noble pour remplacer le platine, mais son activité plus faible et le transport de matière avec ce type de catalyseur restent problématiques. Dans ce manuscrit, une série de catalyseurs à base d'aérogels de Fe-N-C a été synthétisée par pyrolyse d'aérogels de résorcinol-mélamine-formaldéhyde (RMF) contenant un précurseur de Fe. La structure très poreuse de l'aérogel facilite le transport de matière et sa méthode de synthèse permet de contrôler sa composition. Les impacts de la nature du précurseur de Fe et de la teneur en mélamine sur les propriétés des centres actifs et l'activité ORR des catalyseurs ont été étudiés et des liens entre paramètres de synthèse et performances électrochimiques ont été établi, en RDE comme en monocellule. Concernant la durabilité, une étude de l'ajout de CeO2 comme piégeur de peroxyde a également été menée

Synthèse et caractérisation de catalyseurs sans platine pour pile à combustible PEM

La pile à combustible à membrane échangeuse de protons (PEMFC) est un dispositif crucial pour le développement de l'économie basée sur l'hydrogène comme vecteur énergétique. Une grande quantité de catalyseur à base de platine est nécessaire à la cathode pour accélérer la réaction de réduction de l'oxygène, ce qui limite la commercialisation de la pile à combustible à grande échelle. Aujourd'hui, le matériau Fe-N-C est considéré comme un catalyseur prometteur à base de métal non noble pour remplacer le platine, mais son activité plus faible et le transport de matière avec ce type de catalyseur restent problématiques. Dans ce manuscrit, une série de catalyseurs à base d'aérogels de Fe-N-C a été synthétisée par pyrolyse d'aérogels de résorcinol-mélamine-formaldéhyde (RMF) contenant un précurseur de Fe. La structure très poreuse de l'aérogel facilite le transport de matière et sa méthode de synthèse permet de contrôler sa composition. Les impacts de la nature du précurseur de Fe et de la teneur en mélamine sur les propriétés des centres actifs et l'activité ORR des catalyseurs ont été étudiés et des liens entre paramètres de synthèse et performances électrochimiques ont été établi, en RDE comme en monocellule. Concernant la durabilité, une étude de l'ajout de CeO2 comme piégeur de peroxyde a également été menée.The proton exchange membrane fuel cell (PEMFC) is a crucial device for the development of the hydrogen energy economy. A large amount of platinum-based catalyst is required at the cathode to accelerate the oxygen reduction reaction, which limits the commercialization of the fuel cell on a large scale. Today, Fe-N-C material is regarded as a promising non-noble metal catalyst to replace platinum, but its lower activity and material transport with this type of catalyst remain problematic. In this manuscript, a series of Fe-N-C aerogel catalysts were synthesized by pyrolysis of resorcinol-melamine-formaldehyde (RMF) aerogels containing an Fe precursor. The highly porous structure of the aerogel facilitates the transport of material and its synthesis method allows to control its composition. The impacts of the nature of the Fe precursor and the melamine content on the properties of the active centers and the ORR activity of the catalysts have been studied and links between synthesis parameters and electrochemical performances have been established, in RDE as well as in single cell. Concerning the durability, a study of the addition of CeO2 as a peroxide scavenger has also been carried out