The Different Facets of Triclocarban: A Review

In the late 1930s and early 1940s, it was discovered that the substitution on aromatic rings of hydrogen atoms with chlorine yielded a novel chemistry of antimicrobials. However, within a few years, many of these compounds and formulations showed adverse effects, including human toxicity, ecotoxicity, and unwanted environmental persistence and bioaccumulation, quickly leading to regulatory bans and phase-outs. Among these, the triclocarban, a polychlorinated aromatic antimicrobial agent, was employed as a major ingredient of toys, clothing, food packaging materials, food industry floors, medical supplies, and especially of personal care products, such as soaps, toothpaste, and shampoo. Triclocarban has been widely used for over 50 years, but only recently some concerns were raised about its endocrine disruptive properties. In September 2016, the U.S. Food and Drug Administration banned its use in over-the-counter hand and body washes because of its toxicity. The withdrawal of triclocarban has prompted the efforts to search for new antimicrobial compounds and several analogues of triclocarban have also been studied. In this review, an examination of different facets of triclocarban and its analogues will be analyzed.     

Ca2+ Regulates ERp57-Calnexin Complex Formation

ERp57, a member of the protein disulfide isomerase family, is a ubiquitous disulfide catalyst that functions in the oxidative folding of various clients in the mammalian endoplasmic reticulum (ER). In concert with ER lectin-like chaperones calnexin and calreticulin (CNX/CRT), ERp57 functions in virtually all folding stages from co-translation to post-translation, and thus plays a critical role in maintaining protein homeostasis, with direct implication for pathology. Here, we present mechanisms by which Ca²⁺ regulates the formation of the ERp57-calnexin complex. Biochemical and isothermal titration calorimetry analyses revealed that ERp57 strongly interacts with CNX via a non-covalent bond in the absence of Ca²⁺. The ERp57-CNX complex not only promoted the oxidative folding of human leukocyte antigen heavy chains, but also inhibited client aggregation. These results suggest that this complex performs both enzymatic and chaperoning functions under abnormal physiological conditions, such as Ca²⁺ depletion, to effectively guide proper oxidative protein folding. The findings shed light on the molecular mechanisms underpinning crosstalk between the chaperone network and Ca²⁺.     

AdipoRon,an Orally Active,Synthetic Agonist of AdipoR1 and AdipoR2 Receptors Has Gastroprotective Effect in Experimentally Induced Gastric Ulcers in Mice

Introduction: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism. Methods: We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg/kg p.o.) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1β, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue. Results: AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1β expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity. Conclusions: Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers.     

Multiple-Molecule Drug Design Based on Systems Biology Approaches and Deep Neural Network to Mitigate Human Skin Aging

Human skin aging is affected by various biological signaling pathways, microenvironment factors and epigenetic regulations. With the increasing demand for cosmetics and pharmaceuticals to prevent or reverse skin aging year by year, designing multiple-molecule drugs for mitigating skin aging is indispensable. In this study, we developed strategies for systems medicine design based on systems biology methods and deep neural networks. We constructed the candidate genomewide genetic and epigenetic network (GWGEN) via big database mining. After doing systems modeling and applying system identification, system order detection and principle network projection methods with real time-profile microarray data, we could obtain core signaling pathways and identify essential biomarkers based on the skin aging molecular progression mechanisms. Afterwards, we trained a deep neural network of drug–target interaction in advance and applied it to predict the potential candidate drugs based on our identified biomarkers. To narrow down the candidate drugs, we designed two filters considering drug regulation ability and drug sensitivity. With the proposed systems medicine design procedure, we not only shed the light on the skin aging molecular progression mechanisms but also suggested two multiple-molecule drugs for mitigating human skin aging from young adulthood to middle age and middle age to old age, respectively.     

PEP-1-GLRX1 Reduces Dopaminergic Neuronal Cell Loss by Modulating MAPK and Apoptosis Signaling in Parkinson’s Disease

Parkinson’s disease (PD) is characterized mainly by the loss of dopaminergic neurons in the substantia nigra (SN) mediated via oxidative stress. Although glutaredoxin-1 (GLRX1) is known as one of the antioxidants involved in cell survival, the effects of GLRX1 on PD are still unclear. In this study, we investigated whether cell-permeable PEP-1-GLRX1 inhibits dopaminergic neuronal cell death induced by 1-methyl-4-phenylpyridinium (MPP⁺) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We showed that PEP-1-GLRX1 protects cell death and DNA damage in MPP⁺-exposed SH-SY5Y cells via the inhibition of MAPK, Akt, and NF-κB activation and the regulation of apoptosis-related protein expression. Furthermore, we found that PEP-1-GLRX1 was delivered to the SN via the blood–brain barrier (BBB) and reduced the loss of dopaminergic neurons in the MPTP-induced PD model. These results indicate that PEP-1-GLRX1 markedly inhibited the loss of dopaminergic neurons in MPP⁺- and MPTP-induced cytotoxicity, suggesting that this fusion protein may represent a novel therapeutic agent against PD.     

Early Oxidative Transformations During the Biosynthesis of Terrein and Related Natural Products

The mycotoxin terrein is derived from the C₁₀-precursor 6-hydroxymellein (6-HM) via an oxidative ring contraction. Although the corresponding biosynthetic gene cluster (BGC) has been identified, details of the enzymatic oxidative transformations are lacking. Combining heterologous expression and in vitro studies we show that the flavin-dependent monooxygenase (FMO) TerC catalyzes the initial oxidative decarboxylation of 6-HM. The reactive intermediate is further hydroxylated by the second FMO TerD to yield a highly oxygenated aromatic species, but further reconstitution of the pathway was hampered. A related BGC was identified in the marine-derived Roussoella sp. DLM33 and confirmed by heterologous expression. These studies demonstrate that the biosynthetic pathways of terrein and related (polychlorinated) congeners diverge after oxidative decarboxylation of the lactone precursor that is catalyzed by a conserved FMO and further indicate that early dehydration of the side chain is an essential step.     

5-Hydroxymethyl-, 5-Formyl- and 5-Carboxydeoxycytidines as Oxidative Lesions and Epigenetic Marks

The four non-canonical nucleotides in the human genome 5-methyl-, 5-hydroxymethyl-, 5-formyl- and 5-carboxydeoxycytidine (mdC, hmdC, fdC and cadC) form a second layer of epigenetic information that contributes to the regulation of gene expression. Formation of the oxidized nucleotides hmdC, fdC and cadC requires oxidation of mdC by ten-eleven translocation (Tet) enzymes that require oxygen, Fe(II) and α-ketoglutarate as cosubstrates. Although these oxidized forms of mdC are widespread in mammalian genomes, experimental evidence for their presence in fungi and plants is ambiguous. This vagueness is caused by the fact that these oxidized mdC derivatives are also formed as oxidative lesions, resulting in unclear basal levels that are likely to have no epigenetic function. Here, we report the xdC levels in the fungus Amanita muscaria in comparison to murine embryonic stem cells (mESCs), HEK cells and induced pluripotent stem cells (iPSCs), to obtain information about the basal levels of hmdC, fdC and cadC as DNA lesions in the genome.     

Nitrogen‐doped mesoporous carbon materials for oxidative dehydrogenation of propane

The CN‐15‐x series materials with different doses of SBA‐15 template and the CN‐y‐2.0 series materials with different hard templates were prepared by the hard template method with hexamethylenetetramine as the carbon and nitrogen source. The obtained mesoporous carbon materials were characterized by X‐ray diffraction (XRD), N₂ adsorption–desorption, transmission electron microscopy (TEM), Raman spectroscopy, and X‐ray photoelectron spectroscopy (XPS). The catalytic performance of propane oxidative dehydrogenation was determined. The characterization results indicate that the catalytic activity of CN‐15‐2.0 with a bipartite hexagonal ordered structure was higher than those of the other materials. The conversion of propane was 22.98%, and the selectivity toward propylene was 41.70%.     

Structure evolution mechanism of poly(acrylonitrile/itaconic acid/acrylamide) during thermal oxidative stabilization process

Polyacrylonitrile (PAN) polymers with different compositions were prepared by an efficient aqueous free-radical polymerization technique.Thermal properties of polyacrylonitrile homopolymer (PAN),poly(acrylonitrile/itaconic acid) [P(AN/IA)] and poly(acrylonitrile/itaconic acid/acrylamide) [P(AN/IA/AM)] were studied by Fourier transform infrared spectroscopy,X-ray diffraction,differential scanning calorimetry and thermogravimetry in detail.It was found that AM had the ability to initiate and accelerate thermal oxidative stabilization process,which was confirmed by the lower initiation temperature and broader exothermic peak in P(AN/IA/AM) as compared with that in P(AN/IA) and PAN.The intensity of heat releasing during the thermal treatment was relaxed due to the presence of two separated exothermic peaks.Accompanied by DSC analysis and calculation of the apparent activation energy of cyclization reaction,two peaks were assigned to the ionic and free radical induction mechanisms,respectively.The higher rate constant in P(AN/IA/AM) indicated that the ionic mechanism actually had a kinetic advantage at promoting thermal stability over the free radical mechanism.This study clearly show that the synthesized P(AN/IA/AM) terpolymers possess larger room to adjust manufacture parameters to fabricate high performance of PAN-based carbon fibers.     

Characterization and oxidative addition reactions for iridium cod complexes

Three different [Ir(LL′)(cod)] complexes (LL′ = N-aryl-N-nitrosohydroxylaminato) (cupf), trifluoroacetylacetonato (tfaa), and (methyl 2-(methylamino)-1-cyclopentene-1-dithiocarboxylato-κN,κS) (macsm)) were synthesized, characterized, and their rates of oxidative addition with methyl iodide were determined. Formation of an isosbestic point during the oxidative addition of methyl iodide with the complexes containing tfaa and cupf as bidentate ligands indicated formation of only one product, while an increase in absorbance maximum observed for macsm confirms that the same reaction between the complex and methyl iodide occurs. Kinetic results for all complexes, except [Ir(tfaa)(cod)], showed simple second-order kinetics with a zero intercept (within experimental error). Rates of oxidative addition for bidentate ligands in acetonitrile showed an increase of an order of magnitude with a change in the type of bidentate ligands. Computational chemistry using density functional theory calculations showed that the oxidative addition reaction proceeds through a “linear” transition state with the methyl iodide unit tilted towards the LL′-bidentate ligand.