What's Hot, What's Not: The Trends of the Past 20 Years in the Chemistry of Odorants.

This review is the sequel to the 2000 report on the recent advances in the chemistry of odorants and it summarizes the developments in fragrance chemistry over the past 20 years. Following the olfactory spectrum set out in that report, trendsetting so-called captive odorants (patent-protected ingredients unavailable to the market) are presented according to the main odor families: "fruity", "marine", "green", "floral", "spicy", "woody", "amber", and "musky". The design of odorants, their chemical synthesis, and their use in modern perfumery are illustrated with prominent examples. Featured are new fruity odorants that provide signature in the top note, as well as precursor technology. In the green domain, focus is on leafy notes and green pear. New benzodioxepines and benzodioxoles have modernized the marine family and required a revision of the existing olfactophore models. The replacement of Lilial and Lyral kept the industry busy in the floral domain with a plethora of new "muguets". There was continued activity in the domain of rose odorants, especially in the area of rose ketones. Biotechnology became significant, for example, with Clearwood and Ambrofix, and the principal odorants of vetiver oil in the woody family have been found. Fourth and fifth families of musk odorants were also discovered and populated. Thus, new avenues for further explorations into fragrance chemistry have been opened.

Lixisenatide requires a functional gut-vagus nerve-brain axis to trigger insulin secretion in controls and type 2 diabetic mice.

Endogenous glucagon-like peptide-1 (GLP-1) regulates glucose-induced insulin secretion through both direct ß-cell-dependent and indirect gut-brain axis-dependent pathways. However, little is known about the mode of action of the GLP-1 receptor agonist lixisenatide. We studied the effects of lixisenatide (intraperitoneal injection) on insulin secretion, gastric emptying, vagus nerve activity, and brain c-Fos activation in naive, chronically vagotomized, GLP-1 receptor knockout (KO), high-fat diet-fed diabetic mice, or db/db mice. Lixisenatide dose-dependently increased oral glucose-induced insulin secretion that is correlated with a decrease of glycemia. In addition, lixisenatide inhibited gastric emptying. These effects of lixisenatide were abolished in vagotomized mice, characterized by a delay of gastric emptying and in GLP-1 receptor KO mice. Intraperitoneal administration of lixisenatide also increased the vagus nerve firing rate and the number of c-Fos-labeled neurons in the nucleus tractus solitarius (NTS) of the brainstem. In diabetic mouse models, lixisenatide increased the firing rate of the vagus nerve when administrated simultaneously to an intraduodenal glucose. It increased also insulin secretion and c-Fos activation in the NTS. Altogether, our findings show that lixisenatide requires a functional vagus nerve and neuronal gut-brain-islets axis as well as the GLP-1 receptor to regulate glucose-induced insulin secretion in healthy and diabetic mice. NEW & NOTEWORTHY Lixisenatide is an agonist of the glucagon-like protein (GLP)-1 receptor, modified from exendin 4, used to treat type 2 diabetic patients. However, whereas the mode of action of endogenous GLP-1 is extensively studied, the mode of action of the GLP-1 analog lixisenatide is poorly understood. Here, we demonstrated that lixisenatide activates the vagus nerve and recruits the gut-brain axis through the GLP-1 receptor to decrease gastric emptying and stimulate insulin secretion to improve glycemia.

Effect of Fluorination on Skin Sensitization Potential and Fragrant Properties of Cinnamyl Compounds.

A series of three α- and three ß-fluorinated representatives of the family of cinnamate-derived odorants (cinnamaldehyde (1), cinnamyl alcohol (2), and ethyl cinnamate (3)) as used as fragrance ingredients is described. Olfactive evaluation shows that the fluorinated compounds exhibit a similar odor profile to their parent compounds, but the olfactive detection thresholds are clearly higher. In vitro evaluation of the skin sensitizing properties with three different assays indicates that α-fluorination of Michael acceptor systems 1 and 3 slightly improves the skin sensitization profile. α-Fluorocinnamyl alcohol 2b is a weaker skin sensitizer than cinnamyl alcohol 2a by in vitro tests and the fluorinated product drops below the sensitization threshold of the KeratinoSens® assay. On the other hand, ß-fluorination of compounds 1 - 3 results in highly reactive products which display a worsened in vitro skin sensitization profile.

Iodanes as Trifluoromethylation Reagents.

This chapter describes synthesis, structural properties, activation modes, and applications of hypervalent iodine reagents for trifluoromethylation, thereby focusing on recent advances.

Expanding the Scope of Hypervalent Iodine Reagents for Perfluoroalkylation: From Trifluoromethyl to Functionalized Perfluoroethyl.

A series of new hypervalent iodine reagents based on the 1,3-dihydro-3,3-dimethyl-1,2-benziodoxole and 1,2-benziodoxol-3-(1H)-one scaffolds, which contain a functionalized tetrafluoroethyl group, have been prepared, characterized, and used in synthetic applications. Their corresponding electrophilic fluoroalkylation reactions with various sulfur, oxygen, phosphorus, and carbon-centered nucleophiles afford products that feature a tetrafluoroethylene unit, which connects two functional moieties. A related λ(3) -iodane that contains a fluorophore was shown to react with a cysteine derivative under mild conditions to give a thiol-tagged product that is stable in the presence of excess thiol. Therefore, these new reagents show a significant potential for applications in chemical biology as tools for fast, irreversible, and selective thiol bioconjugation.

Gut microbiota dysbiosis of type 2 diabetic mice impairs the intestinal daily rhythms of GLP-1 sensitivity.

The gut-brain-beta cell glucagon-like peptide-1 (GLP-1)-dependent axis and the clock genes both control insulin secretion. Evidence shows that a keystone of this molecular interaction could be the gut microbiota. We analyzed in mice the circadian profile of GLP-1 sensitivity on insulin secretion and the impact of the autonomic neuropathy, antibiotic treated in different diabetic mouse models and in germ-free colonized mice. We show that GLP-1sensitivity is maximal during the dark feeding period, i.e., the postprandial state. Coincidently, the ileum expression of GLP-1 receptor and peripherin is increased and tightly correlated with a subset of clock gene. Since both are markers of enteric neurons, it suggests a role in the gut-brain-beta cell GLP-1-dependent axis. We evaluated the importance of gut microbiota dysbiosis and found that the abundance of ileum bacteria, particularly Ruminococcaceae and Lachnospiraceae, oscillated diurnally, with a maximum during the dark period, along with expression patterns of a subset of clock genes. This diurnal pattern of circadian gene expression and Lachnospiraceae abundance was also observed in two separate mouse models of gut microbiota dysbiosis and of autonomic neuropathy with impaired GLP-1 sensitivity (1.high-fat diet-fed type 2 diabetic, 2.antibiotic-treated/germ-free mice). Our data show that GLP-1 sensitivity relies on specific pattern of intestinal clock gene expression and specific gut bacteria. This new statement opens opportunities to treat diabetic patient with GLP-1-based therapies by using on a possible pre/probiotic co-treatment to improve the time-dependent efficiency of these therapies.

CX3CR1 regulates gut microbiota and metabolism. A risk factor of type 2 diabetes.

OBJECTIVE: The intestinal microbiota to immune system crosstalk is a major regulator of metabolism and hence metabolic diseases. An impairment of the chemokine receptor CX3CR1, as a key regulator shaping intestinal microbiota under normal chow feeding, could be one of the early events of dysglycemia. METHODS: We studied the gut microbiota ecology by sequencing the gut and tissue microbiota. We studied its role in energy metabolism in CX3CR1-deficent and control mice using various bioassays notably the glycemic regulation during fasting and the respiratory quotient as two highly sensitive physiological features. We used antibiotics and prebiotics treatments, and germ free mouse colonization. RESULTS: We identify that CX3CR1 disruption impairs gut microbiota ecology and identified a specific signature associated to the genotype. The glycemic control during fasting and the respiratory quotient throughout the day are deeply impaired. A selected four-week prebiotic treatment modifies the dysbiotic microbiota and improves the fasting state glycemic control of the CX3CR1-deficent mice and following a glucose tolerance test. A 4 week antibiotic treatment also improves the glycemic control as well. Eventually, germ free mice colonized with the microbiota from CX3CR1-deficent mice developed glucose intolerance. CONCLUSIONS: CX3CR1 is a molecular mechanism in the control of the gut microbiota ecology ensuring the maintenance of a steady glycemia and energy metabolism. Its impairment could be an early mechanism leading to gut microbiota dysbiosis and the onset of metabolic disease.

Liraglutide targets the gut microbiota and the intestinal immune system to regulate insulin secretion.

AIMS: Liraglutide controls type 2 diabetes (T2D) and inflammation. Gut microbiota regulates the immune system and causes at least in part type 2 diabetes. We here evaluated whether liraglutide regulates T2D through both gut microbiota and immunity in dysmetabolic mice. METHODS: Diet-induced dysmetabolic mice were treated for 14 days with intraperitoneal injection of liraglutide (100 µg/kg) or with vehicle or Exendin 4 (10 µg/kg) as controls. Various metabolic parameters, the intestinal immune cells were characterized and the 16SrDNA gene sequenced from the gut. The causal role of gut microbiota was shown using large spectrum antibiotics and by colonization of germ-free mice with the gut microbiota from treated mice. RESULTS: Besides, the expected metabolic impacts liraglutide treatment induced a specific gut microbiota specific signature when compared to vehicle or Ex4-treated mice. However, liraglutide only increased glucose-induced insulin secretion, reduced the frequency of Th1 lymphocytes, and increased that of TReg in the intestine. These effects were abolished by a concomitant antibiotic treatment. Colonization of germ-free mice with gut microbiota from liraglutide-treated diabetic mice improved glucose-induced insulin secretion and regulated the intestinal immune system differently from what observed in germ-free mice colonized with microbiota from non-treated diabetic mice. CONCLUSIONS: Altogether, our result demonstrated first the influence of liraglutide on gut microbiota and the intestinal immune system which could at least in part control glucose-induced insulin secretion.

SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations.

Insulin resistance is a key event in type 2 diabetes onset and a major comorbidity of obesity. It results from a combination of fat excess-triggered defects, including lipotoxicity and metaflammation, but the causal mechanisms remain difficult to identify. Here, we report that hyperactivation of the tyrosine phosphatase SHP2 found in Noonan syndrome (NS) led to an unsuspected insulin resistance profile uncoupled from altered lipid management (for example, obesity or ectopic lipid deposits) in both patients and mice. Functional exploration of an NS mouse model revealed this insulin resistance phenotype correlated with constitutive inflammation of tissues involved in the regulation of glucose metabolism. Bone marrow transplantation and macrophage depletion improved glucose homeostasis and decreased metaflammation in the mice, highlighting a key role of macrophages. In-depth analysis of bone marrow-derived macrophages in vitro and liver macrophages showed that hyperactive SHP2 promoted a proinflammatory phenotype, modified resident macrophage homeostasis, and triggered monocyte infiltration. Consistent with a role of SHP2 in promoting inflammation-driven insulin resistance, pharmaceutical SHP2 inhibition in obese diabetic mice improved insulin sensitivity even better than conventional antidiabetic molecules by specifically reducing metaflammation and alleviating macrophage activation. Together, these results reveal that SHP2 hyperactivation leads to inflammation-triggered metabolic impairments and highlight the therapeutical potential of SHP2 inhibition to ameliorate insulin resistance.

A 3-week nonalcoholic steatohepatitis mouse model shows elafibranor benefits on hepatic inflammation and cell death.

The long duration of animal models represents a clear limitation to quickly evaluate the efficacy of drugs targeting nonalcoholic steatohepatitis (NASH). We, therefore, developed a rapid mouse model of liver inflammation (i.e., the mouse fed a high-fat/high-cholesterol diet, where cyclodextrin is co-administered to favor hepatic cholesterol loading, liver inflammation, and NASH within 3 weeks), and evaluated the effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist elafibranor (ELA). C57BL6/J mice were fed a 60% high-fat, 1.25% cholesterol, and 0.5% cholic acid diet with 2% cyclodextrin in drinking water (HFCC/CDX diet) for 3 weeks. After 1 week of the diet, mice were treated orally with vehicle or ELA 20 mg/kg q.d. for 2 weeks. Compared with vehicle, ELA markedly reduced liver lipids and nonalcoholic fatty liver disease activity scoring, through steatosis, inflammation, and fibrosis (all P < 0.01 vs. vehicle). Flow cytometry analysis showed that ELA significantly improved the HFCC/CDX diet-induced liver inflammation by preventing the increase in total number of immune cells (CD45+), Kupffer cells, dendritic cells, and monocytes population, as well as the reduction in natural killer and natural killer T cells, and by blocking conversion of T cells in regulatory T cells. ELA did not alter pyroptosis (Gasdermin D), but significantly reduced necroptosis (cleaved RIP3) and apoptosis (cleaved caspase 3) in the liver. In conclusion, ELA showed strong benefits on NASH, including improvement in hepatic inflammation, necroptosis, and apoptosis in the 3-week NASH mouse. This preclinical model will be useful to rapidly detect the effects of novel drugs targeting NASH.

Substituent-controlled, mild oxidative fluorination of iodoarenes: synthesis and structural study of aryl I(iii)- and I(v)-fluorides.

We report a mild approach to the synthesis of difluoro(aryl)-λ3-iodanes (aryl-IF2 compounds) and tetrafluoro(aryl)-λ5-iodanes (aryl-IF4 compounds) using trichloroisocyanuric acid (TCICA) and potassium fluoride (KF). Under these reaction conditions, selective access to either the I(iii)- or I(v)-derivatives is predictable based solely on the substitution pattern of the iodoarene starting material. Moreover, the discovery of this TCICA/KF approach prompted detailed dynamic NMR, kinetic, computational, and crystallographic studies on the relationship between the IF2 group and the ortho-substituents on carefully designed probe molecules. It was during these experiments that the role of the ortho-substituent in inhibiting further oxidative fluorination of I(iii)-compounds to I(v)-compounds during the reaction with TCICA and KF was revealed. Additionally, a notable exception to this empirical trend is discussed herein.

Publisher Correction: Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.

In the version of this article originally published, the received date was missing. It should have been listed as 2 January 2018. The error has been corrected in the HTML and PDF versions of this article.

Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.

Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.

A Specific Gut Microbiota Dysbiosis of Type 2 Diabetic Mice Induces GLP-1 Resistance through an Enteric NO-Dependent and Gut-Brain Axis Mechanism.

Glucagon-like peptide-1 (GLP-1)-based therapies control glycemia in type 2 diabetic (T2D) patients. However, in some patients the treatment must be discontinued, defining a state of GLP-1 resistance. In animal models we identified a specific set of ileum bacteria impairing the GLP-1-activated gut-brain axis for the control of insulin secretion and gastric emptying. Using prediction algorithms, we identified bacterial pathways related to amino acid metabolism and transport system modules associated to GLP-1 resistance. The conventionalization of germ-free mice demonstrated their role in enteric neuron biology and the gut-brain-periphery axis. Altogether, insulin secretion and gastric emptying require functional GLP-1 receptor and neuronal nitric oxide synthase in the enteric nervous system within a eubiotic gut microbiota environment. Our data open a novel route to improve GLP-1-based therapies.

Ultrasonographic, endoscopic and histological appearance of the caecum in clinically healthy cats.

Objectives The aim of the study was to describe the ultrasonographic and endoscopic appearance and characteristics of the caecum in asymptomatic cats, and to correlate these findings with histology. Methods Ex vivo ultrasonographic and histologic evaluations of a fresh caecum were initially performed. Then, 20 asymptomatic cats, privately owned or originating from a reproductive colony, were recruited. All cats had an ultrasonographic examination of the ileocaecocolic junction, where the thickness of the caecal wall, ileocolic lymph nodes and the echogenicity of the local fat were assessed. They all underwent a colonoscopy with a macroscopic assessment of the mucosa and biopsies for histology. Results An ultrasonographic hypoechoic nodular inner layer, which corresponded to the coalescence of multiple lymphoid follicles originating from the submucosa and protruding in the mucosa on histology, was visible in all parts of the caecum. The combined mucosa and submucosa was measured ultrasonographically and defined as the follicular layer. Although all cats were asymptomatic, 3/19 cats showed mild caecal inflammation on histology. The most discriminatory ultrasonographic parameter in assessing this subclinical inflammation was the thickness of the follicular layer at the entrance of the caecum, with a cut-off value of 2.0 mm. All cats (20/20) showed some degree of macroscopic 'dimpling' of the caecal mucosa on endoscopy. Conclusions and relevance Lymphoid follicles in the caecal mucosa and submucosa constitute a unique follicular layer on ultrasound. In asymptomatic cats, a subtle, non-clinically relevant inflammation may exist and this is correlated with an increased thickness of the follicular layer on ultrasound. On endoscopy, a 'dimpled aspect' to the caecal mucosa is a normal finding in the asymptomatic cat.

Ultrasonographic, endoscopic and histological appearances of the caecum in cats presenting with chronic clinical signs of caecocolic disease.

Objectives This study aimed to describe the ultrasonographic, endoscopic and histological characteristics of the caecum and ileocaecocolic junction in cats suffering from chronic clinical signs compatible with caecocolic disease. Methods Cats presenting with clinical signs suggestive of a caecocolic disease were prospectively recruited. All cats underwent an ultrasonographic examination of the caecum, ileum, colon, ileocolic lymph nodes and local mesenteric fat, in addition to comprehensive abdominal ultrasonography. This was followed by a colonoscopy with a macroscopic assessment of the caecocolic mucosa; caecocolic tissue samples were systematically collected for histologic analysis. Results Eighteen cats were included. Eleven of 18 cats had ultrasonographic abnormalities adjacent to the ileocaecocolic junction (lymphadenopathy, local steatitis) and 13/18 cats had abnormalities directly related to the junction (wall thickening, loss of wall layering). Seventeen of 18 cats had at least one ultrasonographic abnormality. Endoscopically, hyperaemia, oedema, discoloration and/or erosions were found in all cats. Each cat was classified as having mild or moderate-to-severe lesions according to endoscopic results; no classification could be established statistically for ultrasonographic results. The accentuation of the dimpled pattern tended to be inversely related to the severity of endoscopic lesion scoring. Histologically, a large proportion of cats showed typhlitis (13/16), one had lymphoma and two were normal. All cats with typhlitis also had colitis. There was only slight agreement between endoscopic and histological caecal results regarding the severity of lesions. Loss of caecal wall layering on ultrasound was found in 7/18 cats and, surprisingly, did not appear as a reliable predictor of the severity of inflammation or of malignancy; neither did local steatitis nor lymph node size. Conclusions and relevance Ultrasonography and endoscopy should not be used as the sole methods to investigate the ileocaecocolic region in cats with clinical signs suggestive of caecocolic disease. The presence of chronic clinical signs should routinely prompt histological biopsy.

Tandem Radical Fluoroalkylation-Cyclization: Synthesis of Tetrafluoro Imidazopyridines.

A copper-catalyzed fluoroalkylation-cyclization sequence of alkenes and alkynes enables the synthesis of fluorinated tetra- and dihydroimidazopyridines in moderate to excellent yields within 1 h at 70 °C. This reaction, which is carried out using copper(I) acetate as the catalyst, makes use of a new class of functionalized tetrafluoroethyl reagents based on a hypervalent iodine scaffold.

The Gut Microbiota Regulates Intestinal CD4 T Cells Expressing RORγt and Controls Metabolic Disease.

A high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease.