A simulated natural heatwave perturbs bumblebee immunity and resistance to infection.

As a consequence of ongoing climate change, heatwaves are predicted to increase in frequency, intensity, and duration in many regions. Such extreme events can shift organisms from thermal optima for physiology and behaviour, with the thermal stress hypothesis predicting reduced performance at temperatures where the maintenance of biological functions is energetically costly. Performance includes the ability to resist biotic stressors, including infectious diseases, with increased exposure to extreme temperatures having the potential to synergise with parasite infection. Climate change is a proposed threat to native bee pollinators, directly and through indirect effects on floral resources, but the thermal stress hypothesis, particularly pertaining to infectious disease resistance, has received limited attention. We exposed adult Bombus impatiens bumblebee workers to simulated, ecologically relevant heatwave or control thermal regimes and assessed longevity, immunity, and resistance to concurrent or future parasite infections. We demonstrate that survival and induced antibacterial immunity are reduced following heatwaves. Supporting that heatwave exposure compromised immunity, the cost of immune activation was thermal regime dependent, with survival costs in control but not heatwave exposed bees. However, in the face of real infections, an inability to mount an optimal immune response will be detrimental, which was reflected by increased trypanosomatid parasite infections following heatwave exposure. These results demonstrate interactions between heatwave exposure and bumblebee performance, including immune and infection outcomes. Thus, the health of bumblebee pollinator populations may be affected through altered interactions with parasites and pathogens, in addition to other effects of extreme manifestations of climate change.

Glycine: The Smallest Anti-Inflammatory Micronutrient.

Glycine is a non-essential amino acid with many functions and effects. Glycine can bind to specific receptors and transporters that are expressed in many types of cells throughout an organism to exert its effects. There have been many studies focused on the anti-inflammatory effects of glycine, including its abilities to decrease pro-inflammatory cytokines and the concentration of free fatty acids, to improve the insulin response, and to mediate other changes. However, the mechanism through which glycine acts is not clear. In this review, we emphasize that glycine exerts its anti-inflammatory effects throughout the modulation of the expression of nuclear factor kappa B (NF-κB) in many cells. Although glycine is a non-essential amino acid, we highlight how dietary glycine supplementation is important in avoiding the development of chronic inflammation.

Whole Blood Expression Levels of Long Noncoding RNAs: HOTAIRM1, GAS5, MZF1-AS1, and OIP5-AS1 as Biomarkers in Adolescents with Obesity-Related Asthma.

Asthma is a heterogeneous entity encompassing distinct endotypes and varying phenotypes, characterized by common clinical manifestations, such as shortness of breath, wheezing, and variable airflow obstruction. Two major asthma endotypes based on molecular patterns are described: type 2 endotype (allergic-asthma) and T2 low endotype (obesity-related asthma). Long noncoding RNAs (lncRNAs) are transcripts of more than 200 nucleotides in length, currently involved in many diverse biological functions, such as chromatin remodeling, gene transcription, protein transport, and microRNA processing. Despite the efforts to accurately classify and discriminate all the asthma endotypes and phenotypes, if long noncoding RNAs could play a role as biomarkers in allergic asthmatic and adolescent obesity-related asthma, adolescents remain unknown. To compare expression levels of lncRNAs: HOTAIRM1, OIP5-AS1, MZF1-AS1, and GAS5 from whole blood of Healthy Adolescents (HA), Obese adolescents (O), allergic asthmatic adolescents (AA) and Obesity-related asthma adolescents (OA). We measured and compared expression levels from the whole blood of the groups mentioned above through RT-q-PCR. We found differentially expressed levels of these lncRNAs between the groups of interest. In addition, we found a discriminative value of previously mentioned lncRNAs between studied groups. Finally, we generated an interaction network through bioinformatics. Expression levels of OIP5-AS1, MZF1-AS1, HOTAIRM1, and GAS5 in whole blood from the healthy adolescent population, obese adolescents, allergic asthma adolescents, and obesity-related asthma adolescents are differently expressed. Moreover, these lncRNAs could act as molecular biomarkers that help to discriminate between all studied groups, probably through molecular mechanisms with several genes and miRNAs implicated.

Investigating the influence of diet diversity on infection outcomes in a bumble bee (Bombus impatiens) and microsporidian (Nosema bombi) host-pathogen system.

Diet can have an array of both direct and indirect effects on an organism's health and fitness, which can influence the outcomes of host-pathogen interactions. Land use changes, which could impact diet quantity and quality, have imposed foraging stress on important natural and agricultural pollinators. Diet related stress could exacerbate existing negative impacts of pathogen infection. Accounting for most of its nutritional intake in terms of protein and many micronutrients, pollen can influence bee health through changes in immunity, infection, and various aspects of individual and colony fitness. We investigate how adult pollen consumption, pollen type, and pollen diversity influence bumble bee Bombus impatiens survival and infection outcomes for a microsporidian pathogen Nosema (Vairimorpha) bombi. Experimental pathogen exposures of larvae occurred in microcolonies and newly emerged adult workers were given one of three predominantly monofloral, polyfloral, or no pollen diets. Workers were assessed for size, pollen consumption, infection 8-days following adult-eclosion, survival, and the presence of extracellular microsporidian spores at death. Pollen diet treatment, specifically absence of pollen, and infection independently reduced survival, but we saw no effects of pollen, pollen type, or pollen diet diversity on infection outcomes. The latter suggests infection outcomes were likely already set, prior to differential diets. Although infection outcomes were not altered by pollen diet in our study, it highlights both pathogen infection and pollen availability as important for bumble bee health, and these factors may interact at different stages of bumble bee development, at the colony level, or under different dietary regimes.

Promoter methylation status of RORC, IL17A, and TNFA in peripheral blood leukocytes in adolescents with obesity-related asthma.

A higher Th17-immune response characterises obesity and obesity-related asthma phenotype. Nevertheless, obesity-related asthma has a more significant Th17-immune response than obesity alone. Retinoid-related orphan receptor C (RORC) is the essential transcription factor for Th17 polarisation. Previous studies have found that adolescents with obesity-related asthma presented upregulation of RORC, IL17A, and TNFA. However, the mechanisms that cause these higher mRNA expression levels in this asthmatic phenotype are poorly understood. Methylation directly regulates gene expression by adding a methyl group to carbon 5 of dinucleotide CpG cytosine. Thus, we evaluated the relationship between RORC, IL17A, and TNFA methylation status and mRNA expression levels to investigate a possible epigenetic regulation. A total of 102 adolescents (11-18 years) were studied in the following four groups: 1) healthy participants (HP), 2) allergic asthmatic participants (AAP), 3) obese participants without asthma (OP), and 4) non-allergic obesity-related asthma participants (OAP). Real-time qPCR assessed the methylation status and gene expression levels in peripheral blood leukocytes. Remarkably, the OAP and AAP groups have lower promoter methylation patterns of RORC, IL17A, and TNFA than the HP group. Notably, the OAP group presents lower RORC promoter methylation status than the OP group. Interestingly, RORC promoter methylation status was moderately negatively associated with gene expression of RORC (r s = -0.39, p < 0.001) and IL17A (r s = -0.37, p < 0.01), respectively. Similarly, the promoter methylation pattern of IL17A was moderately negatively correlated with IL17A gene expression (r s = -0.3, p < 0.01). There is also a moderate inverse relationship between TNFA promoter methylation status and TNFA gene expression (r s = -0.3, p < 0.01). The present study suggests an association between lower RORC, IL17A, and TNFA gene promoter methylation status with obesity-related asthma and allergic asthma. RORC, IL17A, and TNFA gene promoter methylation patterns are moderately inversely correlated with their respective mRNA expression levels. Therefore, DNA methylation may regulate RORC, IL17A, and TNF gene expression in both asthmatic phenotypes.

Synthesis, molecular docking, dynamic simulation and pharmacological characterization of potent multifunctional agent (dual GPR40-PPARγ agonist) for the treatment of experimental type 2 diabetes.

The current manuscript describes two molecules that were designed against PPARγ and GPR40 receptors. The preparation of the compounds was carried out following a synthetic route of multiple steps. Then, the mRNA expression levels of PPARγ, GLUT4, and GPR40 induced by compounds were measured and quantified in adipocyte and ß-pancreatic cell cultures. The synthesized compound 1 caused an increase in the 4-fold expression of mRNA of PPARγ regarding the control and had a similar behavior to the pioglitazone, while compound 2 only increased 2-fold the expression. Also, the compound 1 increased to 7-fold the GLUT4 expression levels, respect to the control and twice against the pioglitazone. On the other hand, the 1 increase 3-fold GPR40 expression, and compound 2 had a minor activity. Besides, 1 and 2 showed a moderated increase on insulin secretion and calcium mobilization versus the glibenclamide. Based on the molecular docking studies, the first compound had a similar conformation to co-crystal ligands into the binding site of both receptors. The poses were docked keeping the most important interactions and maintaining the interaction along the Molecular Dynamics simulation (20 ns). Finally, compound (1) showed an antihyperglycemic effect at 5 mg/kg, however at higher doses of 25 mg/kg it controlled blood glucose levels associated with feeding intake and without showing the adverse effects associated with insulin secretagogues (hypoglycemia). For these reasons, we have concluded that molecule 1 acts as a dual PPARγ and GPR40 agonist offering a better glycemic control than current treatments.

High fructose exposure modifies the amount of adipocyte-secreted microRNAs into extracellular vesicles in supernatants and plasma.

BACKGROUND: High fructose exposure induces metabolic and endocrine responses in adipose tissue. Recent evidence suggests that microRNAs in extracellular vesicles are endocrine signals secreted by adipocytes. Fructose exposure on the secretion of microRNA by tissues and cells is poorly studied. Thus, the aim of this study was to evaluate the effect of fructose exposure on the secretion of selected microRNAs in extracellular vesicles from 3T3-L1 cells and plasma from Wistar rats. METHODS: 3T3-L1 cells were exposed to 550 µM of fructose or standard media for four days, microRNAs levels were determined in extracellular vesicles of supernatants and cells by RT-qPCR. Wistar rats were exposed to either 20% fructose drink or tap water for eight weeks, microRNAs levels were determined in extracellular vesicles of plasma and adipose tissue by RT-qPCR. RESULTS: This study showed that fructose exposure increased the total number of extracellular vesicles released by 3T3-L1 cells (p = 0.0001). The levels of miR-143-5p were increased in extracellular vesicles of 3T3-L1 cells exposed to fructose (p = 0.0286), whereas miR-223-3p levels were reduced (p = 0.0286). Moreover, in plasma-derived extracellular vesicles, miR-143-5p was higher in fructose-fed rats (p = 0.001), whereas miR-223-3p (p = 0.022), miR-342-3p (p = 0.0011), miR-140-5p (p = 0.0129) and miR-146b-5p (p = 0.0245) were lower. CONCLUSION: Fructose exposure modifies the levels of microRNAs in extracellular vesicles in vitro and in vivo. In particular, fructose exposure increases miR-143-5p, while decreases miR-223-3p and miR-342-3p.

Glycine is a competitive antagonist of the TNF receptor mediating the expression of inflammatory cytokines in 3T3-L1 adipocytes.

OBJECTIVE: To determine the involvement of TNF-α and glycine receptors in the inhibition of pro-inflammatory adipokines in 3T3-L1 cells. METHODS: RT-PCR evidenced glycine receptors in 3T3-L1 adipocytes. 3T3-L1 cells were transfected with siRNA for the glycine (Glrb) and TNF1a (Tnfrsf1a) receptors and confirmed by confocal microscopy. Transfected cells were treated with glycine (10 mM). The expressions of TNF-α and IL-6 mRNA were measured by qRT-PCR, while concentrations were quantified by ELISA. RESULTS: Glycine decreased the expression and concentration of TNF-α and IL-6; this effect did not occur in the absence of TNF-α receptor due to siRNA. In contrast, glycine produced only slight changes in the expression of TNF-α and IL-6 in the absence of the glycine receptor due to siRNA. A docking analysis confirmed the possibility of binding glycine to the TNF-α1a receptor. CONCLUSION: These findings support the idea that glycine could partially inhibit the binding of TNF-α to its receptor and provide clues about the mechanisms by which glycine inhibits the secretion of pro-inflammatory adipokines in adipocytes through the TNF-α receptor.

Associations of TNFA, IL17A, and RORC mRNA expression levels in peripheral blood leukocytes with obesity-related asthma in adolescents.

Obesity is associated with a unique non-T2 asthma phenotype, characterised by a Th17 immune response. Retinoid-related orphan receptor C (RORC) is the master transcription factor for Th17 polarisation. We investigated the association of TNFA, IL17A, and RORC mRNA expression levels with the non-T2 phenotype. We conducted a cross-sectional study in adolescents, subdivided as follows: healthy (HA), allergic asthma without obesity (AA), obesity without asthma (OB), and non-allergic asthma with obesity (NAO). TNFA, IL17A, and RORC mRNA expression in peripheral blood leukocytes were assessed by RT-PCR. NAO exhibited higher TNFA mRNA expression levels than HA or OB, as well as the highest IL17A and RORC mRNA expression levels among the four groups. The best biomarker for discriminating non-allergic asthma among obese adolescents was RORC mRNA expression levels (area under the curve: 0.95). RORC mRNA expression levels were associated with the non-T2 asthma phenotype, hinting at a therapeutic target in obesity-related asthma.

α-Amyrin induces GLUT4 translocation mediated by AMPK and PPARδ/γ in C2C12 myoblasts.

α-Amyrin, a natural pentacyclic triterpene, has an antihyperglycemic effect in mice and dual PPARδ/γ action in 3T3-L1 adipocytes, and potential in the control of type 2 diabetes (T2D). About 80% of glucose uptake occurs in skeletal muscle cells, playing a significant role in insulin resistance (IR) and T2D. Peroxisome-proliferator activated receptors (PPARs), in particular PPARδ and PPARγ, are involved in the regulation of lipids and carbohydrates and, along with adenosine-monophosphate (AMP) - activated protein kinase (AMPK) and protein kinase B (Akt), are implicated in translocation of glucose transporter 4 (GLUT4); however, it is still unknown whether α-amyrin can affect these pathways in skeletal muscle cells. Our objective was to determine the action of α-amyrin in PPARδ, PPARγ, AMPK, and Akt in C2C12 myoblasts. The expression of PPARδ, PPARγ, fatty acid transporter protein (FATP), and GLUT4 was quantified using reverse transcription quantitative PCR and Western blot. α-Amyrin increased these markers along with phospho-AMPK (p-AMPK) but not p-Akt. Molecular docking showed that α-amyrin acts as an AMPK-allosteric activator, and may be related to GLUT4 translocation, as evidenced by confocal microscopy. These data support that α-amyrin could have an insulin-mimetic action in C2C12 myoblasts and should be considered as a bioactive molecule for new multitarget drugs with utility in T2D and other metabolic diseases.

Ahorro en los hogares de México: ¿importa el lugar de residencia? / Saving Profiles in Mexican Households. Does the Place of Residence Matter? / Poupança em famílias no México: o local de residência é importante?

En este artículo se analiza el perfil de ahorro de los hogares rurales y urbanos en México. A partir de la Encuesta Nacional de Ingresos y Gastos de los Hogares de 1994 a 2014 se construye un panel sintético y se estima un modelo semiparamétrico que permite identificar los perfiles por edades. Los resultados contrastan con la hipótesis del ciclo de vida, el perfil por edades no muestra una forma de U invertida, hay evidencia de mayor ahorro en las edades avanzadas. Los perfiles de ahorro son mayores en los hogares urbanos, en particular en aquellos con personas mayores y acceso a la salud.

This paper analyzes the saving profile of rural and urban Mexican households. Based on the National Survey of Household Income and Expenditure from 1994 to 2014, a synthetic panel is constructed and a semi-parametric model is estimated to identify profiles by age. Results show a contrast with the life cycle hypothesis. The age profile does not show an inverted U shape and there is evidence of greater savings in advanced ages. Saving profiles are higher in urban households, particularly for the elderly and regarding access to health.

Este artigo analisa o perfil de poupança de famílias rurais e urbanas no México. Com base na Pesquisa Nacional de Renda e Despesa Domiciliar de 1994 a 2014, é construído um painel sintético e estimado um modelo semiparamétrico que permite identificar os perfis por idade. Os resultados contrastam com a hipótese do ciclo de vida. O perfil da idade não apresenta a forma de U invertido e há evidências de maior economia em idades avançadas. Os perfis de poupança são mais elevados nos domicílios urbanos, especialmente naqueles com idosos e com acesso à saúde.

IL-17A and TNF-α as potential biomarkers for acute respiratory distress syndrome and mortality in patients with obesity and COVID-19.

Coronavirus disease 2019 (COVID-19) was declared a pandemic and international health emergency by the World Health Organization. Patients with obesity with COVID-19 are 7 times more likely to need invasive mechanical ventilation than are patients without obesity (OR 7.36; 95% CI: 1.63-33.14, p = 0.021). Acute respiratory distress syndrome (ARDS) is one of the main causes of death related to COVID-19 and is triggered by a cytokine storm that damages the respiratory epithelium. Interleukins that cause the chronic low-grade inflammatory state of obesity, such as interleukin (IL)-1ß, IL-6, monocyte chemoattractant peptide (MCP)-1, and, in particular, IL-17A and tumour necrosis factor alpha (TNF-α), also play very important roles in lung damage in ARDS. Therefore, obesity is associated with an immune state favourable to a cytokine storm. Our hypothesis is that serum concentrations of TNF-α and IL-17A are more elevated in patients with obesity and COVID-19, and consequently, they have a greater probability of developing ARDS and death. The immunobiology of IL-17A and TNF-α opens a new fascinating field of research for COVID-19.

Oleanolic acid induces a dual agonist action on PPARγ/α and GLUT4 translocation: A pentacyclic triterpene for dyslipidemia and type 2 diabetes.

Type 2 diabetes (T2D) is a metabolic disease characterized by defects in glycemia regulation. This disease is associated with alterations in insulin action and lipid metabolism, generating hyperglycemia and dyslipidemias. Currently, it is necessary to develop new or known drugs that promote the sensitization of insulin action. Thus, activation of peroxisome proliferator-activated receptors (PPARs) is probably the key to doing this. PPARs participate in maintaining an energetic balance between storage and the expenditure of energy. The activation of PPARγ produces the storage of energy, mainly as glycogen and fat. Meanwhile, PPARα activation promotes lipid degradation. Oleanolic acid (OA), a pentacyclic triterpenoid of numerous edible and medicinal plants, decreases hyperglycemia and lipid accumulation. However, the effects on PPARs and their regulated genes are unknown. Our aim was to determine the effects of OA on PPAR γ/α expression and their regulated genes (adiponectin, type 4 glucose transporter, fatty acid transport protein, and long-chain acyl-CoA synthetase) in C2C12 myoblasts by RT-PCR, Western blot, GLUT-4 translocation, and lipid storage in 3T3-L1 adipocytes. In C2C12 myoblasts, OA increased the expression of mRNA in both PPARγ/α and their regulated genes; also, PPARγ, GLUT-4, and FATP-1 protein expression increased, as well as GLUT-4 translocation. In 3T3-L1, OA increased the expression of mRNA in both PPARγ/α and maintained lipid storage unchanged. In conclusion, OA exhibited a dual action on PPARγ/α, which might explain in part its antihyperglycemic effect. This compound represents an alternative for designing novel therapeutic strategies in the control of T2D.

Direct Catalytic Conversion of Ethanol to C5+ Ketones: Role of Pd-Zn Alloy on Catalytic Activity and Stability.

Ethanol can be used as a platform molecule for synthesizing valuable chemicals and fuel precursors. Direct synthesis of C5+ ketones, building blocks for lubricants and hydrocarbon fuels, from ethanol was achieved over a stable Pd-promoted ZnO-ZrO2 catalyst. The sequence of reaction steps involved in the C5+ ketone formation from ethanol was determined. The key reaction steps were found to be the in situ generation of the acetone intermediate and the cross-aldol condensation between the reaction intermediates acetaldehyde and acetone. The formation of a Pd-Zn alloy in situ was identified to be the critical factor in maintaining high yield to the C5+ ketones and the stability of the catalyst. A yield of >70 % to C5+ ketones was achieved over a 0.1 % Pd-ZnO-ZrO2 mixed oxide catalyst, and the catalyst was demonstrated to be stable beyond 2000 hours on stream without any catalyst deactivation.

Protein supplement use and prevalence of microalbuminuria in gym members.

BACKGROUND: Protein supplement use is common in bodybuilders because protein supplements are thought to increase muscle mass by preventing protein catabolism during exercise routines. Information on the consequences of protein supplement use is scarce and contradictory. Therefore, the identification of a kidney damage marker, such as microalbuminuria, could be transcendent in preventing probable organ compromise in healthy persons. The aim of this study is to determine the presence of microalbuminuria in gym members and whether there is an associated risk with protein supplement use. METHODS: An analytic, descriptive, cross-sectional study was conducted. It included gym members whose clinical and nutritional histories were taken, identifying protein supplement use. Microalbuminuria was then determined through a random urine sample. Descriptive and inferential statistics were used for the data analysis. The objective was to determine the presence of microalbuminuria in gym members and whether there is an associated risk with protein supplement use. RESULTS: A total of 107 gym members, 71 men and 36 women, that met the inclusion criteria of the study were analyzed. Their mean age was 35±13 years, and the prevalence of microalbuminuria was 9.34%. There was active protein supplement use in 58% of the study participants, with a mean consumption duration of 16±22 months. No association with the presence of microalbuminuria was found (P=0.35). CONCLUSIONS: The prevalence of microalbuminuria in gym members was higher than that of the general healthy population and was not associated with protein supplement use.

Infection Outcomes are Robust to Thermal Variability in a Bumble Bee Host-Parasite System.

Climate change-related increases in thermal variability and rapid temperature shifts will affect organisms in multiple ways, including imposing physiological stress. Furthermore, the effects of temperature may alter the outcome of biotic interactions, such as those with pathogens and parasites. In the context of host-parasite interactions, the beneficial acclimation hypothesis posits that shifts away from acclimation or optimum performance temperatures will impose physiological stress on hosts and will affect their ability to resist parasite infection. We investigated the beneficial acclimation hypothesis in a bumble bee-trypanosome parasite system. Freshly emerged adult worker bumble bees, Bombus impatiens, were acclimated to 21, 26, or 29°C. They were subsequently experimentally exposed to the parasite, Crithidia bombi, and placed in a performance temperature that was the same as the acclimation temperature (constant) or one of the other temperatures (mismatched). Prevalence of parasite transmission was checked 4 and 6 days post-parasite exposure, and infection intensity in the gut was quantified at 8 days post-exposure. Parasite strain, host colony, and host size had significant effects on transmission prevalence and infection load. However, neither transmission nor infection intensity were significantly different between constant and mismatched thermal regimes. Furthermore, acclimation temperature, performance temperature, and the interaction of acclimation and performance temperatures had no significant effects on infection outcomes. These results, counter to predictions of the beneficial acclimation hypothesis, suggest that infection outcomes in this host-parasite system are robust to thermal variation within typically experienced ranges. This could be a consequence of adaptation to commonly experienced natural thermal regimes or a result of individual and colony level heterothermy in bumble bees. However, thermal variability may still have a detrimental effect on more sensitive stages or species, or when extreme climatic events push temperatures outside of the normally experienced range.

Triterpenoids from Hibiscus sabdariffa L. with PPARδ/γ Dual Agonist Action: In Vivo, In Vitro and In Silico Studies.

Hibiscus sabdariffa is a medicinal plant consumed as a diuretic and anti-obesity remedy. Several pharmacological studies have shown its beneficial effects in metabolism. Peroxisome proliferator-activated receptors δ and γ may play a role in the actions of H. sabdariffa. These nuclear receptors regulate lipid and glucose metabolism and are therapeutic targets for type 2 diabetes. This research aimed to perform a phytochemical study guided by a bioassay from H. sabdariffa to identify compounds with peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ agonist activity, supported by messenger ribonucleic acid expression, molecular docking, lipid accumulation, and an antihyperglycemic effect. An oral glucose tolerance test in mice with the aqueous extract of H. sabdariffa and the dichloromethane extract of H. sabdariffa was performed. The dichloromethane extract of H. sabdariffa exhibited an antihyperglycemic effect. The dichloromethane extract of H. sabdariffa was fractioned, and four fractions were evaluated in 3T3-L1 adipocytes on peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 messenger ribonucleic acid expression. Fraction F3 exhibited peroxisome proliferator-activated receptor δ/γ dual agonist activity, and a further fractionation yielded two subfractions, F3-1 and F3-2, which also increased peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ expression. Subfractions were analyzed by GC/MS. The main compounds identified in F3-1 were linoleic acid, oleic acid, and palmitic acid, while in F3-2, the main compounds identified were α-amyrin and lupeol. These molecules were subjected to molecular docking analysis. α-Amyrin and lupeol showed the highest affinity. Moreover, both produced an increase in peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 expression. Additionally, α-amyrin and lupeol decreased lipid accumulation in 3T3-L1 adipocytes and blood glucose in mice. Until now, α-amyrin and lupeol have not been reported with activity on peroxisome proliferator-activated receptors. This study provides evidence that α-amyrin and lupeol possess antidiabetic effects through a peroxisome proliferator-activated receptor δ/γ dual agonist action.

Ligand-mediated reversal of the oxidation state dependent ROS scavenging and enzyme mimicking activity of ceria nanoparticles.

Nanoceria is considered as a potent antioxidant (free radical scavenger) and its enzymatic activity is reported to be a function of the oxidation state of surface cerium ions. Here we demonstrate phosphine ligand-dependent enzymatic activity of nanoceria irrespective of its as-synthesized oxidation state.

Design, synthesis, in vitro, in vivo and in silico pharmacological characterization of antidiabetic N-Boc-l-tyrosine-based compounds.

In this study, we synthesized five N-Boc-L-tyrosine-based analogues to glitazars. The in vitro effects of compounds 1-5 on protein tyrosine phosphatase 1B (PTP-1B), peroxisome proliferator-activated receptor alpha and gamma (PPARα/γ), glucose transporter type-4 (GLUT-4) and fatty acid transport protein-1 (FATP-1) activation are reported in this paper. Compounds 1 and 3 were the most active in the in vitro PTP-1B inhibition assay, showing IC50s of approximately 44 µM. Treatment of adipocytes with compound 1 increased the mRNA expression of PPARγ and GLUT-4 by 8- and 3-fold, respectively. Moreover, both compounds (1 and 3) also increased the relative mRNA expression of PPARα (by 8-fold) and FATP-1 (by 15-fold). Molecular docking studies were performed in order to elucidate the polypharmacological binding mode of the most active compounds on these targets. Finally, a murine model of hyperglycemia was used to evaluate the in vivo effectiveness of compounds 1 and 3. We found that both compounds are orally active using an exploratory dose of 100 mg/kg, decreasing the blood glucose concentration in an oral glucose tolerance test and a non-insulin-dependent diabetes mellitus murine model. In conclusion, we demonstrated that both molecules showed strong in vitro and in vivo effects and can be considered polypharmacological antidiabetic candidates.