Xanthohumol improves cognition in farnesoid X receptor-deficient mice on a high-fat diet.

Xanthohumol (XN) improves cognition of wild-type rodents on a high-fat diet (HFD). Bile acids and ceramide levels in the liver and hippocampus might be linked to these effects. XN modulates activity of the nuclear farnesoid X receptor (FXR; also known as NR1H4), the primary receptor for bile acids. To determine the role of FXR in the liver and intestine in mediating the effects of XN on cognitive performance, mice with intestine- and liver-specific FXR ablation (FXRIntestine-/- and FXRLiver-/-, respectively) on an HFD or an HFD containing XN were cognitively tested. XN improved cognitive performance in a genotype- and sex-dependent manner, with improved task learning in females (specifically wild-type), reversal learning in males (specifically wild-type and FXRIntestine-/- mutant) and spatial learning (both sexes). XN increased hippocampal diacylglycerol and sphingomyelin levels in females but decreased them in males. XN increased the ratio of shorter-chain to longer-chain ceramides and hexaceramides. Higher diacylglycerol and lower longer-chain ceramide and hexaceramide levels were linked to improved cognitive performance. Thus, the beneficial sex-dependent cognitive effects of XN are linked to changes in hippocampal diacylglycerol and ceramide levels. This article has an associated First Person interview with the first author of the paper.

ApoE isoform-dependent effects of xanthohumol on high fat diet-induced cognitive impairments and hippocampal metabolic pathways.

Consumption of a high fat diet (HFD) is linked to metabolic syndrome and cognitive impairments. This is exacerbated in age-related cognitive decline (ACD) and in individuals with a genetic risk for Alzheimer's disease (AD). Apolipoprotein E (apoE) is involved in cholesterol metabolism. In humans, there are three major isoforms, E2, E3, and E4. Compared to E3, E4 increases ACD and AD risk and vulnerability to the deleterious cognitive effects of a HFD. The plant compound Xanthohumol (XN) had beneficial effects on cognition and metabolism in C57BL/6J wild-type (WT) male mice put on a HFD at 9 weeks of age for 13 weeks. As the effects of XN in the context of a HFD in older WT, E3, and E4 female and male mice are not known, in the current study male and female WT, E3, and E4 mice were fed a HFD alone or a HFD containing 0.07% XN for 10 or 19 weeks, starting at 6 months of age, prior to the beginning of behavioral and cognitive testing. XN showed sex- and ApoE isoform-dependent effects on cognitive performance. XN-treated E4 and WT, but not E3, mice had higher glucose transporter protein levels in the hippocampus and cortex than HFD-treated mice. E3 and E4 mice had higher glucose transporter protein levels in the hippocampus and lower glucose transporter protein levels in the cortex than WT mice. In the standard experiment, regardless of XN treatment, E4 mice had nearly double as high ceramide and sphingomyelin levels than E3 mice and male mice had higher level of glycosylated ceramide than female mice. When the differential effects of HFD in E3 and E4 males were assessed, the arginine and proline metabolism pathway was affected. In the extended exposure experiment, in E3 males XN treatment affected the arginine and proline metabolism and the glycine, serine, and threonine metabolism. Myristic acid levels were decreased in XN-treated E3 males but not E3 females. These data support the therapeutic potential for XN to ameliorate HFD-induced cognitive impairments and highlight the importance of considering sex and ApoE isoform in determining who might most benefit from this dietary supplement.

Computation-Assisted Identification of Bioactive Compounds in Botanical Extracts: A Case Study of Anti-Inflammatory Natural Products from Hops.

The slow pace of discovery of bioactive natural products can be attributed to the difficulty in rapidly identifying them in complex mixtures such as plant extracts. To overcome these hurdles, we explored the utility of two machine learning techniques, i.e., Elastic Net and Random Forests, for identifying the individual anti-inflammatory principle(s) of an extract of the inflorescences of the hops (Humulus lupulus) containing hundreds of natural products. We fractionated a hop extract by column chromatography to obtain 40 impure fractions, determined their anti-inflammatory activity using a macrophage-based bioassay that measures inhibition of iNOS-mediated formation of nitric oxide, and characterized the chemical composition of the fractions by flow-injection HRAM mass spectrometry and LC-MS/MS. Among the top 10 predictors of bioactivity were prenylated flavonoids and humulones. The top Random Forests predictor of bioactivity, xanthohumol, was tested in pure form in the same bioassay to validate the predicted result (IC50 7 µM). Other predictors of bioactivity were identified by spectral similarity with known hop natural products using the Global Natural Products Social Networking (GNPS) algorithm. Our machine learning approach demonstrated that individual bioactive natural products can be identified without the need for extensive and repetitive bioassay-guided fractionation of a plant extract.

Phytochemical characterization and bioactivity toward breast cancer cells of unhydrolyzed and acid-hydrolyzed extracts of Fagonia indica.

Phytochemicals from the genus, Fagonia, have been attracting increasing attention due to their potential beneficial effects on human health. Fagonia species contain various types of phytochemicals such as flavonoids, alkaloids, saponins, terpenoids, coumarins and tannins. In this study, we investigated the phytochemical composition of unhydrolyzed and acid-hydrolyzed extracts of Fagonia indica and their bioactivity toward breast cancer MCF-7 cells in vitro. The results revealed that F. indica contains phytochemicals consistent with the reported phytochemical composition of this Fagonia species, with greater amounts of aglycones detected in the hydrolyzed extract. The crude extract of F. indica without acid hydrolysis was found to be ineffective in inhibiting the growth of MCF-7 cells at doses below 1000 µg/mL. However, after acid hydrolysis (to mimic gastro-intestinal hydrolysis), the F. indica extract became growth-inhibitory to MCF-7 cells as low as 10 µg/mL and the cytotoxicity increased with increasing dose and time of treatment. The results suggest that F. indica extracts contain phytochemicals in glycosidic forms whose aglycones are active as anti-proliferative agents toward breast cancer cells in vitro.

Abordaje multidisciplinar en el paciente con linfedema: de la rehabilitación a la microcirugía / Multidisciplinary approach in the lymphedema patient: From rehabilitation to microsurgery

El linfedema es una enfermedad crónica con una elevada incidencia en nuestra sociedad. En este trabajo presentamos una revisión bibliográfica con los últimos avances en técnicas de imagen y tratamiento quirúrgico con técnicas reconstructivas del linfedema (anastomosis linfático-venosas, trasplante vascularizado de ganglios linfáticos y cirugía profiláctica del linfedema). Además, se establece un protocolo basado en el trabajo de un equipo multidisciplinar (compuesto por rehabilitadores, cirujanos plásticos, radiólogos y médicos nucleares) que optimiza el tratamiento de estos pacientes.(AU)

Lymphedema is a chronic disease with a high incidence in our society. In this paper, we present a review with the latest advances in imaging techniques and surgical reconstructive treatment of lymphedema (lymphovenous anastomosis, vascularized lymph node transfer, and prophylactic lymphedema surgery). In addition, a protocol is established based on a multidisciplinary team (composed of physiatrists, plastic surgeons, radiologists and nuclear medicine radiologists) to optimize the treatment of these patients.(AU)

[Multidisciplinary approach in the lymphedema patient: From rehabilitation to microsurgery]. / Abordaje multidisciplinar en el paciente con linfedema: de la rehabilitación a la microcirugía.

Lymphedema is a chronic disease with a high incidence in our society. In this paper, we present a review with the latest advances in imaging techniques and surgical reconstructive treatment of lymphedema (lymphovenous anastomosis, vascularized lymph node transfer, and prophylactic lymphedema surgery). In addition, a protocol is established based on a multidisciplinary team (composed of physiatrists, plastic surgeons, radiologists and nuclear medicine radiologists) to optimize the treatment of these patients.

Xanthohumol Pyrazole Derivative Improves Diet-Induced Obesity and Induces Energy Expenditure in High-Fat Diet-Fed Mice.

The energy intake exceeding energy expenditure (EE) results in a positive energy balance, leading to storage of excess energy and weight gain. Here, we investigate the potential of a newly synthesized compound as an inducer of EE for the management of diet-induced obesity and insulin resistance. Xanthohumol (XN), a prenylated flavonoid from hops, was used as a precursor for the synthesis of a pyrazole derivative tested for its properties on high-fat diet (HFD)-induced metabolic impairments. In a comparative study with XN, we report that 4-(5-(4-hydroxyphenyl)-1-methyl-1H-pyrazol-3-yl)-5-methoxy-2-(3-methylbut-2-en-1-yl)benzene-1,3-diol (XP) uncouples oxidative phosphorylation in C2C12 cells. In HFD-fed mice, XP improved glucose tolerance and decreased weight gain by increasing EE and locomotor activity. Using an untargeted metabolomics approach, we assessed the effects of treatment on metabolites and their corresponding biochemical pathways. We found that XP and XN reduced purine metabolites and other energy metabolites in the plasma of HFD-fed mice. The induction of locomotor activity was associated with an increase in inosine monophosphate in the cortex of XP-treated mice. Together, these results suggest that XP, better than XN, affects mitochondrial respiration and cellular energy metabolism to prevent obesity in HFD-fed mice.

Xanthohumol Requires the Intestinal Microbiota to Improve Glucose Metabolism in Diet-Induced Obese Mice.

SCOPE: The polyphenol xanthohumol (XN) improves dysfunctional glucose and lipid metabolism in diet-induced obesity animal models. Because XN changes intestinal microbiota composition, the study hypothesizes that XN requires the microbiota to mediate its benefits. METHODS AND RESULTS: To test the hypothesis, the study feeds conventional and germ-free male Swiss Webster mice either a low-fat diet (LFD, 10% fat derived calories), a high-fat diet (HFD, 60% fat derived calories), or a high-fat diet supplemented with XN at 60 mg kg-1 body weight per day (HXN) for 10 weeks, and measure parameters of glucose and lipid metabolism. In conventional mice, the study discovers XN supplementation decreases plasma insulin concentrations and improves Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). In germ-free mice, XN supplementation fails to improve these outcomes. Fecal sample 16S rRNA gene sequencing analysis suggests XN supplementation changes microbial composition and dramatically alters the predicted functional capacity of the intestinal microbiota. Furthermore, the intestinal microbiota metabolizes XN into bioactive compounds, including dihydroxanthohumol (DXN), an anti-obesogenic compound with improved bioavailability. CONCLUSION: XN requires the intestinal microbiota to mediate its benefits, which involves complex diet-host-microbiota interactions with changes in both microbial composition and functional capacity. The study results warrant future metagenomic studies which will provide insight into complex microbe-microbe interactions and diet-host-microbiota interactions.

Tetrahydroxanthohumol, a xanthohumol derivative, attenuates high-fat diet-induced hepatic steatosis by antagonizing PPARγ.

We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN), attenuates high-fat diet (HFD)-induced obesity and metabolic syndrome in C57Bl/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated that TXN might antagonize lipogenic PPARγ actions in vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A peroxisome proliferator activated receptor gamma (PPARγ) competitive binding assay showed that XN and TXN bind to PPARγ with an IC50 similar to pioglitazone and 8-10 times stronger than oleate. Molecular docking simulations demonstrated that XN and TXN bind in the PPARγ ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPARγ.

Targeting the Liver-Brain Axis with Hop-Derived Flavonoids Improves Lipid Metabolism and Cognitive Performance in Mice.

SCOPE: Sphingolipids including ceramides are implicated in the pathogenesis of obesity and insulin resistance. Correspondingly, inhibition of pro-inflammatory and neurotoxic ceramide accumulation prevents obesity-mediated insulin resistance and cognitive impairment. Increasing evidence suggests the farnesoid X receptor (FXR) is involved in ceramide metabolism, as bile acid-FXR crosstalk controls ceramide levels along the gut-liver axis. The authors previously reported that FXR agonist xanthohumol (XN), the principal prenylated flavonoid in hops (Humulus lupulus), and its hydrogenated derivatives, α,ß-dihydroxanthohumol (DXN), and tetrahydroxanthohumol (TXN), ameliorated obesity-mediated insulin resistance, and cognitive impairment in mice fed a high-fat diet. METHODS AND RESULTS: To better understand how the flavonoids improve both, lipid and bile acid profiles in the liver are analyzed, sphingolipid relative abundance in the hippocampus is measured, and linked them to metabolic and neurocognitive performance. XN, DXN, and TXN (30 mg kg-1 BW per day) decrease ceramide content in liver and hippocampus; the latter is linked to improvements in spatial learning and memory. In addition, XN, DXN, and TXN decrease hepatic cholesterol content by enhancing de novo synthesis of bile acids. CONCLUSION: These observations suggest that XN, DXN, and TXN may alleviate obesity-induced metabolic and neurocognitive impairments by targeting the liver-brain axis.

Germ-Free Swiss Webster Mice on a High-Fat Diet Develop Obesity, Hyperglycemia, and Dyslipidemia.

A calorie-dense diet is a well-established risk factor for obesity and metabolic syndrome (MetS), whereas the role of the intestinal microbiota (IMB) in the development of diet-induced obesity (DIO) is not completely understood. To test the hypothesis that Swiss Webster (Tac:SW) mice can develop characteristics of DIO and MetS in the absence of the IMB, we fed conventional (CV) and germ-free (GF) male Tac:SW mice either a low-fat diet (LFD; 10% fat derived calories) or a high-fat diet (HFD; 60% fat derived calories) for 10 weeks. The HFD increased feed conversion and body weight in GF mice independent of the increase associated with the microbiota in CV mice. In contrast to CV mice, GF mice did not decrease feed intake on the HFD and possessed heavier fat pads. The HFD caused hyperglycemia, hyperinsulinemia, and impaired glucose absorption in GF mice independent of the increase associated with the microbiota in CV mice. A HFD also elevated plasma LDL-cholesterol and increased hepatic triacylglycerol, free fatty acids, and ceramides in all mice, whereas hypertriglyceridemia and increased hepatic medium and long-chain acylcarnitines were only observed in CV mice. Therefore, GF male Tac:SW mice developed several detrimental effects of obesity and MetS from a high-fat, calorie dense diet.

Vitamin C Activates the Folate-Mediated One-Carbon Cycle in C2C12 Myoblasts.

Vitamin C (L-ascorbic acid, AA) is an essential cellular antioxidant and cofactor for several α-ketoglutarate-dependent dioxygenases. As an antioxidant, AA interacts with vitamin E to control oxidative stress. While several reports suggest an interaction of AA with folate (vitamin B9) in animals and humans, little is known about the nature of the interaction and the underlying molecular mechanisms at the cellular level. We used an untargeted metabolomics approach to study the impact of AA on the metabolome of C2C12 myoblast cells. Compared to untreated cells, treatment of C2C12 cells with AA at 100 µM resulted in enhanced concentrations of folic acid (2.5-fold) and 5-methyl-tetrahydrofolate (5-methyl-THF, 10-fold increase) whereas the relative concentrations of 10-formyl-tetrahydrofolate decreased by >90% upon AA pretreatment, indicative of increased utilization for the biosynthesis of active THF metabolites. The impact of AA on the folate-mediated one-carbon cycle further manifested itself as an increase in the levels of methionine, whose formation from homocysteine is 5-methyl-THF dependent, and an increase in thymidine, whose formation from deoxyuridine monophosphate (dUMP) is dependent on 5,10-methylene-THF. These findings shed new light on the interaction of AA with the folate-mediated one-carbon cycle and partially explain clinical findings that AA supplementation enhances erythrocyte folate status and that it may decrease serum levels of homocysteine, which is considered as a biomarker of cardiovascular disease risk.

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities.

Osteosarcoma (OS) is the most common bone cancer in children and young adults. Solid tumors are characterized by intratumoral hypoxia, and hypoxic cells are associated with the transformation to aggressive phenotype and metastasis. The proteome needed to support an aggressive osteosarcoma cell phenotype remains largely undefined. To link metastatic propensity to a hypoxia-induced proteotype, we compared the protein profiles of two isogenic canine OS cell lines, POS (low metastatic) and HMPOS (highly metastatic), under normoxia and hypoxia. Label-free shotgun proteomics was applied to comprehensively characterize the hypoxia-responsive proteome profiles in the OS cell phenotypes. Hypothesis-driven parallel reaction monitoring was used to validate the differential proteins observed in the shotgun data and to monitor proteins of which we expected to exhibit hypoxia responsiveness, but which were absent in the label-free shotgun data. We established a "distance" score (|zHMPOS - zPOS|), and "sensitivity" score (|zHypoxia - zNormoxia) to quantitatively evaluate the proteome shifts exhibited by OS cells in response to hypoxia. Evaluation of the sensitivity scores for the proteome shifts observed and principal component analysis of the hypoxia-responsive proteins indicated that both cell types acquire a proteome that supports a Warburg phenotype with enhanced cell migration and proliferation characteristics. Cell migration and glucose uptake assays combined with protein function inhibitor studies provided further support that hypoxia-driven adaption of pathways associated with glycolytic metabolism, collagen biosynthesis and remodeling, redox regulation and immunomodulatory proteins typify a proteotype associated with an aggressive cancer cell phenotype. Our findings further suggest that proteins involved in collagen remodeling and immune editing may warrant further evaluation as potential targets for anti-metastatic treatment strategies in osteosarcoma.

Improvements in Metabolic Syndrome by Xanthohumol Derivatives Are Linked to Altered Gut Microbiota and Bile Acid Metabolism.

SCOPE: Two hydrogenated xanthohumol (XN) derivatives, α,ß-dihydro-XN (DXN) and tetrahydro-XN (TXN), improved parameters of metabolic syndrome (MetS), a critical risk factor of cardiovascular disease (CVD) and type 2 diabetes, in a diet-induced obese murine model. It is hypothesized that improvements in obesity and MetS are linked to changes in composition of the gut microbiota, bile acid metabolism, intestinal barrier function, and inflammation. METHODS AND RESULTS: To test this hypothesis, 16S rRNA genes were sequenced and bile acids were measured in fecal samples from C57BL/6J mice fed a high-fat diet (HFD) or HFD containing XN, DXN or TXN. Expression of genes associated with epithelial barrier function, inflammation, and bile acid metabolism were measured in the colon, white adipose tissue (WAT), and liver, respectively. Administration of XN derivatives decreases intestinal microbiota diversity and abundance-specifically Bacteroidetes and Tenericutes-alters bile acid metabolism, and reduces inflammation. In WAT, TXN supplementation decreases pro-inflammatory gene expression by suppressing macrophage infiltration. Transkingdom network analysis connects changes in the microbiota to improvements in MetS in the host. CONCLUSION: Changes in the gut microbiota and bile acid metabolism may explain, in part, the improvements in obesity and MetS associated with administration of XN and its derivatives.

Antiproliferative and Cytotoxic Activity of Xanthohumol and Its Non-Estrogenic Derivatives in Colon and Hepatocellular Carcinoma Cell Lines.

Xanthohumol (XN), a prenylated flavonoid found in hops, inhibits growth in a variety of cancer cell lines; however, its use raises concerns as gut microbiota and the host's hepatic cytochrome P450 enzymes metabolize it into the most potent phytoestrogen known, 8-prenylnaringenin (8-PN). The XN derivatives dihydroxanthohumol (DXN) and tetrahydroxanthohumol (TXN) are not metabolized into 8-PN and they show higher tissue concentrations in vivo compared with XN when orally administered to mice at the same dose. Here we show that DXN and TXN possess improved anti-proliferative activity compared with XN in two colon (HCT116, HT29) and two hepatocellular (HepG2, Huh7) carcinoma cell lines, as indicated by their respective IC50 values. Furthermore, XN, DXN, and TXN induce extensive apoptosis in all these carcinoma cell lines. Finally, TXN induces G0/G1 cell cycle arrest in the colon carcinoma cell line HT29. Our findings suggest that DXN and TXN could show promise as therapeutic agents against colorectal and liver cancer in preclinical studies without the drawback of metabolism into a phytoestrogen.

Phytochemical characterization of Tabernanthe iboga root bark and its effects on dysfunctional metabolism and cognitive performance in high-fat-fed C57BL/6J mice.

Preparations of the root bark of Tabernanthe iboga have long been used in Central and West African traditional medicine to combat fatigue, as a neuro-stimulant in rituals, and for treatment of diabetes. The principal alkaloid of T. iboga, ibogaine, has attracted attention in many countries around the world for providing relief for opioid craving in drug addicts. Using a plant metabolomics approach, we detected five phenolic compounds, including 3-O-caffeoylquinic acid, and 30 alkaloids, seven of which were previously reported from T. iboga root bark. Following a report that iboga extracts contain insulinotropic agents, we aimed to determine the potential alleviating effects of the water extract of iboga root bark on high-fat diet (HFD)-induced hyperglycemia as well as its effects on cognitive function in male C57BL/6J mice. Feeding a HFD to mice for 10 weeks produced manifestations of metabolic syndrome such as increased body weight and increased plasma levels of glucose, triacylglycerols, total cholesterol, LDL-cholesterol, insulin, leptin, and pro-inflammatory mediators (IL-6, MCP-1, ICAM-1), as compared to mice fed a low-fat diet (LFD). Supplementation of HFD with iboga extract at ibogaine doses of 0.83 (low) and 2.07 (high) mg/kg/day did not improve these HFD-induced metabolic effects except for a reduction of plasma MCP-1 in the low dose group, indicative of an anti-inflammatory effect. When the HFD mice were tested in the water maze, the high-dose iboga extract caused hippocampus-dependent impairments in spatial learning and memory, as compared to mice receiving only a HFD.

Metabolomics-Driven Elucidation of Cellular Nitrate Tolerance Reveals Ascorbic Acid Prevents Nitroglycerin-Induced Inactivation of Xanthine Oxidase.

Glyceryl trinitrate (GTN) has found widespread use for the treatment of angina pectoris, a pathological condition manifested by chest pain resulting from insufficient blood supply to the heart. Metabolic conversion of GTN, a nitric oxide (NO) pro-drug, into NO induces vasodilation and improves blood flow. Patients develop tolerance to GTN after several weeks of continuous use, limiting the potential for long-term therapy. The mechanistic cause of nitrate tolerance is relatively unknown. We developed a cell culture model of nitrate tolerance that utilizes stable isotopes to measure metabolism of 15N3-GTN into 15N-nitrite. We performed global metabolomics to identify the mechanism of GTN-induced nitrate tolerance and to elucidate the protective role of vitamin C (ascorbic acid). Metabolomics analyses revealed that GTN impaired purine metabolism and depleted intracellular ATP and GTP. GTN inactivated xanthine oxidase (XO), an enzyme that is critical for the metabolic bioactivation of GTN into NO. Ascorbic acid prevented inactivation of XO, resulting in increased NO production from GTN. Our studies suggest that ascorbic acid has the ability to prevent nitrate tolerance by protecting XO, but not aldehyde dehydrogenase (another GTN bioactivating enzyme), from GTN-induced inactivation. Our findings provide a mechanistic explanation for the previously observed beneficial effects of ascorbic acid in nitrate therapy.

Photoprotective Properties of Isothiocyanate and Nitrile Glucosinolate Derivatives From Meadowfoam (Limnanthes alba) Against UVB Irradiation in Human Skin Equivalent.

Exposure to ultraviolet B (UVB) irradiation of the skin leads to numerous dermatological concerns including skin cancer and accelerated aging. Natural product glucosinolate derivatives, like sulforaphane, have been shown to exhibit chemopreventive and photoprotective properties. In this study, we examined meadowfoam (Limnanthes alba) glucosinolate derivatives, 3-methoxybenzyl isothiocyanate (MBITC) and 3-methoxyphenyl acetonitrile (MPACN), for their activity in protecting against the consequences of UV exposure. To that end, we have exposed human primary epidermal keratinocytes (HPEKs) and 3D human skin reconstructed in vitro (EpiDermTM FT-400) to UVB insult and investigated whether MBITC and MPACN treatment ameliorated the harmful effects of UVB damage. Activity was determined by the compounds' efficacy in counteracting UVB-induced DNA damage, matrix-metalloproteinase (MMP) expression, and proliferation. We found that in monolayer cultures of HPEK, MBITC and MPACN did not protect against a UVB-induced loss in proliferation and MBITC itself inhibited cell proliferation. However, in human reconstructed skin-equivalents, MBITC and MPACN decrease epidermal cyclobutane pyrimidine dimers (CPDs) and significantly reduce total phosphorylated γH2A.X levels. Both MBITC and MPACN inhibit UVB-induced MMP-1 and MMP-3 expression indicating their role to prevent photoaging. Both compounds, and MPACN in particular, showed activity against UVB-induced proliferation as indicated by fewer epidermal PCNA+ cells and prevented UVB-induced hyperplasia as determined by a reduction in reconstructed skin epidermal thickness (ET). These data demonstrate that MBITC and MPACN exhibit promising anti-photocarcinogenic and anti-photoaging properties in the skin microenvironment and could be used for therapeutic interventions.

Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice.

Xanthohumol (XN), a prenylated flavonoid from hops, improves dysfunctional glucose and lipid metabolism in animal models of metabolic syndrome (MetS). However, its metabolic transformation into the estrogenic metabolite, 8-prenylnaringenin (8-PN), poses a potential health concern for its use in humans. To address this concern, we evaluated two hydrogenated derivatives, α,ß-dihydro-XN (DXN) and tetrahydro-XN (TXN), which showed negligible affinity for estrogen receptors α and ß, and which cannot be metabolically converted into 8-PN. We compared their effects to those of XN by feeding C57BL/6J mice a high-fat diet (HFD) containing XN, DXN, or TXN for 13 weeks. DXN and TXN were present at higher concentrations than XN in plasma, liver and muscle. Mice administered XN, DXN or TXN showed improvements of impaired glucose tolerance compared to the controls. DXN and TXN treatment resulted in a decrease of HOMA-IR and plasma leptin. C2C12 embryonic muscle cells treated with DXN or TXN exhibited higher rates of uncoupled mitochondrial respiration compared to XN and the control. Finally, XN, DXN, or TXN treatment ameliorated HFD-induced deficits in spatial learning and memory. Taken together, DXN and TXN could ameliorate the neurocognitive-metabolic impairments associated with HFD-induced obesity without risk of liver injury and adverse estrogenic effects.

Fractura de clavícula distal con cortical superior indemne: cirugía mínimamente invasiva / Distal clavicle fracture with intact upper cortex: minimally invasive surgery

INTRODUCCIÓN Las fracturas de clavícula distal desplazadas son manejadas generalmente de manera quirúrgica dada la alta probabilidad de no-unión con el tratamiento ortopédico. El propósito de este trabajo es evaluar el uso del sistema de fijación con doble botón cortical para la reducción y estabilización de la fractura de clavícula distal que presenten indemnidad de la cortical superior. MÉTODOS: Estudio retrospectivo observacional clínico-imagenológico de pacientes con fractura desplazada de clavícula distal operados con técnica mínimamente invasiva mediante reducción con sistema de fijación con doble botón cortical. Se describe como criterio radiológico de "Cortical Superior Indemne (CSI)" la presencia del rasgo de fractura a 1cm o más, hacia distal desde el tubérculo conoide, identificándose ese criterio como característica necesaria para la indicación del tratamiento propuesto. Se describen las complicaciones post-operatorias, progresión radiológica y resultados funcionales. RESULTADOS: 21 pacientes fueron tratados con esa técnica con un seguimiento promedio de 23,4 meses. No hubo casos de no unión, infección o herida dehiscente y ningún paciente requirió el retiro del dispositivo. Se encontró un Simple Shoulder Test (SST) promedio de 79,4 (66 - 91,7) y QuickDASH de 11 (6,8 - 15,9). El 87,5% de las fracturas desplazadas de clavícula distal tenían indemnidad de la cortical superior. CONCLUSIÓN: La técnica mínimamente invasiva para la reducción y fijación de la fractura de clavícula distal desplazada con botones corticales es una alternativa simple, reproducible, con pocas complicaciones y excelentes resultados funcionales.

BACKGROUND: Displaced distal clavicle fractures are commonly managed through surgery due to a high probability of nonunion with conservative treatments. The purpose of this study is to evaluate the use of Flip-buttons as a minimally invasive method for fixing and stabilizing displaced distal clavicle fractures when the upper cortical it́s intact. METHODS: A retrospective observational study of radiological and clinical results of patients with displaced distal clavicle fracture that were treated with the Flip-button technique. The indication for using this surgical method was based on the radiological criteria of "Intact Upper Cortical (IUC)" described by the authors as the presence of the fracture 1cm or more, distally to de conoid tubercle. Post-operative complications, radiologic and functional progress were recorded. RESULTS: 21 patients were treated with this technique, all with complete bony union. No patients presented infection or wound dehiscence and implant removal was not necessary in any case. The mean follow-up was of 23,4 months. The mean score in Simple Shoulder Test (SST) was 79,4 (66 - 91,7) and a mean QuickDASH of 11 (6,8 - 15,9). 87,5% of all the displaced distal clavicle fractures had IUC. CONCLUSION: The minimally invasive technique for the reduction and fixation of the displaced distal clavicle fracture with cortical buttons is a simple and reproducible alternative, with few complications and excellent functional results.