Metabolic Advantage of 25(OH)D3 versus 1,25(OH)2D3 Supplementation in Infantile Nephropathic Cystinosis-Associated Adipose Tissue Browning and Muscle Wasting.

Manifestations of infantile nephropathic cystinosis (INC) often include cachexia and deficiency of circulating vitamin D metabolites. We examined the impact of 25(OH)D3 versus 1,25(OH)2D3 repletion in Ctns null mice, a mouse model of INC. Six weeks of intraperitoneal administration of 25(OH)D3 (75 µg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) resulted in Ctns-/- mice corrected low circulating 25(OH)D3 or 1,25(OH)2D3 concentrations. While 25(OH)D3 administration in Ctns-/- mice normalized several metabolic parameters characteristic of cachexia as well as muscle function in vivo, 1,25(OH)2D3 did not. Administration of 25(OH)D3 in Ctns-/- mice increased muscle fiber size and decreased fat infiltration of skeletal muscle, which was accompanied by a reduction of abnormal muscle signaling pathways. 1,25(OH)2D3 administration was not as effective. In conclusion, 25(OH)D3 supplementation exerts metabolic advantages over 1,25(OH)2D3 supplementation by amelioration of muscle atrophy and fat browning in Ctns-/- mice.

Differential Effects of 25-Hydroxyvitamin D3 versus 1α 25-Dihydroxyvitamin D3 on Adipose Tissue Browning in CKD-Associated Cachexia.

Patients with chronic kidney disease (CKD) often have low serum concentrations of 25(OH)D3 and 1,25(OH)2D3. We investigated the differential effects of 25(OH)D3 versus 1,25(OH)2D3 repletion in mice with surgically induced CKD. Intraperitoneal supplementation of 25(OH)D3 (75 µg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) for 6 weeks normalized serum 25(OH)D3 or 1,25(OH)2D3 concentrations in CKD mice, respectively. Repletion of 25(OH)D3 normalized appetite, significantly improved weight gain, increased fat and lean mass content and in vivo muscle function, as well as attenuated elevated resting metabolic rate relative to repletion of 1,25(OH)2D3 in CKD mice. Repletion of 25(OH)D3 in CKD mice attenuated adipose tissue browning as well as ameliorated perturbations of energy homeostasis in adipose tissue and skeletal muscle, whereas repletion of 1,25(OH)2D3 did not. Significant improvement of muscle fiber size and normalization of fat infiltration of gastrocnemius was apparent with repletion of 25(OH)D3 but not with 1,25(OH)2D3 in CKD mice. This was accompanied by attenuation of the aberrant gene expression of muscle mass regulatory signaling, molecular pathways related to muscle fibrosis as well as muscle expression profile associated with skeletal muscle wasting in CKD mice. Our findings provide evidence that repletion of 25(OH)D3 exerts metabolic advantages over repletion of 1,25(OH)2D3 by attenuating adipose tissue browning and muscle wasting in CKD mice.

Carotenoid Cocktail Produced by An Antarctic Soil Flavobacterium with Biotechnological Potential.

Carotenoids are highly important in pigmentation, and its content in farmed crustaceans and fish correlates to their market value. These pigments also have a nutritional role in aquaculture where they are routinely added as a marine animal food supplement to ensure fish development and health. However, there is little information about carotenoids obtained from Antarctic bacteria and its use for pigmentation improvement and flesh quality in aquaculture. This study identified carotenoids produced by Antarctic soil bacteria. The pigmented strain (CN7) was isolated on modified Luria-Bertani (LB) media and incubated at 4 °C. This Gram-negative bacillus was identified by 16S rRNA analysis as Flavobacterium segetis. Pigment extract characterization was performed through high-performance liquid chromatography (HPLC) and identification with liquid chromatography-mass spectrometry (LC-MS). HPLC analyses revealed that this bacterium produces several pigments in the carotenoid absorption range (six peaks). LC-MS confirms the presence of one main peak corresponding to lutein or zeaxanthin (an isomer of lutein) and several other carotenoid pigments and intermediaries in a lower quantity. Therefore, we propose CN7 strain as an alternative model to produce beneficial carotenoid pigments with potential nutritional applications in aquaculture.

Vitamin D ameliorates adipose browning in chronic kidney disease cachexia.

Patients with chronic kidney disease (CKD) are often 25(OH)D3 and 1,25(OH)2D3 insufficient. We studied whether vitamin D repletion could correct aberrant adipose tissue and muscle metabolism in a mouse model of CKD-associated cachexia. Intraperitoneal administration of 25(OH)D3 and 1,25(OH)2D3 (75 µg/kg/day and 60 ng/kg/day respectively for 6 weeks) normalized serum concentrations of 25(OH)D3 and 1,25(OH)2D3 in CKD mice. Vitamin D repletion stimulated appetite, normalized weight gain, and improved fat and lean mass content in CKD mice. Vitamin D supplementation attenuated expression of key molecules involved in adipose tissue browning and ameliorated expression of thermogenic genes in adipose tissue and skeletal muscle in CKD mice. Furthermore, repletion of vitamin D improved skeletal muscle fiber size and in vivo muscle function, normalized muscle collagen content and attenuated muscle fat infiltration as well as pathogenetic molecular pathways related to muscle mass regulation in CKD mice. RNAseq analysis was performed on the gastrocnemius muscle. Ingenuity Pathway Analysis revealed that the top 12 differentially expressed genes in CKD were correlated with impaired muscle and neuron regeneration, enhanced muscle thermogenesis and fibrosis. Importantly, vitamin D repletion normalized the expression of those 12 genes in CKD mice. Vitamin D repletion may be an effective therapeutic strategy for adipose tissue browning and muscle wasting in CKD patients.

Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis-associated cachexia.

BACKGROUND: Ctns-/- mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Ctns-/- mice are 25(OH)D3 and 1,25(OH)2 D3 insufficient. We investigated whether vitamin D repletion could ameliorate adipose tissue browning and muscle wasting in Ctns-/- mice. METHODS: Twelve-month-old Ctns-/- mice and wild-type controls were treated with 25(OH)D3 and 1,25(OH)2 D3 (75 µg/kg/day and 60 ng/kg/day, respectively) or an ethylene glycol vehicle for 6 weeks. Serum chemistry and parameters of energy homeostasis were measured. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning, energy metabolism, and inflammation. We measured lean mass content, skeletal muscle fibre size, in vivo muscle function (grip strength and rotarod activity), and expression of molecules regulating muscle metabolism. We also analysed the transcriptome of skeletal muscle in Ctns-/- mice using RNAseq. RESULTS: Supplementation of 25(OH)D3 and 1,25(OH)2 D3 normalized serum concentration of 25(OH)D3 and 1,25(OH)2 D3 in Ctns-/- mice, respectively. Repletion of vitamin D partially or fully normalized food intake, weight gain, gain of fat, and lean mass, improved energy homeostasis, and attenuated perturbations of uncoupling proteins and adenosine triphosphate content in adipose tissue and muscle in Ctns-/- mice. Vitamin D repletion attenuated elevated expression of beige adipose cell biomarkers (UCP-1, CD137, Tmem26, and Tbx1) as well as aberrant expression of molecules implicated in adipose tissue browning (Cox2, Pgf2α, and NF-κB pathway) in inguinal white adipose tissue in Ctns-/- mice. Vitamin D repletion normalized skeletal muscle fibre size and improved in vivo muscle function in Ctns-/- mice. This was accompanied by correcting the increased muscle catabolic signalling (increased protein contents of IL-1ß, IL-6, and TNF-α as well as an increased gene expression of Murf-2, atrogin-1, and myostatin) and promoting the decreased muscle regeneration and myogenesis process (decreased gene expression of Igf1, Pax7, and MyoD) in skeletal muscles of Ctns-/- mice. Muscle RNAseq analysis revealed aberrant gene expression profiles associated with reduced muscle and neuron regeneration, increased energy metabolism, and fibrosis in Ctns-/- mice. Importantly, repletion of 25(OH)D3 and 1,25(OH)2 D3 normalized the top 20 differentially expressed genes in Ctns-/- mice. CONCLUSIONS: We report the novel findings that correction of 25(OH)D3 and 1,25(OH)2 D3 insufficiency reverses cachexia and may improve quality of life by restoring muscle function in an animal model of infantile nephropathic cystinosis. Mechanistically, vitamin D repletion attenuates adipose tissue browning and muscle wasting in Ctns-/- mice via multiple cellular and molecular mechanisms.

Efficacy and Safety of Vitamin D Supplementation in Patients With Systemic Lupus Erythematosus: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The efficacy of vitamin D supplementation in patients with systemic lupus erythematosus (SLE) remains uncertain. This meta-analysis aimed to systematically evaluate the efficacy and safety of vitamin D supplementation in patients with SLE. MATERIALS AND METHODS: Randomized controlled trials (RCTs) were searched in PubMed, Embase, Cochrane CENTRAL and Web of Science databases. The retrieved studies were subjected to meta-analysis using the fixed-effect or random-effect model. RESULTS: Five eligible RCTs enrolling 490 participants were included. Compared to the placebo treatment, vitamin D supplementation significantly increased the level of serum 25-hydroxyvitamin D (25(OH)D) (5 trials, 490 participants: standard mean difference (SMD) = 2.072, 95% CI: 1.078-3.066, P < 0.001). The pooled result from 2 RCTs showed that vitamin D supplementation decreased the fatigue severity scale scores in patients with SLE (2 trials, 79 participants: SMD = -1.179, 95% CI: -1.897 to -0.460, P = 0.001). The SLE disease activity index scores and positivity of anti-double-stranded DNA antibodies (anti-dsDNA) did not differ significantly (4 trials, 223 participants: SMD = -0.507, 95% CI: -1.055-0.041, P = 0.070; 3 trials, 361 participants: Risk ratio = 0.880, 95% CI: 0.734-1.054, P = 0.165) between the vitamin D supplementation group and the placebo treatment group. None of the included studies reported severe adverse events associated with vitamin D supplementation. CONCLUSIONS: This meta-analysis suggested that vitamin D supplementation is effective in increasing the serum 25(OH)D levels, may improve fatigue, and is well-tolerated in patients with SLE, however, it does not seem to have significant effects in decreasing the positivity of anti-dsDNA and disease activity.

Isolation and molecular characterization of Thraustochytrium strain isolated from Antarctic Peninsula and its biotechnological potential in the production of fatty acids

ABSTRACT Thraustochytrids are unicellular protists belonging to the Labyrinthulomycetes class, which are characterized by the presence of a high lipid content that could replace conventional fatty acids. They show a wide geographic distribution, however their diversity in the Antarctic Region is rather scarce. The analysis based on the complete sequence of 18S rRNA gene showed that strain 34-2 belongs to the species Thraustochytrium kinnei, with 99% identity. The total lipid profile shows a wide range of saturated fatty acids with abundance of palmitic acid (16:0), showing a range of 16.1-19.7%. On the other hand, long-chain polyunsaturated fatty acids, mainly docosahexaenoic acid and eicosapentaenoic acid are present in a range of 24-48% and 6.1-9.3%, respectively. All factors analyzed in cells (biomass, carbon consumption and lipid content) changed with variations of culture temperature (10 °C and 25 °C). The growth in glucose at a temperature of 10 °C presented the most favorable conditions to produce omega-3fatty acid. This research provides the identification and characterization of a Thraustochytrids strain, with a total lipid content that presents potential applications in the production of nutritional supplements and as well biofuels.

Isolation and molecular characterization of Thraustochytrium strain isolated from Antarctic Peninsula and its biotechnological potential in the production of fatty acids.

Thraustochytrids are unicellular protists belonging to the Labyrinthulomycetes class, which are characterized by the presence of a high lipid content that could replace conventional fatty acids. They show a wide geographic distribution, however their diversity in the Antarctic Region is rather scarce. The analysis based on the complete sequence of 18S rRNA gene showed that strain 34-2 belongs to the species Thraustochytrium kinnei, with 99% identity. The total lipid profile shows a wide range of saturated fatty acids with abundance of palmitic acid (16:0), showing a range of 16.1-19.7%. On the other hand, long-chain polyunsaturated fatty acids, mainly docosahexaenoic acid and eicosapentaenoic acid are present in a range of 24-48% and 6.1-9.3%, respectively. All factors analyzed in cells (biomass, carbon consumption and lipid content) changed with variations of culture temperature (10°C and 25°C). The growth in glucose at a temperature of 10°C presented the most favorable conditions to produce omega-3fatty acid. This research provides the identification and characterization of a Thraustochytrids strain, with a total lipid content that presents potential applications in the production of nutritional supplements and as well biofuels.

Design, synthesis and biological evaluation of pyrido[2,3-d]pyrimidin-7-(8H)-ones as HCV inhibitors.

The design and selection of a combinatorial library of pyrido[2,3-d]pyrimidin-7(8H)-ones (4) has allowed the synthesis of 121 compounds, using known and new synthetic methodologies, and the evaluation of the inhibitory activity against hepatitis C virus (HCV) genotype 1b replicon. Among these compounds, 21{4,10} and 24{2,10} presented very high activities [EC50 = 0.027 µM (CC50 = 5.3 µM) and EC50 = 0.034 µM (CC50 = 13.5 µM), respectively] and high selectivity indexes, 196 and 397. These values are similar to the EC50 reported for sofosbuvir (2) (0.048 µM) using a similar methodological approach and the same virus subtype. 21{4,10} and 24{2,10} are obtained through shorter synthetic itineraries than sofosbuvir and 24{2,10} is achiral contrary to sofosbuvir which presents 4 stereogenic centers. In silico studies suggest that 21{4,10} and 24{2,10} inhibits NS5B polymerase through allosteric site binding.

Comprehensive transgender healthcare: the gender affirming clinical and public health model of Fenway Health.

This report describes the evolution of a Boston community health center's multidisciplinary model of transgender healthcare, research, education, and dissemination of best practices. This process began with the development of a community-based approach to care that has been refined over almost 20 years where transgender patients have received tailored services through the Transgender Health Program. The program began as a response to unmet clinical needs and has grown through recognition that our local culturally responsive approach that links clinical care with biobehavioral and health services research, education, training, and advocacy promotes social justice and health equity for transgender people. Fenway Health's holistic public health efforts recognize the key role of gender affirmation in the care and well-being of transgender people worldwide.

Efecto cicatrizante del aceite de Copaifera officinalis (copaiba), en pacientes con úlcera péptica / Cicatrizing effect of Copaifera officinalis (copaiba) oil in patients with peptic ulcer

Objetivos: Determinar la eficacia cicatrizante del aceite de copaiba obtenido de la corteza de Copaifera officinalis, comparado con omeprazol 20 mg, en pacientes con diagnóstico definitivo de úlcera péptica. Diseño: Estudio experimental, clínico comparativo, de fase II, aleatorio, doble ciego, grupo paralelo. Institución: Instituto de Investigaciones Clínicas, Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima, Perú. Participantes: Pacientes con diagnóstico definitivo de úlcera péptica. Intervenciones: El diagnóstico fue tanto por exploración física como complementaria, siendo la endoscopia la técnica de elección, con evaluación pre y postratamiento con aceite de copaiba, formulada en cápsulas de 80 mg y 120 mg. El ensayo clínico incluyó 60 pacientes que voluntariamente ingresaron al programa de estudio, previa firma del consentimiento informado aprobado por el Comité institucional de Ética en Investigación. Los pacientes fueron distribuidos aleatoriamente en tres grupos, de 20 casos cada uno, según orden de llegada; los dos primeros grupos recibieron cápsulas de aceite de copaiba, en dosis de 80 y 120 mg, respectivamente; y un tercer grupo recibió omeprazol 20 mg. Los tratamientos fueron administrados en ayunas, una vez por la mañana, 30 minutos antes de la ingesta del primer alimento. Los datos fueron evaluados mediante técnicas multivariadas, considerando estadísticamente significativo p<0,05. Se tuvo en cuenta el consentimiento informado aprobado por el Comité de Bioética en Investigación del Centro Asistencial. Principales medidas de resultados: Porcentaje de cicatrización. Resultados: Se logró 65 por ciento y 75 por ciento de cicatrización de la úlcera péptica con aceite de copaiba, respectivamente, contra 100 por ciento en el grupo de omeprazol, sin efectos adversos significativos; dos presentaron náuseas y tres epigastralgia. Conclusiones: Los pacientes con úlcera péptica y con tratamiento de las cápsulas conteniendo aceite de copaiba mostraron cicatrización de la úlcera de 65 a 75 por ciento y sin efectos adversos significativos.

Objectives: To determine the cicatrizing effect of Copaifera officinalisÆ stem bark copaiba oil compared with omeprazole 20 mg in patients with diagnosis of peptic ulcer. Design: Experimental, comparative, phase II, randomized, double-blind, parallel-group clinical trial. Setting: Clinical Investigation Institute, Faculty of Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru. Participants: Patients with diagnosis of peptic ulcer. Interventions: Clinical diagnosis of peptic ulcer was done by endoscopy as well as pre and post treatment evaluation following administration of copaiba oil formulated capsules (80 mg and 120 mg). Sixty patients enrolled voluntarily to the study and signed informed consent as approved by the Institutional Review Board. Patients were randomly distributed in three groups of 20 cases each according to arrival order; the first and second group received respectively copaiba oil 80 mg and 120 mg capsules, and the third group omeprazole 20 mg, fasting, once daily in the morning, half hour before breakfast. Data was evaluated through multivariate techniques, considering p<0.05 as statistically significant. Main outcome measures: Percentage of patients healing their ulcer. Results: Peptic ulcer cicatrized in 65 per cent and 75 per cent respectively versus 100 per cent in the omeprazole group, without significant adverse effects. Two patients presented nausea and three epigastric pain. Conclusions: Patients with peptic ulcer treated with copaiba oil capsules showed ulcer scarring in 65 per cent to 75 per cent and without significant adverse effects.

Biocomposites from abaca strands and polypropylene. Part I: Evaluation of the tensile properties.

In this paper, abaca strands were used as reinforcement of polypropylene matrix and their tensile mechanical properties were studied. It was found relevant increments on the tensile properties of the abaca strand-PP composites despite the lack of good adhesion at fiber-matrix interface. Afterwards, it was stated the influence of using maleated polypropylene (MAPP) as compatibilizer to promote the interaction between abaca strands and polypropylene. The intrinsic mechanical properties of the reinforcement were evaluated and used for modeling both the tensile strength and elastic modulus of the composites. For these cases, the compatibility factor for the ultimate tensile strength was deduced from the modified rule of mixtures. Additionally, the experimental fiber orientation coefficient was measured, allowing determining the interfacial shear strengths of the composites and the critical fiber length of the abaca strand reinforcement. The mechanical improvement was compared to that obtained for fiberglass-reinforced PP composites and evaluated under an economical and technical point of view.

Suppression of human immunodeficiency virus type 1 viral load with selenium supplementation: a randomized controlled trial.

BACKGROUND: Despite findings that selenium supplementation may improve immune functioning, definitive evidence of its impact on human immunodeficiency virus (HIV) disease severity is lacking. METHODS: High selenium yeast supplementation (200 mug/d) was evaluated in a double-blind, randomized, placebo-controlled trial. Intention-to-treat analyses assessed the effect on HIV-1 viral load and CD4 count after 9 months of treatment. Unless otherwise indicated, values are presented as mean +/- SD. RESULTS: Of the 450 HIV-1-seropositive men and women who underwent screening, 262 initiated treatment and 174 completed the 9-month follow-up assessment. Mean adherence to study treatment was good (73.0% +/- 24.7%) with no related adverse events. The intention-to-treat analyses indicated that the mean change (Delta) in serum selenium concentration increased significantly in the selenium-treated group and not the placebo-treated group (Delta = 32.2 +/- 24.5 vs 0.5 +/- 8.8 microg/L; P<.001), and greater levels predicted decreased HIV-1 viral load (P<.02), which predicted increased CD4 count (P<.04). Findings remained significant after covarying age, sex, ethnicity, income, education, current and past cocaine and other drug use, HIV symptom classification, antiretroviral medication regimen and adherence, time since HIV diagnosis, and hepatitis C virus coinfection. Follow-up analyses evaluating treatment effectiveness indicated that the nonresponding selenium-treated subjects whose serum selenium change was less than or equal to 26.1 microg/L displayed poor treatment adherence (56.8% +/- 29.8%), HIV-1 viral load elevation (Delta = +0.29 +/- 1.1 log(10) units), and decreased CD4 count (Delta = -25.8 +/- 147.4 cells/microL). In contrast, selenium-treated subjects whose serum selenium increase was greater than 26.1 microg/L evidenced excellent treatment adherence (86.2% +/- 13.0%), no change in HIV-1 viral load (Delta = -0.04 +/- 0.7 log(10) units), and an increase in CD4 count (Delta = +27.9 +/- 150.2 cells/microL). CONCLUSIONS: Daily selenium supplementation can suppress the progression of HIV-1 viral burden and provide indirect improvement of CD4 count. The results support the use of selenium as a simple, inexpensive, and safe adjunct therapy in HIV spectrum disease. Trial Registration isrctn.org Identifier: ISRCTN22553118.

High concordance of daidzein-metabolizing phenotypes in individuals measured 1 to 3 years apart.

Particular intestinal bacteria are capable of metabolizing the soya isoflavone daidzein to equol and/or O-desmethylangolensin (O-DMA), and the presence of these metabolites in urine after soya consumption are markers of particular intestinal bacteria profiles. Prevalences of equol producers and O-DMA producers are approximately 30-50 % and 80-90 %, respectively, and limited observations have suggested that these daidzein-metabolizing phenotypes are stable within individuals over time. Characterizing stability of these phenotypes is important to understand their potential as markers of long-term exposure to particular intestinal bacteria and their associations with disease risk. We evaluated concordance within an individual for the equol-producer and O-DMA-producer phenotypes measured at two time points (T1, T2), 1-3 years apart. Phenotypes were ascertained by analysing equol and O-DMA using GC-MS in a spot urine sample collected after 3 d soya (source of daidzein) supplementation. In ninety-two individuals without recent (within 3 months before phenotyping) or current antibiotics use, 41 % were equol producers at T1 and 45 % were equol producers at T2, and 90 % were O-DMA producers at T1 and 95 % were O-DMA producers at T2. The percentage agreement for the equol-producer phenotype was 82 and for the O-DMA-producer phenotype was 89. These results indicate that these phenotypes are stable in most individuals over time, suggesting that they provide a useful biomarker for evaluating disease risk associated with harbouring particular intestinal bacteria responsible for, or associated with, the metabolism of the soya isoflavone daidzein.