Association of ultra-processed food intake with risk of inflammatory bowel disease: prospective cohort study.

OBJECTIVE: To evaluate the relation between intake of ultra-processed food and risk of inflammatory bowel disease (IBD). DESIGN: Prospective cohort study. SETTING: 21 low, middle, and high income countries across seven geographical regions (Europe and North America, South America, Africa, Middle East, south Asia, South East Asia, and China). PARTICIPANTS: 116 087 adults aged 35-70 years with at least one cycle of follow-up and complete baseline food frequency questionnaire (FFQ) data (country specific validated FFQs were used to document baseline dietary intake). Participants were followed prospectively at least every three years. MAIN OUTCOME MEASURES: The main outcome was development of IBD, including Crohn's disease or ulcerative colitis. Associations between ultra-processed food intake and risk of IBD were assessed using Cox proportional hazard multivariable models. Results are presented as hazard ratios with 95% confidence intervals. RESULTS: Participants were enrolled in the study between 2003 and 2016. During the median follow-up of 9.7 years (interquartile range 8.9-11.2 years), 467 participants developed incident IBD (90 with Crohn's disease and 377 with ulcerative colitis). After adjustment for potential confounding factors, higher intake of ultra-processed food was associated with a higher risk of incident IBD (hazard ratio 1.82, 95% confidence interval 1.22 to 2.72 for ≥5 servings/day and 1.67, 1.18 to 2.37 for 1-4 servings/day compared with <1 serving/day, P=0.006 for trend). Different subgroups of ultra-processed food, including soft drinks, refined sweetened foods, salty snacks, and processed meat, each were associated with higher hazard ratios for IBD. Results were consistent for Crohn's disease and ulcerative colitis with low heterogeneity. Intakes of white meat, red meat, dairy, starch, and fruit, vegetables, and legumes were not associated with incident IBD. CONCLUSIONS: Higher intake of ultra-processed food was positively associated with risk of IBD. Further studies are needed to identify the contributory factors within ultra-processed foods. STUDY REGISTRATION: ClinicalTrials.gov NCT03225586.

Asian Indians With Prediabetes Have Similar Skeletal Muscle Mass and Function to Those With Type 2 Diabetes.

Background: Type 2 Diabetes (T2D) is a major concern among Asian Indians, not least because many develop T2D at despite having a normal BMI (body mass index), and with relatively low body fat. Asian Indians are also generally considered to have relatively low skeletal muscle mass and strength, this has not been explored in the context of T2D. Aim: The present study aimed to compare skeletal muscle mass, function and contractile quality (strength/mass) between healthy controls, those with prediabetes (PD) as well as T2D middle-aged non-obese Asian Indians. Methods: Adult males between the age of 20-50 years, consisting of healthy controls (n = 44), PD (n = 125) and T2D (n = 55) were studied. Skeletal muscle mass was measured using Dual X-ray Absorptiometry (DXA). Isometric and dynamic muscle function was measured using an isokinetic dynamometer (at 0, 60, 120, 180 degree/s). Muscle contractile quality was derived by dividing the peak muscle torque with the respective LMM (lower limb muscle mass). Fasting blood glucose (FBG) and insulin were used to derive insulin resistance (HOMA-IR). Results: The control group was on average 10 years younger than the other two groups (p < 0.01). The LMM was similar across the three study groups. However, the age-adjusted mean muscle torque was significantly lower in both absolute and normalized isometric and isokinetic strength in PD and T2D groups compared to controls (p ≤ 0.01), with the difference persisting even after adjusting for age and other covariates. However, there was no difference in muscle strength and contractile quality between the PD and T2D study groups. Conclusions: Muscle strength and contractile quality would appear to be sensitive and early indices of the trajectory toward diabetes in Asian Indians and more so than skeletal muscle mass. It is thus important to recognize the importance of functional measurements among this population when considering the role of muscle in diabetes. The data also would suggest that specific muscle conditioning (e.g., resistance training) might have efficacy in improving function as well as muscle mass, and thus aiding in the prevention of the trajectory toward the development of T2D.

An enantiomerically pure formulation of esmolol attenuates hypotension and preserves heart rate control in dogs.

BACKGROUND: Esmolol is marketed as a racemate (RS-esmolol) with hypotension being the most frequently reported adverse event. Previously, it has been shown that the S-enantiomer (S-esmolol) possesses all of the heart rate (HR) control. The authors studied whether S-esmolol alone mitigates hypotension at similar degrees of HR control compared with RS-esmolol. METHODS: The effects of RS- and S-esmolol on blood pressure (BP) were compared at multiple infusion rates producing similar HR control in dogs (N=21). Differences in BP were further interrogated by monitoring global cardiovascular function and included the R-enantiomer (R-esmolol) (N=3). RESULTS: S-esmolol at half the rate (µg kg min) of RS-esmolol provided the same degree of HR control over all infusion rates. RS-esmolol lowered BP by 3, 6, 11, 20, and 38 mmHg at 90, 300, 600, 1,000, and 2,000 µg kg min, compared with 2, 4, 5, 10, and 16 mmHg at 45, 150, 300, 500, and 1,000 µg kg min for S-esmolol. Decreased BP with RS-esmolol was attributed to decreases in left ventricular developed pressure (LVDP) (-34 mmHg), LVdP/dt+max (-702 mmHg/s), and cardiac output (-1 l/min). R-esmolol also decreased BP (-10 mmHg), LVDP (-10 mmHg), LVdP/dt+max (-241 mmHg/s), and cardiac output (to -0.2 l/min). S-esmolol reversed these trends toward pre-esmolol values by increasing BP (+13 mmHg), LVDP (+12 mmHg), LVdP/dt+max (+76 mmHg/s), and cardiac output (+0.4 l/min). CONCLUSIONS: R-enantiomer provided no HR control, but contributed to the hypotension with RS-esmolol, which appears to be due to negative inotropy. Thus, an S-enantiomer formulation of esmolol may provide similar HR control with less hypotension.

Finding homes for orphan cytochrome P450s: CYP4V2 and CYP4F22 in disease states.

The cytochrome P450 (CYP) 4 family of enzymes contains several recently identified membersthat are referred to as "orphan P450s" because their endogenous substrates are unknown.Human CYP4V2 and CYP4F22 are two such orphan P450s that are strongly linked to ocular andskin disease, respectively. Genetic analyses have identified a wide spectrum of mutations in the CYP4V2gene from patients suffering from Bietti's crystalline corneoretinal dystrophy, and mutations in theCYP4F22 gene have been linked to lamellar ichthyosis. The strong gene­disease associations provideunique opportunities for elucidating the substrate specificity of these orphan P450s and unraveling thebiochemical pathways that may be impacted in patients with CYP4V2 and CYP4F22 functional deficits.

Characterization of a molecular switch system that regulates gene expression in mammalian cells through a small molecule.

BACKGROUND: Molecular switch systems that activate gene expression by a small molecule are effective technologies that are widely used in applied biological research. Nuclear receptors are valuable candidates for these regulation systems due to their functional role as ligand activated transcription factors. Previously, our group engineered a variant of the retinoid x receptor to be responsive to the synthetic compound, LG335, but not responsive to its natural ligand, 9-cis-retinoic acid. RESULTS: This work focuses on characterizing a molecular switch system that quantitatively controls transgene expression. This system is composed of an orthogonal ligand/nuclear receptor pair, LG335 and GRQCIMFI, along with an artificial promoter controlling expression of a target transgene. GRQCIMFI is composed of the fusion of the DNA binding domain of the yeast transcription factor, Gal4, and a retinoid x receptor variant. The variant consists of the following mutations: Q275C, I310M, and F313I in the ligand binding domain. When introduced into mammalian cell culture, the switch shows luciferase activity at concentrations as low as 100 nM of LG335 with a 6.3 +/- 1.7-fold induction ratio. The developed one-component system activates transgene expression when introduced transiently or virally. CONCLUSIONS: We have successfully shown that this system can induce tightly controlled transgene expression and can be used for transient transfections or retroviral transductions in mammalian cell culture. Further characterization is needed for gene therapy applications.

Creation and discovery of ligand-receptor pairs for transcriptional control with small molecules.

The nuclear receptor retinoid X receptor (RXR) is a ligand-activated transcription factor. To create receptors for a new ligand, a structure-based approach was used to generate a library of approximately 380,000 mutant RXR genes. To discover functional variants within the library, we used chemical complementation, a method of protein engineering that uses the power of genetic selection. Wild-type RXR has an EC50 of 500 nM for 9-cis retinoic acid (9cRA) and an EC50 of >10 microM for the synthetic retinoid-like compound LG335 in yeast. The library produced ligand-receptor pairs with LG335 that have a variety of EC50 values (40 nM to >2 microM) and activation levels (10-80% of wild-type RXR with 9cRA) in yeast. The variant I268V;A272V;I310L;F313M has an EC50 for LG335 of 40 nM and an EC50 for 9cRA of >10 microM in yeast. This variant has essentially the reverse ligand specificity of wild-type RXR and is transcriptionally active at a 10-fold-lower ligand concentration in yeast. This EC50 is 25-fold lower than the best receptor we have engineered through site-directed mutagenesis, Q275C;I310M;F313I. Furthermore, the variants' EC50 values and activation levels in yeast and mammalian cells correlate. This protein engineering method should be extendable to produce other functional ligand-receptor pairs, which can be selected and characterized from libraries within weeks. Coupling large library construction with chemical complementation could be used to engineer proteins that bind virtually any small molecule for conditional gene expression, applications in metabolic engineering, and biosensors and to engineer enzymes through genetic selection.