Combination of curcumin and luteolin synergistically inhibits TNF-α-induced vascular inflammation in human vascular cells and mice

Emerging evidence shows that phytochemicals, the secondary plant metabolites present in a large variety of foods, have the potential ability in reducing the risk of cardiovascular diseases. However, the dosages of phytochemicals in the cellular and animal studies are too high to reach in humans by relevant foods or dietary supplement intake. The aims of this study were to investigate whether and how combined curcumin and luteolin synergistically inhibit tumor necrosis factor-alpha (TNF-α)-induced monocytes adhesion endothelium, a crucial step of the development of endothelial dysfunction, both in human vascular cells and mouse aortic endothelium. Our results show that combined curcumin (1 μM) and luteolin (0.5 μM) synergistically (combination index is 0.60) inhibited TNF-α-induced monocytes adhesion to human EA.hy926 endothelial cells while the individual chemicals did not have such effect at the selected concentrations. We also found that TNF-α-enhanced protein expressions of vascular cell adhesion molecule 1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1) and nuclear factor (NF)-κB translocation were synergistically reduced by the combined curcumin and luteolin in EA.hy 926 cells while the individual chemical did not have this inhibitory effect. Consistently, 2 weeks dietary intake of combined curcumin (500 mg/kg) and luteolin (500 mg/kg) in C57BL/6 mice synergistically prevented TNF-α-stimulated adhesion of mouse monocytes to aortic endothelium ex vivo as well as the TNF-α-increased aortic protein expression of MCP-1 and VCAM-1. Therefore, combined curcumin and luteolin at physiological concentrations synergistically inhibits TNF-α-induced monocytes adhesion to endothelial cells and expressions of MCP-1 and VCAM-1 via suppressing NF-κB translocation into the nucleus

Prompting GPT-3 To Be Reliable

Large language models (LLMs) show impressive abilities via few-shot prompting. Commercialized APIs such as OpenAI GPT-3 further increase their use in real-world language applications. However, the crucial problem of how to improve the reliability of GPT-3 is still under-explored. While reliability is a broad and vaguely defined term, we decompose reliability into four main facets that correspond to the existing framework of ML safety and are well-recognized to be important: generalizability, social biases, calibration, and factuality. Our core contribution is to establish simple and effective prompts that improve GPT-3's reliability as it: 1) generalizes out-of-distribution, 2) balances demographic distribution and uses natural language instructions to reduce social biases, 3) calibrates output probabilities, and 4) updates the LLM's factual knowledge and reasoning chains. With appropriate prompts, GPT-3 is more reliable than smaller-scale supervised models on all these facets. We release all processed datasets, evaluation scripts, and model predictions. Our systematic empirical study not only sheds new insights on the reliability of prompting LLMs, but more importantly, our prompting strategies can help practitioners more reliably use LLMs like GPT-3.Comment: ICLR 202

Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice

We recently reported that epicatechin, a bioactive compound that occurs naturally in various common foods, promoted general health and survival of obese diabetic mice. It remains to be determined whether epicatechin extends health span and delays the process of aging. In the present study, epicatechin or its analogue epigallocatechin gallate (EGCG) (0.25% w/v in drinking water) was administered to 20-mo-old male C57BL mice fed a standard chow. The goal was to determine the antiaging effect. The results showed that supplementation with epicatechin for 37 wk strikingly increased the survival rate from 39 to 69%, whereas EGCG had no significant effect. Consistently, epicatechin improved physical activity, delayed degeneration of skeletal muscle (quadriceps), and shifted the profiles of the serum metabolites and skeletal muscle general mRNA expressions in aging mice toward the profiles observed in young mice. In particular, we found that dietary epicatechin significantly reversed age-altered mRNA and protein expressions of extracellular matrix and peroxisome proliferator–activated receptor pathways in skeletal muscle, and reversed the age-induced declines of the nicotinate and nicotinamide pathway both in serum and skeletal muscle. The present study provides evidence that epicatechin supplementation can exert an antiaging effect, including an increase in survival, an attenuation of the aging-related deterioration of skeletal muscles, and a protection against the aging-related decline in nicotinate and nicotinamide metabolism.—Si, H., Wang, X., Zhang, L., Parnell, L. D., Ahmed, B., LeRoith, T., Ansah, T.-A., Zhang, L., Li, J., Ordovás, J. M., Si, H., Liu, D., Lai, C.-Q. Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice. FASEB J. 33, 965–977 (2019)

Ginsenoside Rb2 Alleviates Obesity by Activation of Brown Fat and Induction of Browning of White Fat

Ginsenoside Rb2 (Rb2), the most abundant saponin contained in Panax ginseng, has been used to treat variety of metabolic diseases. However, its effects in obesity and potential mechanisms are not well-understood. In the present study, we investigated metabolic performance with a Rb2 supplement in diet-induced obese (DIO) mice, focusing on the effects and mechanisms of Rb2 on brown and beige fat functions. Our results demonstrated that Rb2 effectively reduced body weight, improved insulin sensitivity, as well as induced energy expenditure in DIO mice. Histological and gene analysis revealed that Rb2 induced activation of brown fat and browning of white fat by reducing lipid droplets, stimulating uncoupling protein 1 (UCP1) staining, and increasing expression of thermogenic and mitochondrial genes, which could be recapitulated in 3T3-L1, C3H10T1/2, and primary adipocytes. In addition, Rb2 induced phosphorylation of AMP-activated protein kinase (AMPK) both in vitro and in vivo. These effects were shown to be dependent on AMPK since its inhibitor blocked Rb2 from inducing expressions of Pgc1α and Ucp1. Overall, the present study revealed that Rb2 activated brown fat and induced browning of white fat, which increased energy expenditure and thermogenesis, and consequently ameliorated obesity and metabolic disorders. These suggest that Rb2 holds promise in treating obesity

Surface deformation law of mining under thick loose layer and thin bedrock: taking the southern Shandong Mining Area as an example

The surface subsidence in the thick loose layer and thin bedrock mining area in the east of China has the characteristics of large subsidence value, wide movement range and long settling time. Taking a coal mine in Southern Shandong Mining Area as an example,this paper discusses the variation rules of coal seam mining surface deformation parameters under different loose layer and bedrock thickness ratio conditions, on the basis of field measurements, using FLAC3D, and establishes a surface deformation calculation model for coal seam mining under the conditions of different loose layer bedrock thickness ratios (0.25−5.00), studies the characteristics of surface deformation, analyzed the influence of ratio of loose layer thickness to bedrock thickness on the parameters of probability integral method, and quantitatively analyzed and discussed the conditions of thick loose layer and thin bedrock from the perspective of mining subsidence. Research shows: ①Under the same mining thickness conditions,when the ratio of loose layer thickness to bedrock thickness increases, the surface deformation amount obviously increases first and then decrease, when the ratio reaches a certain limit, the ground surface deformation tends to be stabilized; ②The subsidence coefficient, the horizontal movement coefficient and the tangent of the main influence angle all increase first and then decreases, and the inflection point is 1.75,1.25 and 1.25, respectively; ③The proportion of loose bed thickness in the average mining depth has great influence on the angle of draw and boundary angle. The boundary angle and the angle of draw gradually decrease with the increase of the ratio. Based on the above research, it is proposed that the ratio of 1.25−1.75 is the critical value for the condition of thick loose bedding and thin bedrock, which provides a theoretical basis and technical reference for the prediction of surface deformation and the prevention and control of mining subsidence disasters in typical thick loose layer thin bedrock mining areas in eastern China

Three Pairs of New Spirocyclic Alkaloid Enantiomers From the Marine-Derived Fungus Eurotium sp. SCSIO F452

Three pairs of new spirocyclic alkaloid enantiomers eurotinoids A–C (1–3), as well as a known biogenetically related racemate dihydrocryptoechinulin D (4) were isolated from a marine-derived fungus Eurotium sp. SCSIO F452. Their structures were determined by spectroscopic analyses and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 represent the first two “meta” products from a non-stereoselective [4 + 2] Diels-Alder cycloaddition presumably between an enone group of a diketopiperazine alkaloid and a diene group of a benzaldehyde derivative via a new head-to-tail coupling mode biosynthetically, while 3 and 4 were “ortho” products. Their enantiomers exhibited different antioxidative and cytotoxic activities. The modes of action were investigated by a preliminary molecular docking study

A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects

Mammals have three HP1 protein isotypes HP1β (CBX1), HP1γ (CBX3) and HP1α (CBX5) that are encoded by the corresponding genes Cbx1, Cbx3 and Cbx5. Recent work has shown that reduction of CBX3 protein in homozygotes for a hypomorphic allele (Cbx3 hypo) causes a severe postnatal mortality with around 99% of the homozygotes dying before weaning. It is not known what the causes of the postnatal mortality are. Here we show that Cbx3 hypo/hypo conceptuses are significantly reduced in size and the placentas exhibit a haplo-insufficiency. Late gestation Cbx3 hypo/hypo placentas have reduced mRNA transcripts for genes involved in growth regulation, amino acid and glucose transport. Blood vessels within the Cbx3 hypo/hypo placental labyrinth are narrower than wild-type. Newborn Cbx3 hypo/hypo pups are hypoglycemic, the livers are depleted of glycogen reserves and there is almost complete loss of stored lipid in brown adipose tissue (BAT). There is a 10-fold reduction in expression of the BAT-specific Ucp1 gene, whose product is responsible for non-shivering themogenesis. We suggest that it is the small size of the Cbx3 hypo/hypo neonates, a likely consequence of placental growth and transport defects, combined with a possible inability to thermoregulate that causes the severe postnatal mortality

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions