Photocatalytic fluoroalkylation by ligand-to-metal charge transfer.

Trifluoromethyl (CF3) and other fluoroalkyl groups are of great significance in the fields of pharmaceutical chemistry and agricultural chemicals. Fluoroalkyl acids, especially trifluoroacetic acid (TFA) is considered the most ideal fluoroalkylation reagent due to its low cost and easy availability. However, the extremely high oxidation potential requirement of TFA limits its wide application. In recent years, since visible-light-induced fluoroalkylation through the ligand-to-metal charge transfer (LMCT) process can overcome the above limitations, it has become an effective synthetic tool for the construction of fluorinated compounds with complex molecules and structures. In this review, according to the classification of different metal catalysts, we summarize the trifluoromethylation and fluoroalkylation of olefins, heteroaromatics, and terminal alkynes in different metal catalytic systems and their corresponding reaction mechanisms. The photocatalytic fluoroalkylation via LMCT is believed to expedite the development of fluoro-containing drugs, and more novel fluoroalkylation methologies using this strategy will be disclosed.

Tangeretin Enhances Muscle Endurance and Aerobic Metabolism in Mice via Targeting AdipoR1 to Increase Oxidative Myofibers.

Slow oxidative myofibers play an important role in improving muscle endurance performance and maintaining body energy homeostasis. However, the targets and means to regulate slow oxidative myofibers proportion remain unknown. Here, we show that tangeretin (TG), a natural polymethoxylated flavone, significantly activates slow oxidative myofibers-related gene expression and increases type I myofibers proportion, resulting in improved endurance performance and aerobic metabolism in mice. Proteomics, molecular dynamics, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) investigations revealed that TG can directly bind to adiponectin receptor 1 (AdipoR1). Using AdipoR1-knockdown C2C12 cells and muscle-specific AdipoR1-knockout mice, we found that the positive effect of TG on regulating slow oxidative myofiber related markers expression is mediated by AdipoR1 and its downstream AMPK/PGC-1α pathway. Together, our data uncover TG as a natural compound that regulates the identity of slow oxidative myofibers via targeting the AdipoR1 signaling pathway. These findings further unveil the new function of TG in increasing the proportion of slow oxidative myofibers and enhancing skeletal muscle performance.

The association between dietary patterns before pregnancy and gestational diabetes mellitus: a matched case-control study in China.

BACKGROUND AND OBJECTIVES: We aimed to explore the relationship between dietary patterns and gestational diabetes mellitus (GDM) during pre-pregnancy six months using principal component analysis (PCA) and the geometric framework for nutrition (GFN). METHODS AND STUDY DESIGN: We conducted a case-control study that included 210 GDM pregnant women and 210 controls. The dietary intake of all participants was assessed by a validated semi-quantitative food frequency questionnaire (FFQ). Major dietary patterns were extracted by PCA. A conditional logistic regression model was used to determine whether specific dietary patterns are associated with the risk of GDM. Meanwhile, the relationship between dietary patterns and GDM was visualized using GFN. RESULTS: Four major dietary patterns were identified: "protein-rich pattern," "plant-based pattern," "oil-pickles-desserts pattern," and "cereals-nuts pattern." After adjustment for confounders, the "plant-based pattern" was associated with decreased risk of GDM (Q4 vs. Q1: OR = 0.01, 95% CI: 0.00-0.08), whereas no significant association was found in other dietary patterns. Moreover, there was no dietary intake of ice cream cones and deep-fried dough sticks for the population, which would produce fewer patients with GDM. Deep-fried dough sticks had statistically significant differences in the case and control groups (p < 0.001), while ice cream cones had the opposite result. CONCLUSIONS: The "plant-based pattern" may reduce the risk of GDM. Besides, although the "cereals-nuts pattern" had no association with GDM risk, avoiding the intake of deep-fried dough sticks could decrease GDM risk.

Towards an integrated understanding of dietary phenotypes.

Diet and nutrition comprise a complex, multi-faceted interface between animal biology and food environments. With accumulating information on the many facets of this association arises a need for systems-based approaches that integrate dietary components and their links with ecology, feeding, post-ingestive processes and the functional and ecological consequences of these interactions. We briefly show how a modelling approach, nutritional geometry, has used the experimental control afforded in laboratory studies to begin to unravel these links. Laboratory studies, however, have limited ability to establish whether and how the feeding and physiological mechanisms interface with realistic ecological environments. We next provide an overview of observational field studies of free-ranging primates that have examined this, producing largely correlative data suggesting that similar feeding mechanisms operate in the wild as in the laboratory. Significant challenges remain, however, in establishing causal links between feeding, resource variation and physiological processes in the wild. We end with a more detailed account of two studies of temperate primates that have capitalized on the discrete variation provided by seasonal environments to strengthen causal inference in field studies and link patterns of intake to dynamics of nutrient processing. This article is part of the theme issue 'Food processing and nutritional assimilation in animals'.

Normal diet ameliorates obesity more safely and effectively than ketogenic diet does in high-fat diet-induced obesity mouse based on gut microbiota and lipid metabolism.

Growing evidence supports the efficacy of ketogenic diets for inducing weight loss, but there are also potential health risks due to their unbalanced nutrient composition. We aim at assessing relative effectiveness of a balanced diet and ketogenic diet for reversing metabolic syndrome in a diet-induced C57BL/6J mouse model. Mice were fed high-fat diet to induce obesity. Obese individuals were then fed either ketogenic or balanced diets as an obesity intervention. Serum, liver, fat and faecal samples were analysed. We observed that both diet interventions led to significant decrease in body weight. The ketogenic intervention was less effective in reducing adipocyte cell size and led to dyslipidaemia. The composition of the gut microbiome in the balanced diet intervention was more similar to the non-obese control group and had improved functional attributes. Our results indicate intervention with balanced diets ameliorates obesity more safely and effectively than ketogenic diets in diet-induced obesity mouse model.

Ketogenic Diet Combined with Moderate Aerobic Exercise Training Ameliorates White Adipose Tissue Mass, Serum Biomarkers, and Hepatic Lipid Metabolism in High-Fat Diet-Induced Obese Mice.

Obesity is a serious public health issue worldwide. Growing evidence demonstrates the efficacy of the ketogenic diet (KD) for weight loss, but there may be some adverse side effects such as dyslipidemia and hepatic steatosis. Aerobic exercise is a widely recognized approach for improving these metabolic markers. Here we explored the combined impacts of KD and moderate aerobic exercise for an 8-week intervention on body weight and fat loss, serum biomarkers, and hepatic lipid metabolism in a mouse model of high-fat diet-induced obesity. Both KD and KD combined with exercise significantly reduced body weight and fat mass. No significant adverse effects of KD were observed in serum biomarkers or hepatic lipid storage, except for an increase in circulating triglyceride level. However, aerobic exercise lowered serum triglyceride levels, and further ameliorated serum parameters, and hepatic steatosis in KD-fed mice. Moreover, gene and protein expression analysis indicated that KD combined with exercise was associated with increased expression of lipolysis-related genes and protein levels, and reduced expression of lipogenic genes relative to KD without exercise. Overall, our findings for mice indicate that further work on humans might reveal that KD combined with moderate aerobic exercise could be a promising therapeutic strategy for obesity.

An 8-week ketogenic diet improves exercise endurance and liver antioxidant capacity after weight loss in obese mice.

Evolving evidence supports the role of the ketogenic diet (KD) in weight loss. However, no coherent conclusions are drawn on its impact on the effect of KD on exercise and antioxidant capacity after weight loss in obese individuals. We evaluated the exercise performance, energy metabolism and antioxidant capacity of mice after weight loss using high-fat diet-induced obese mice, and used KD and normal diet (ND) intervention, respectively, to provide a theoretical basis for further study of the health effects of KD. Our results showed that the 8-week KD significantly reduced the body weight of obese mice and improved the performance of treadmill exercise, but had no significant effect on grip strength. Serum biochemical results suggest that KD has the risk of elevating blood lipid. In liver tissue, KD significantly reduced the level of oxidative stress and increased the antioxidant capacity of the liver. Our findings suggest that the intervention with KD led to weight loss, modulate energy metabolism and improve aerobic exercise endurance in obese mice. Despite its antioxidant potential in the liver, the utilization of KD still requires caution. This study underscores the need for further investigation into the health impacts of KD, especially in regard to its potential risks.

Sesamin Activates Skeletal Muscle FNDC5 Expression and Increases Irisin Secretion via the SIRT1 Signaling Pathway.

Sesamin, a major lignin mainly found in sesame (Sesamum indicum) oil and sesame seeds, has been demonstrated to possess lipoclasis-promoting, antiobesity, and antidiabetic effects. Irisin is a newly discovered myokine that has attracted great interest as a key target to prevent/treat obesity and its related metabolic diseases. However, the effect and potential mechanism of sesamin on FNDC5/irisin are still vacant. In this study, we showed that sesamin treatment increased FNDC5/irisin activation and regulated SIRT1, PGC-1α, and p-SMAD3/SMAD3 expression in C2C12 cells. By using specific inhibitors and lentivirus in C2C12 cells, we found that the SIRT1/SMAD3 axis plays an important role in sesamin regulated FNDC5/irisin activation. We also found that sesamin treatment activated FNDC5 expression and regulated the SIRT1/SMAD3 signaling axis in mice's skeletal muscle. What is more, by the high-fat diet induced obese model, we further showed that sesamin improved the high-fat diet induced decrease in irisin production and secretion, which results in an improvement of body weight gain and skeletal muscle dysfunction. Our results suggested that sesamin could activate FNDC5 expression and stimulate irisin secretion through the SIRT1 pathway both in vitro and in vivo, which may provide a new strategy for preventing and improving irisin deficiency related diseases.

An integrative approach to dietary balance across the life course.

Animals require specific blends of nutrients that vary across the life course and with circumstances, e.g., health and activity levels. Underpinning and complicating these requirements is that individual traits may be optimized on different dietary compositions leading to nutrition-mediated trade-offs among outcomes. Additionally, the food environment may constrain which nutrient mixtures are achievable. Natural selection has equipped animals for solving such multi-dimensional, dynamic challenges of nutrition, but little is understood about the details and their theoretical and practical implications. We present an integrative framework, nutritional geometry, which models complex nutritional interactions in the context of multiple nutrients and across levels of biological organization (e.g., cellular, individual, and population) and levels of analysis (e.g., mechanistic, developmental, ecological, and evolutionary). The framework is generalizable across different situations and taxa. We illustrate this using examples spanning insects to primates and settings (laboratory, and the wild), and demonstrate its relevance for human health.

Seasonal diet and microbiome shifts in wild rhesus macaques are better correlated at the level of nutrient components than food items.

Food supply is one of the major drivers of animal behavior, and the gut microbiome is an important mediator between food supply and its effects on physiology. However, predicting the outcome of diet change on microbiome and consequences for the animal has proven extremely challenging. We propose this reflects processes occurring at different scales. Inadequate accounting for the multi-level complexity of nutrition (nutrients, foods, diets) obscures the diet influence on microbiome and subsequently animal. Here, we present a detailed year-round, multi-level analysis of diet and microbiome changes in a wild population of a temperate primate, the rhesus macaque (Macaca mulatta). Total daily food and nutrient intake of 6 male and 6 female macaques was monitored in each of the 4 seasons (total 120 days observations). For each individual, we found significant variation in the microbiome between all 4 seasons. This response was more strongly correlated with changes in macronutrient intake than with food items and much of the response could be explained at the level of 6 ecological guilds-sets of taxa sharing similar responses to nutrient intake. We conclude that study of diet, microbiome, and animal performance in ecology will more effectively identify patterns if diet is recorded at the level of nutrient intake. Although microbiome response to diet does show variation in species-level taxa in response to food items, there is greater commonality in response at the level of guilds. A goal for microbiome researchers should be to identify genes encoding microbial attributes that can define such guilds.

Naringin Promotes Skeletal Muscle Fiber Remodeling by the AdipoR1-APPL1-AMPK Signaling Pathway.

Naringin, a natural flavonoid mainly found in citrus fruit, has been reported to exert a positive effect on improving skeletal muscle health. However, the effects and potential mechanisms of naringin on skeletal muscle fiber switching is still unclear. Here, we discovered that oral administration of naringin increased the low-speed running time, four-limb hanging time, body oxygen consumption in mice, enhanced aerobic enzyme activity, MyHC I expression, and slow-twitch fiber percentage in mice skeletal muscle. By contrast, naringin decreased α-GPDH enzyme activity, MyHC IIb expression, and fast-twitch fiber percentage. Moreover, naringin increased the concentration of serum adiponectin and activated the expression of AdipoR1, APPL1, AMPK, and PGC-1α. Furthermore, by the in vitro experiment and AdipoR1 knockdown, we found that inhibition of the AdipoR1 signaling pathway significantly reduced the effect of naringin on slow-twitch fiber-/fast-twitch fiber-related gene and protein expression. In conclusion, our results indicated that naringin could induce skeletal muscle fiber transition from fast twitch to slow twitch via the AdipoR1 signaling pathway. This study may provide new strategy for improving exercise endurance and slow muscle fiber deficiency-related diseases.

Nobiletin activates thermogenesis of brown and white adipose tissue in high-fat diet-fed C57BL/6 mice by shaping the gut microbiota.

Increasing energy expenditure by activating thermogenesis in brown and beige adipocytes is a critical approach to protect against obesity. Here, we investigated the action and mechanism of a natural polymethoxyflavone on adaptive thermogenesis in high-fat diet-induced obesity mouse model. Nobiletin treatment significantly ameliorated obesity, alleviated the whitening of brown adipose tissue, and promoted browning of white adipose tissue in mice fed a high-fat diet. Gut microbiota analysis and metabolomic profiling revealed that nobiletin treatment resulted in a composition shift in the gut microbiota thereby altering fermentation products acetate levels in the host feces and serum. Further, transplantation of the microbiota from nobiletin-treated mice to microbiota-depleted mice activated brown adipose tissue activity, promoted beige adipocytes formation, and improved high-fat diet-induced obesity. Our results indicate that nobiletin could be used as a dietary therapy to prevent HFD-induced obesity, and provide a potential target-specific gut microbial species-driven mechanism for activating thermogenesis in brown and beige adipocytes.

Antinociceptive Effects of Shenling Baizhu through PI3K-Akt-mTOR Signaling Pathway in a Mouse Model of Bone Metastasis with Small-Cell Lung Cancer.

Shenling Baizhu additive powder (SLBZ-AP), a formulation of a variety of natural medicinal plants, has clinical efficacy in treating cancers in previous studies. We explored the effect of SLBZ-AP in bone metastasis of lung cancer (BMLC) mice, and the possible mechanism involved was further investigated in the present study. Mice model of BMLC was made and treated with SLBZ-AP. Pain behavioral tests were performed to explore the effect on BMLC-induced pain in mice. TUNEL staining was used to investigate apoptosis. The mRNA expression of markers in the PI3K/Akt/mTOR pathway was measured by qPCR, and protein expression was detected by western blotting and immunohistochemistry analysis. SLBZ-AP relieved BMLC-induced pain and prolonged animals' survival, promoted cell apoptosis in the marrow from the tibia of BMLC mice, and inhibited mRNA and protein expression of AKT, mTOR, P70S6, and VEGF, as well as protein expression of p-AKT, p-mTOR, p-P70S6, and VEGF upregulation in the marrow of tibia induced by BMLC, an effect which was similar to rapamycin. Our results suggested that SLBZ-AP may have antinociceptive effect and prolong survival of BMLC mice at least partially by inhibiting cell proliferation and promoting apoptosis through the PI3K/Akt/mTOR signaling pathway. SLBZ-AP may be a potential candidate for BMLC therapy.

Expression patterns of clock genes in the hypothalamus and eye of two Lasiopodomys species.

To investigate the relationship between light sensing systems in the eye and circadian oscillators in the hypothalamus of subterranean rodents, we studied subterranean Mandarin voles (Lasiopodomys mandarinus) that spend their entire lives under dark conditions with degenerated eyes, and compared oscillatory expression patterns of clock genes in the hypothalamus and eye between Mandarin voles and their aboveground relatives, Brandt's voles (L. brandtii). Individuals of both vole species were kept under a 12-h light/12-h dark condition or continuous dark condition for 4 weeks. In both species, the expressions of most genes showed significant cosine rhythmicity in the hypothalamus but relatively weak rhythmicity in the eye. The number of rhythmic genes in the eye of Mandarin voles increased under the dark condition, but the opposite trend was observed in the eye of Brandt's voles. The expression levels of most clock genes in the hypothalamus of both vole species did not significantly differ between the two conditions, but unlike in Mandarin voles, these expression levels significantly decreased in the eye of Brandt's voles kept under the dark condition. In both vole species, the peak phase of most clock genes exhibited advanced or invariant change in the hypothalamus under the dark condition, and the peak phase of most clock genes showed consistent changes between the eye and hypothalamus of Mandarin voles. However, most clock genes in the eye showed a delayed phase in Brandt's voles kept under the dark condition. In conclusion, the hypothalamus plays an important role in both vole species irrespective of the light condition. However, the expression patterns of clock genes in the eye differed between the vole species, indicating that each species adapted differently to their environments.

Living near the limits: Effects of interannual variation in food availability on diet and reproduction in a temperate primate, the Taihangshan macaque (Macaca mulatta tcheliensis).

Nutrient intake of animals is influenced by an interplay of external and internal factors, such as food availability and reproductive state, respectively. We used the nutritional geometry framework to analyze individual-based data on energy and nutrient intake in relation to reproductive state in a population of rhesus macaques (Macaca mulatta tcheliensis), which live in a harsh high-latitude habitat, the Taihangshan mountains of China, and exhibit strong reproductive seasonality. We combined data over a 3-year period on food availability, diets, reproductive output, and components of maternal investment to understand how Taihangshan macaques respond to variation in food availability and nutrition in reproduction. Our results show there was high interannual variation in availability of an important staple source of fat and carbohydrates (nonprotein energy), seeds of oak (Quercus spp). Despite this variability in seed availability skewing the dietary macronutrient ratios considerably (from 12.96% to 30.12% dietary energy from protein), total metabolizable energy intake was maintained across years during pregnancy. Lactating females had higher mean daily energy intakes than pregnant females. As in pregnant females, energy intake was maintained constant across years, but only when seed availability enabled the contribution of available protein to energy intake to be maintained between 15.32% (2013) and 17.97% (2015). In 2014, when seeds were scarce, lactating females had a shortfall in energy intake compared with 2013 and 2015. This corresponded with a reduction in the number of females giving birth (11 out of 23), but there was no interannual difference in survival rates. Compared to 2013 and 2015, in 2014 females had greater weight loss (drew on body reserves), moved less, and spent more time nursing their offspring. We discuss implications of these results for range limitation in Taihangshan macaques.

Dietary diversity of an ecological and macronutritional generalist primate in a harsh high-latitude habitat, the Taihangshan macaque (Macaca mulatta tcheliensis).

Recent advances in niche theory have stressed the importance of understanding dietary generalism at multiple levels, including the range of habitat and foods exploited by a species, foods exploited within populations, and patterns of nutrient intake. Here we apply this framework to examine the dietary strategy of the Macaca mulatta, a primate species that is second only to humans in their breadth of geographical distribution, and occupy diverse ecological habitats from cold temperate to tropical latitudes. A recent study showed that the Taihangshan subspecies ( M. mulatta tcheliensis) in China, which is found at the northern latitudinal limit of the species range, respond to ecologically constrained interannual variation in the macronutrient ratios of the spring diet in a way that theory predicts should be associated with ecological generalism. Here we further extend this study, examining the relationships between seasonal variation in food availability and the patterns of food selection across a full year. We found that, despite the ecological and macronutritional generalism of the species, Taihangshan macaques subsist on a relatively small range of foods (57 different foods, spread across 8 categories comprising seeds, fruits, buds, flowers, leaves, herbs, young bark, and twigs), but face considerable seasonal variation in the combinations available. In spring and summer, when seeds were scarce, leaves accounted for 60.3 ± 13.8% of their diet (dry matter [DM] %), and herbs contributed 31.7 ± 22.2%. However, in autumn and winter, when seeds were abundant, they contributed 68.5 ± 22.7% of the diet while herbs accounted for 18.9 ± 12.9% on a DM. Although young bark and twigs were available in all seasons, the macaques only fed on them in winter. We present comparative data from the literature on the diets of M. mulatta and other Macaca species, to interpret this pattern of resource use within the framework of multilevel niche theory.

Low-ranking individuals present high and unstable fecal cortisol levels in provisioned free-ranging adult male rhesus macaques (Macaca mulatta) during the birth season in a mountain area of northern China.

Social hierarchy commonly exists in animal societies, affecting both the endocrine functioning and the behavior of animals. In nonhuman primates, the relationship between social rank and cortisol levels varies across species and even within species. Here, we assessed the relationships between social rank and fecal cortisol levels in adult male Taihangshan macaques (rhesus macaques, Macaca mulatta tcheliensis) from the provisioned, free-ranging Wulongkou-2 (WLK-2) group inhabiting Wulongkou Scenic Area, Jiyuan, China. From March to May 2014, we recorded 195 agonistic behaviors and collected 54 fresh fecal samples from eight adult male Taihangshan macaques. Males were assigned a social rank according to an agonistic behavior matrix, and enzyme-linked immunosorbent assay was then used to measure the cortisol concentration in the fecal samples. We found that social rank among the eight male Taihangshan macaques in WLK-2 group followed a strict linear hierarchy, and that fecal cortisol levels were significantly higher and more variable in low-ranking males than in more dominant individuals. Age was not significantly associated with social rank or fecal cortisol levels. Our results suggest that social rank and maintenance of the social hierarchy within the WLK-2 group is a chronic stressor, with low-ranking males maintaining heightened stress levels and enlarged reactive scope relative to dominant males. This provides new support for the theory that social environment can influence endocrine functioning.

Establishment of a microsatellite set for noninvasive paternity testing in free-ranging Macaca mulatta tcheliensis in Mount Taihangshan area, Jiyuan, China.

BACKGROUND: Within multi-male and multi-female mammalian societies, paternity assignment is crucial for evaluating male reproductive success, dominance hierarchy, and inbreeding avoidance. It is, however, difficult to determine paternity because of female promiscuity during reproduction. Noninvasive molecular techniques (e.g., fecal DNA) make it possible to match the genetic father to his offspring. In the current study, a troop of free-ranging Taihangshan macaques (Macaca mulatta tcheliensis) in Mt. Taihangshan area, Jiyuan, China, was selected for studying the paternity. We successfully screened a set of microsatellite loci from fecal DNA and evaluated the efficiency of these loci for paternity testing using clearly recorded data of maternity. RESULTS: The results showed that: 1) ten loci out of 18 candidate microsatellite loci were amplified successfully in the fecal samples of Taihangshan macaques. The error probability in maternity assignments and paternity testing was very low as indicated by their power of discrimination (0.70 to 0.95), power of exclusion (0.43 to 0.84), and the values of polymorphic information content ranging from 0.52 to 0.82; 2) the combined probability of exclusion in paternity testing for ten qualified loci was as high as 99.999%, and the combined probability of exclusion reached 99.99% when the seven most polymorphic loci were adopted; 3) the offspring were assigned to their biological mother correctly and also matched with their genetic father. CONCLUSIONS: We concluded that the ten polymorphic microsatellite loci, especially a core set of seven most polymorphic loci, provided an effective and reliable tool for noninvasive paternity testing in free-ranging rhesus macaques.