Joint association of TyG index and high sensitivity C-reactive protein with cardiovascular disease: a national cohort study.

BACKGROUND: Both the triglyceride-glucose (TyG) index, as a surrogate marker of insulin resistance, and systemic inflammation are predictors of cardiovascular diseases; however, little is known about the coexposures and relative contributions of TyG index and inflammation to cardiovascular diseases. Using the nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS), we conducted longitudinal analyses to evaluate the joint and mutual associations of the TyG index and high-sensitivity C-reactive protein (hsCRP) with cardiovascular events in middle-aged and older Chinese population. METHODS: This study comprised 8 658 participants aged at least 45 years from the CHARLS 2011 who are free of cardiovascular diseases at baseline. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Cardiovascular events were defined as the presence of physician-diagnosed heart disease and/or stroke followed until 2018.We performed adjusted Cox proportional hazards regression and mediation analyses. RESULTS: The mean age of the participants was 58.6 ± 9.0 years, and 3988 (46.1%) were females. During a maximum follow-up of 7.0 years, 2606 (30.1%) people developed cardiovascular diseases, including 2012 (23.2%) cases of heart diseases and 848 (9.8%) cases of stroke. Compared with people with a lower TyG index (< 8.6 [median level]) and hsCRP < 1 mg/L, those concurrently with a higher TyG and hsCRP had the highest risk of overall cardiovascular disease (adjusted hazard ratio [aHR], 1.300; 95% CI 1.155-1.462), coronary heart disease (aHR, 1.294; 95% CI 1.130-1.481) and stroke (aHR, 1.333; 95% CI 1.093-1.628), which were predominant among those aged 70 years or below. High hsCRP significantly mediated 13.4% of the association between the TyG index and cardiovascular disease, while TyG simultaneously mediated 7.9% of the association between hsCRP and cardiovascular risk. CONCLUSIONS: The findings highlight the coexposure effects and mutual mediation between the TyG index and hsCRP on cardiovascular diseases. Joint assessments of the TyG index and hsCRP should be underlined for the residual risk stratification and primary prevention of cardiovascular diseases, especially for middle-aged adults.

Comparison of triglyceride glucose index and modified triglyceride glucose indices in prediction of cardiovascular diseases in middle aged and older Chinese adults.

BACKGROUND: Triglyceride and glucose (TyG) index, a surrogate marker of insulin resistance, has been validated as a predictor of cardiovascular disease. However, effects of TyG-related indices combined with obesity markers on cardiovascular diseases remained unknown. We aimed to investigate the associations between TyG index and modified TyG indices with new-onset cardiovascular disease and the time-dependent predictive capacity using a national representative cohort. METHODS: This study is a retrospective observational cohort study using data from China Health and Retirement Longitudinal Study (CHARLS) of 7 115 participants. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The modified TyG indices were developed combining TyG with body mass index (BMI), waist circumference (WC) and waist-to-height ratio (WHtR). We used adjusted Cox proportional hazards regression to analyze the association and predictive capacity based on hazard ratio (HR) and Harrell's C-index. RESULTS: Over a 7-year follow-up period, 2136 participants developed cardiovascular disease, including 1633 cases of coronary heart disease and 719 cases of stroke. Compared with the lowest tertile group, the adjusted HR (95% CI) for new-onset cardiovascular disease in the highest tertile for TyG, TyG-BMI, TyG-WC, and TyG-WHtR were 1.215 (1.088-1.356), 1.073 (0.967-1.191), 1.078 (0.970-1.198), and 1.112 (1.002-1.235), respectively. The C-indices of TyG index for cardiovascular disease onset were higher than other modified TyG indices. Similar results were observed for coronary heart disease and stroke. CONCLUSION: TyG and TyG-WhtR were significantly associated with new-onset cardiovascular diseases, and TyG outperformed the modified TyG indices to identify individuals at risk of incident cardiovascular event.

The Rational Design and Atroposelective Synthesis of Axially Chiral C2-Arylpyrrole-Derived Amino Alcohols.

Axially chiral biaryl diols have achieved great success in asymmetric catalysis. By contrast, axially chiral biaryl amino alcohols are far less developed. Herein, we have rationally designed a versatile C1 -symmetric biaryl amino alcohol scaffold 1-(1-amino-pyrrol-2-yl)naphthalen-2-ol (NPNOL) on the basis of axially chiral C2-arylpyrrole framework. For its enantioselective synthesis, the chiral phosphoric acid-catalyzed asymmetric Attanasi reaction between 1,3-dicarbonyl compounds and azoalkenes had been established. By using this practical method, a wide range of NPNOLs were readily prepared in high yields and excellent atroposelectivities (38 examples, up to 89 % yield and 99 % ee). DFT calculations were performed to reveal the reaction mechanism and the origins of the enantioselectivity. The easy transformations of NPNOL-derived products into organocatalysts/ligands and their preliminary applications in asymmetric catalytic reactions demonstrated the promising utility of NPNOL.

Intraindividual Discordance Between Remnant Cholesterol and Low-Density Lipoprotein Cholesterol Associated With Incident Stroke: Results From 2 National Cohorts.

BACKGROUND: The atherogenic effect of remnant cholesterol is being increasingly acknowledged. This study aimed to explore the association of discordance between remnant cholesterol and low-density lipoprotein cholesterol with stroke onset using 2 Chinese national cohorts. METHODS AND RESULTS: We studied 11 139 participants from CHARLS (China Health and Retirement Longitudinal Study) and 5993 participants from CHNS (China Health and Nutrition Survey) aged 45 years or older. The discordance between remnant cholesterol and low-density lipoprotein cholesterol was defined using the difference in percentile units (>15 units). There were 988 (8.9%) and 128 (2.1%) stroke events reported during follow-up in the 2 cohorts. Elevated remnant cholesterol was significantly associated with a higher risk of total stroke in 2 cohorts. After adjusting for remnant cholesterol level, the discordantly high remnant cholesterol group was significantly associated with an increased stroke risk (CHARLS: subdistribution hazard ratio [sHR], 1.31 [95 CI, 1.10-1.55]; CHNS: sHR, 1.84 [95 CI, 1.15-3.08]) compared with the discordantly low group. Consistent results were shown even among those with optimal low-density lipoprotein cholesterol level. CONCLUSIONS: The discordance between remnant cholesterol and low-density lipoprotein cholesterol, representing the intraindividual discrepancy, is significantly associated with stroke onset among Chinese adults.

Mutation of Disulfide Bond Sites Reduces the Immunoreactivity of Cra a 4 by Changing the Structural Characteristics.

Sarcoplasmic calcium-binding protein (Cra a 4) from Crassostrea angulata belongs to the EF-hand superfamily, and understanding of its structure-allergenicity relationship is still insufficient. In this study, chemical denaturants were used to destroy the structure of Cra a 4, showing that disruption of the structure reduced its IgG-/IgE-binding activity. To explore which critical amino acid site affects the allergenicity of Cra a 4, the mutants were obtained by site-directed mutations in the disulfide bonds site (C97), conformational epitopes (I105, D114), or Ca2+-binding region (D106, D110) and their IgG-/IgE-binding activity was reduced significantly using serological tests. Notably, C97A had the lowest immunoreactivity. In addition, two conformational epitopes of Cra 4 were verified. Meanwhile, the increase of the α-helical content, surface hydrophobicity, and surface electrostatic potential of C97A affected its allergenicity. Overall, the understanding of the structure-allergenicity relationship of Cra a 4 allowed the development of a hypoallergenic mutant.

Serum cystatin C and stroke risk: a national cohort and Mendelian randomization study.

Purpose: The debate over the causal and longitudinal association between cystatin C and stroke in older adults persists. Our aim was to assess the link between cystatin C levels, both measured and genetically predicted, and stroke risk. Methods: This study employed a retrospective cohort design using samples of the China Health and Retirement Longitudinal Study (CHARLS), which is a nationally representative cohort recruiting individuals aged 45 years or above. A multivariate logistic model and the two-sample Mendelian randomization framework were used to investigate the longitudinal and genetically predicted effect of serum cystatin C on stroke. Results: The study population had a mean age of 59.6 (SD ±9.5), with 2,996 (46.1%) women. After adjusting for confounding factors, compared to those in the first quartile of cystatin C, those in the last quartile had the greatest risk of stroke incidence [odds ratio (OR), 1.380; 95% confidence interval (CI), 1.046-1.825]. The Mendelian randomization analysis showed that a genetically predicted cystatin C level was positively associated with total stroke (OR by inverse variance-weighted method, 1.114; 95% CI, 1.041-1.192). Conclusions: This national cohort study suggests that higher serum cystatin C is associated with an increased risk of total stroke, which is further supported by Mendelian randomization.

Comparative Analysis of Free and Glycoconjugates Oligosaccharide Content in Milk from Different Species.

Human milk is important for infant growth, and oligosaccharides are one of its main functional nutrients. To enable a systematic comparison of free oligosaccharide and glycoconjugate content in milk from different species, the phenol-sulfuric acid and resorcinol assays were combined to determine the content. Using real samples, the method revealed that human milk contained the highest amount of total, neutral (9.84 ± 0.31 g/L), and sialylated (3.21 ± 0.11 g/L) free oligosaccharides, followed by goat milk, with neutral (0.135 ± 0.015 g/L) and sialylated (0.192 ± 0.016 g/L) free oligosaccharides and at a distance by bovine and yak milk. The highest total glycoconjugate content was detected in yak milk (0.798 ± 0.011 g/L), followed by human, bovine, and goat milk. These findings suggest that goat milk is the best source of free oligosaccharides in infant formula and functional dairy products and yak milk is the best source of glycoconjugates.

Catalytic [2,3]-sigmatropic rearrangement of sulfonium ylides derived from azoalkenes: non-carbenoid Doyle-Kirmse reaction.

The Sc(III)-catalyzed [2,3]-sigmatropic rearrangement of sulfonium ylides derived from azoalkenes has been established. Owing to the absence of a carbenoid intermediate, this protocol represents the first non-carbenoid variant of the Doyle-Kirmse reaction. Under mild conditions, a variety of tertiary thioethers have been readily prepared in good to excellent yields.

Catalytic asymmetric interrupted Attanasi reaction: access to fused 2,3-dihydropyrroles with vicinal quaternary carbons.

The first catalytic asymmetric interrupted Attanasi reaction has been established. Under the catalysis of a bifunctional organocatalyst, the condensation of cyclic ß-keto esters with azoalkenes readily occurred, delivering a variety of bicyclic fused 2,3-dihydropyrroles with vicinal quaternary stereogenic centers in good yields and with good to excellent enantioselectivities (27 examples, up to 96% yield and 95% ee).

Pure-Phase, Large-Grained Wide-Band-Gap Perovskite Films for High-Efficiency, Four-Terminal Perovskite/Silicon Tandem Solar Cells.

High-quality, stable perovskite films with a wide band gap between 1.65 and 1.80 eV are highly suitable for efficient and cost-competitive silicon-based tandem solar cells. Herein, we demonstrate that the combined strategies of the Pb(SCN)2 additive and air annealing can enable the Cs0.22FA0.78Pb(I0.85Br0.15)3 films with a wide band gap of 1.65 eV and favored properties including pure composition, high crystallinity, micro-sized grains, and reduced defects. With these desired films, the average efficiencies of semitransparent perovskite solar cells (PSCs) are boosted from (18.13 ± 0.31) to (20.35 ± 0.28)%. Further, the semitransparent PSC is used to assemble the four-terminal perovskite/TOPCon tandem solar cell. Benefiting from its excellent performance and preferred optical properties, the obtained tandem solar cell yields a milestone efficiency of 30.32%.

Catalytic atroposelective synthesis of heterobiaryls with vicinal C-C and N-N diaxes via dynamic kinetic resolution.

Reported herein is a highly efficient dynamic kinetic resolution protocol for the atroposelective synthesis of heterobiaryls with vicinal C-C and N-N diaxes. Atropisomers bearing vicinal diaxes mainly exist in o-triaryls, while that of biaryls is highly challenging in terms of the concerted rotation and deplanarization effects. The combination of C-C biaryl with N-N nonbiaryl delivers a novel class of vicinal-diaxis heterobiaryls. For their atroposelective synthesis, the dynamic kinetic resolution enabled by either quinine-catalyzed allylation or isothiourea-catalyzed acylation has been developed, allowing the preparation of a wide range of vicinal-axis heterobiaryls in good yields with excellent enantioselectivities. Atropisomerization experiments revealed that the C-C bond rotation led to diastereomers, and the N-N bond rotation offered enantiomers. Besides, this protocol could be extended to kinetic resolution by employing substrates with a more hindered axis.

Novel Method for Adulterated Identification of Saneen Goat Milk Based on Free Oligosaccharides α3'-Galactosyllactose and N-Acetylhexaminyllactose as Marker Molecules.

Methods for the detection of adulterated milk are essential for assessing the quality of goat milk products. We hypothesized that goat milk oligosaccharides could provide a basis for this purpose and compared the levels of α3'-galactosyllactose (α3'-GL) and N-acetylhexaminyllactose (NHL) between goat milk and bovine milk oligosaccharides using reverse-phase high-performance liquid chromatography. The α3'-GL was detected to be three times more abundant in goat milk than in bovine milk, whereas NHL showed the opposite trend. Linear relationships were established between the relative proportions of α3'-GL and NHL levels for different ratios of bovine and goat milk, with a minimum detection limit of 2% bovine milk. The new method was validated by analyses of adulterants in eight commercially available goat dairy products. Overall, the degree of adulteration in goat milk products can be determined based on the relative proportions of α3'-GL and NHL.

Human milk whey glycoprotein N-glycans varied greatly among different maternal secretor status.

Human milk glycans are complex carbohydrates, which play a pivotal role in infant health and neonatal development. Maternal secretor status is known to affect free oligosaccharides in milk. Here, the milk N-glycome of secretor (Se+) and nonsecretor (Se-) individuals was qualitatively and quantitatively analyzed by hydrophilic interaction chromatography-electrospray ionization-tandem mass spectrometry. The total glycosylation, fucosylation, and sialylation of N-glycans was three times higher in the Se+ group compared to the Se- group (p < 0.001) per equal volume of milk. Importantly, 52 out of 63 N-glycans-including the eight most abundant ones-differed greatly between Se+ and Se- individuals (p < 0.05). Moreover, nine N-glycans (H5N3F1, H6N3, H3N5F1, H5N5F1, H5N5F1S1, H5N4F3S1, H6N4F2S1, H6N5F4S1, and H8N7S1) were >10 times more abundant in Se+ milk than in Se- milk. These findings lay a glycomics-basis for designing personalized nutrition supplements for infants.

Sea cucumber chondroitin sulfate polysaccharides attenuate OVA-induced food allergy in BALB/c mice associated with gut microbiota metabolism and Treg cell differentiation.

Previous research studies have shown that sulfated polysaccharides can inhibit food allergy, but the detailed mechanism remains largely unknown. In this study, RBL-2H3 cells were used to compare the anti-allergic activities of four sulfated polysaccharides, and an ovalbumin (OVA)-sensitized allergic mouse experiment was used to explore their desensitization effect, with regard to the alteration in gut microbiota and immune cell differentiation. Compared with the shark, bovine and porcine chondroitin sulfate, sea cucumber chondroitin sulfate (SCCS) significantly inhibited the degranulation of RBL-2H3 cells. SCCS reduced allergic symptoms and protected the jejunum from injury in mice. Furthermore, SCCS increased the relative abundance of Lachnospiraceae NK4A136, decreased the relative proportion of Prevotellaceae NK3B31, and up-regulated the secretion of short chain fatty acids such as butyric acid in the feces, resulting in an increase in the mucin 2 (MUC2) secretion by goblet cells HT-29. Meanwhile, SCCS induced the differentiation of regulatory T cells in the mesenteric lymph nodes of mice. This study provides a deeper understanding of the functioning mechanism of SCCS in alleviating food allergy and may guide the development and production of anti-allergy active ingredients.

Catalytic asymmetric dearomatization of phenols via divergent intermolecular (3 + 2) and alkylation reactions.

The catalytic asymmetric dearomatization (CADA) reaction has proved to be a powerful protocol for rapid assembly of valuable three-dimensional cyclic compounds from readily available planar aromatics. In contrast to the well-studied indoles and naphthols, phenols have been considered challenging substrates for intermolecular CADA reactions due to the combination of strong aromaticity and potential regioselectivity issue over the multiple nucleophilic sites (O, C2 as well as C4). Reported herein are the chiral phosphoric acid-catalyzed divergent intermolecular CADA reactions of common phenols with azoalkenes, which deliver the tetrahydroindolone and cyclohexadienone products bearing an all-carbon quaternary stereogenic center in good yields with excellent ee values. Notably, simply adjusting the reaction temperature leads to the chemo-divergent intermolecular (3 + 2) and alkylation dearomatization reactions. Moreover, the stereo-divergent synthesis of four possible stereoisomers in a kind has been achieved via changing the sequence of catalyst enantiomers.

Further developments of ß,γ-unsaturated α-ketoesters as versatile synthons in asymmetric catalysis.

ß,γ-Unsaturated α-ketoesters prove to be versatile organic synthons participating in diverse catalytic asymmetric transformations with the breathtaking development of organo-catalysis, new catalytic systems including ingenious chiral ligands as well as Lewis acid cations. The highly efficient creation of stereogenic centers with excellent enantioselectivity is not a surprise, but owes to the bidentate coordination of its unique 1,2-dicarbonyl motif to artful chiral messenger, establishing a rigid system for the precise chiral-identification of the attack. In the past five years, various reaction modes of ß,γ-unsaturated α-ketoesters have been developed, involving their multiple reaction sites, such as the carbon-carbon double bond (C=C), the carbonyl group (C=O), the entire C=C-C=O fragment, and the ester group. In this review, we summarize the state-of-the-art catalytic asymmetric reactions of ß,γ-unsaturated α-ketoesters, to provide an updated overview to chemists working in this and related fields, facilitating their discoveries in asymmetric catalysis, natural products synthesis, and drug development.

Identification of the Immunoglobulin E Epitope of Arginine Kinase, an Important Allergen from Crassostrea angulata.

Arginine kinase (AK) was identified as an allergen in Crassostrea angulata. However, little information is available about its epitopes. In this study, AK from C. angulata was registered to the World Health Organization/International Union of Immunological Societies allergen nomenclature committee to be named as Cra a 2. The immunoglobulin G/immunoglobulin E-binding capacity of Cra a 2 was significantly reduced after chemical denaturation treatment. Further, eight linear mimotopes and five conformational mimotopes of Cra a 2 were obtained using phage panning. In addition to six linear epitopes that have been identified, two linear epitopes were verified by a synthetic peptide, of which L-Cra a 2-2 was conserved in shellfish. Four conformational epitopes were verified by site-directed mutation, among which mutation of C-Cra a 2-1 affected the structure and reduced the immunoreactivity of Cra a 2 most significantly. Overall, the identified epitopes may lay a foundation for the development of hypoallergenic oyster products through food processing.

2-Indolymethanols as 4-atom-synthons in oxa-Michael reaction cascade: access to tetracyclic indoles.

The first Brønsted acid-catalyzed oxa-Michael reaction cascade of 2-indolylmethanols with trione alkenes was accomplished. By using this practical approach, a variety of tetracyclic indoles were readily created in an ordered sequence with excellent regio- and diastereoselectivity. 2-Indolylmethanols commendably served as four-atom synthons, as opposed to the common three-atom synthons in the previous literature reports. The regioselectivity issue was well handled by the employment of a strong Brønsted acid catalyst. In addition, its dual role in activation of substrates via hydrogen-bonding interaction and acceleration of subsequent intramolecular cyclization and dehydration was proposed to account for the high reaction efficiency.

Bmk9 and Uricase Nanoparticle Complex for the Treatment of Gouty Arthritis and Uric Acid Nephropathy.

Uric acid is the final product of purine metabolism, and excessive serum uric acid can cause gouty arthritis and uric acid nephropathy. Therefore, lowering the uric acid level and alleviating inflammation in the body are the key points to treating these diseases. A stable nanosuspension of peptide BmK9 was prepared by the precipitation-ultrasonication method. By combining uricase on the surface of a positively charged carrier, a complex consisting of neutral rod-shaped BmK9 and uricase nanoparticles (Nplex) was formed to achieve the delivery of BmK9 and uricase, respectively. The formulation of Nplex has a diameter of 180 nm and drug loading up to 200%, which releases BmK9 and uricase slowly and steadily in drug release tests in vitro. There was significantly improved pharmacokinetic behavior of the two drugs because Nplex prolonged the half-life and increased tissue accumulation. Histological assessments showed that the dual drug Nplex can reduce the inflammation response in acute gouty arthritis and chronic uric acid nephropathy in vivo. In the macrophage system, there was lower toxicity and increased beneficial effect on inflammation with Nplex than free BmK9 or uricase. Collectively, this novel formulation provides a dual drug delivery system that can treat gouty arthritis and uric acid nephropathy.

Identification of poly(ADP-ribose)polymerase 1 and 2 (PARP1/2) as targets of andrographolide using an integrated chemical biology approach.

Here, we describe the identification of PARP1/2 as direct binding proteins of andrographolide (Andro) using protein microarray, surface plasmon resonance (SPR), and enzyme activity assays. We then evaluated the proliferation inhibition, apoptosis, and cell migration effects of Andro on the MDA-MB-436 cell line in vitro. The final biological evaluation confirmed that Andro was a highly effective single agent in the MDA-MB-436 xenograft model and had a low hERG-mediated cardiac toxicity. Therefore, Andro represents the first natural product, non-amide member of a novel nanomolar-potency PARP1/2 inhibitor family.