Ligand-Enabled Pd-Catalyzed sp3 C‒H Macrocyclization: Synthesis and Evaluation of Macrocyclic Sulfonamide for the Treatment of Parkinson's Disease.

The development of simplified synthetic strategy to create structurally and functionally diverse pseudo-natural macrocyclic molecules is highly appealing but poses a marked challenge. Inspired by natural scaffolds, herein, we describe a practical and concise ligand-enabled Pd(II)-catalysed sp3 C‒H alkylation, olefination and arylation macrocyclization, which could offer a novel set of pseudo-natural macrocyclic sulfonamides. Interestingly, the potential of ligand acceleration in C‒H activation is also demonstrated by an unprecedented enantioselective sp3 C‒H alkylation macrocyclization. Moreover, a combination of in silico screening and biological evaluation led to the identification of a novel spiro-grafted macrocyclic sulfonamide 2a, which showed a promising efficacy for the treatment of Parkinson's disease (PD) in a mouse model through the activation of silent information regulator sirtuin 3 (SIRT3).

Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy.

Mycobacterium tuberculosis (Mtb), the infectious agent of tuberculosis (TB), causes over 1.5 million deaths globally every year. Host-directed therapies (HDT) for TB are desirable for their potential to shorten treatment and reduce the development of antibiotic resistance. Previously, we described a modular biomimetic strategy to identify SMIP-30, targeting PPM1A (IC50 = 1.19 µM), a metal-dependent phosphatase exploited by Mtb to survive intracellularly. SMIP-30 restricted the survival of Mtb in macrophages and lungs of infected mice. Herein, we redesigned SMIP-30 to create SMIP-031, which is a more potent inhibitor for PPM1A (IC50 = 180 nM). SMIP-031 efficiently increased the level of phosphorylation of S403-p62 and the expression of LC3B-II to activate autophagy, resulting in the dose-dependent clearance of Mtb in infected macrophages. SMIP-031 possesses a good pharmacokinetic profile and oral bioavailability (F = 74%). In vivo, SMIP-031 is well tolerated up to 50 mg/kg and significantly reduces the bacteria burden in the spleens of infected mice.

Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors.

Although vaccination remains the prevalent prophylactic means for controlling Influenza A virus (IAV) infections, novel structural antivirus small-molecule drugs with new mechanisms of action for treating IAV are highly desirable. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring oxime, which might target the hemagglutinin (HA)-mediated IAV entry into the host cells. SAR analysis revealed that the size and linker of the macrocycles play an important role in improving potency. Particularly, as a 14-membered macrocyclic oxime, 37 exhibited potent inhibitory activity against IAV H1N1 with an EC50 value of 23 nM and low cytotoxicity, which alleviated cytopathic effects and protected cell survival obviously after H1N1 infection. Furthermore, 37 showed significant synergistic activity with neuraminidase inhibitor oseltamivir in vitro.

A real-world pharmacovigilance analysis of the FDA adverse event reporting system events for polatuzumab vedotin.

BACKGROUND: Polatuzumab vedotin is the first antibody-drug conjugate approved by the US Food and Drug Administration (FDA) for patients with diffuse large B-cell lymphoma. This study evaluated adverse events (AEs) associated with polatuzumab vedotin by data mining of the FDA Adverse Event Reporting System (FAERS). METHODS: This study included AEs registered in FAERS between 2019 Q2 and 2023 Q2. Four algorithms were used to quantify the signals of polatuzumab vedotin-associated AEs, including reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. RESULTS: A total of 7,609,450 reports were collected from the FAERS database, and 1,388 reports of polatuzumab vedotin were identified as primary suspected AEs. Polatuzumab vedotin-associated AEs involved 26 organ systems. According to the four algorithms, 108 significant disproportionality AEs were retained simultaneously. Unexpected significant AEs included gastrointestinal hemorrhage, ileus, gastrointestinal perforation, cholecystitis, hypogammaglobulinemia, hepatitis B reactivation, hypercalcemia, hydronephrosis, cystitis hemorrhagic, interstitial lung disease, and thrombophlebitis. The median time to onset of polatuzumab vedotin-associated AEs was 20 (interquartile range 4-56) days. CONCLUSIONS: Our study identified significant new AE signals for polatuzumab vedotin through real-world disproportionality analysis data and may provide additional evidence for risk identification of polatuzumab vedotin.

Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance.

Natural macrocycles have shown impressive activity to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). However, the total synthesis and structural modification of natural macrocycles are challenging, which would hamper the deeper investigations of their structure-activity relationship (SAR) and drug likeness. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring polysubstituted 1,3-diene, which efficiently inhibited P-gp and reversed MDR in cancer cells. The SAR analysis revealed that the size and linker of the macrocycles are important structural characteristics to restore activity. Particularly, 32 containing a naphthyl group and (d)-Phe moiety has higher potency with an excellent reversal fold than verapamil at a concentration of 5 µM, which induces conformational change of P-gp and inhibits its function instead of altering P-gp expression. Furthermore, 23 and 32 were identified to be attractive leads, which possess a good pharmacokinetic profile and antitumor activity in a KBV200 xenograft mouse model.

Rhodium(III)-Catalyzed C-H/O2 Dual Activation and Macrocyclization: Synthesis and Evaluation of Pyrido[2,1-a]isoindole Grafted Macrocyclic Inhibitors for Influenza H1N1.

The development of environment-friendly, step economic couplings to generate structurally diverse macrocyclic compounds is highly desirable but poses a marked challenge. Inspired by the C-H oxidation mechanism of cytochromes P450, an unprecedented and practical RhIII -catalyzed acylmethylation macrocyclization via C-H/O2 dual activation has been developed by us. The process of macrocyclization is facilitated by a synergic coordination from pyridine and ester group. Interestingly, the reaction mode derives from a three-component coupling which differs from established olefination and alkylation paths. Density functional theory (DFT) calculations and control experiments revealed the mechanism of this unique C-H/O2 dual activation. The newly achieved acylmethylation macrocyclic products and their derivatives showed a potent anti-H1N1 bioactivity, which may provide an opportunity for the discovery of novel anti-H1N1 macrocyclic leading compounds.

A selective PPM1A inhibitor activates autophagy to restrict the survival of Mycobacterium tuberculosis.

Metal-dependent protein phosphatases (PPMs) have essential roles in a variety of cellular processes, including inflammation, proliferation, differentiation, and stress responses, which are intensively investigated in cancer and metabolic diseases. Targeting PPMs to modulate host immunity in response to pathogens is an ambitious proposition. The feasibility of such a strategy is unproven because development of inhibitors against PPMs is challenging and suffers from poor selectivity. Combining a biomimetic modularization strategy with function-oriented synthesis, we design, synthesize and screen more than 500 pseudo-natural products, resulting in the discovery of a potent, selective, and non-cytotoxic small molecule inhibitor for PPM1A, SMIP-30. Inhibition of PPM1A with SMIP-30 or its genetic ablation (ΔPPM1A) activated autophagy through a mechanism dependent on phosphorylation of p62-SQSTM1, which restricted the intracellular survival of Mycobacterium tuberculosis in macrophages and in the lungs of infected mice. SMIP-30 provides proof of concept that PPMs are druggable and promising targets for the development of host-directed therapies against tuberculosis.

Inverse Association of Serum Adipsin with the Remission of Nonalcoholic Fatty-Liver Disease: A 3-Year Community-Based Cohort Study.

PURPOSES: Adipokine alterations contribute to the development and remission of nonalcoholic fatty-liver disease (NAFLD). Adipsin is one of the most abundant adipokines and is almost exclusively produced by adipocytes. However, data on adipsin in human NAFLD are limited and controversial. We performed this study to investigate the association between adipsin and the remission of NAFLD in middle-aged and elderly Chinese adults. METHODS: Whether adipsin is associated with the remission of NAFLD in a 3-year community-based prospective cohort study was investigated. Baseline levels of adipsin were measured in serum samples collected from 908 NAFLD participants. NAFLD was diagnosed using abdominal ultrasonography. Logistic regression analysis and a multiple stepwise logistic regression model including different variables were conducted to evaluate the association between serum adipsin levels and the remission of NAFLD. RESULTS: During a mean follow-up of 3.14 ± 0.36 years, 247 (27.20%) participants with NAFLD at baseline were in remission. At baseline, serum adipsin concentration was positively correlated with body mass index (r: 0.39, p < 0.001), insulin (r: 0.31, p < 0.001), and homeostasis model assessment of insulin resistance (r: 0.31, p < 0.001) and was inversely associated with NAFLD remission with a fully adjusted odds ratio (OR) of 0.28 (0.16-0.48) (p trend < 0.001). In a multiple stepwise logistic regression model, circulating adipsin independently predicted NAFLD remission (OR: 0.284, 95% confidence interval [CI]: 0.172-0.471, p for trend <0.001). The area under the receiver operating characteristic curve was 0.751 (95% CI: 0.717-0.785) (p < 0.001) for the prediction model of NAFLD remission. CONCLUSIONS: We provide evidence for an association between serum adipsin levels and the remission of NAFLD in a community-based prospective cohort study. Serum adipsin can be a potential biomarker for predicting NAFLD remission.

Rh-Catalyzed C-H alkylation enabling modular synthesis of CF3-substituted benzannulated macrocyclic inhibitors of B cell responses.

Inspired by aspirin and chalcone, herein, we describe a modular biomimetic strategy to achieve a new class of CF3-bearing benzannulated macrolactams. The key to the success of macrolactams was the utilization of a highly chemoselective Rh(iii)-catalyzed native carboxylic acid-directed C-H alkylation. Moreover, the unique CF3-containing benzannulated macrocycles showed decent immunosuppressive effects on B cells in vitro, including proliferation, activation, and antibody production upon specific stimulation implicating TLR and BCR signaling.

Resveratrol enhances trans-intestinal cholesterol excretion through selective activation of intestinal liver X receptor alpha.

Resveratrol (RSV) is a dietary polyphenol with well-documented cardio-protective activity, but its effects on blood cholesterol levels remain to be established. Due to its poor bioavailability, tissue accumulation of RSV is extremely low except for that in the small intestine. In the present study, we aimed to investigate the dose-dependent effects of RSV on blood cholesterol levels and the involvement of small intestine in the cholesterol-lowering impacts of RSV. Mice were administrated with RSV at various doses with high-fat diet (HFD) or high-fat and high-cholesterol diet (HCD) for 12 weeks. The fecal neutral sterol contents were analyzed, and intestinal perfusion test was performed. An enteric barrier model using Caco-2 cells was established. We observed that RSV reduced blood cholesterol levels in a dose-dependent manner in mice fed with HFD or HCD. Further investigation revealed that RSV administration increased the bile acid pool size but did not affect cholesterol consumption or de novo cholesterol synthesis. Interestingly, RSV promoted trans-intestinal cholesterol excretion (TICE) by 2-fold in the intestinal perfusion test. In addition, RSV upregulated the expressions of ATP-binding cassette sub-family G member 5 or 8 (Abcg5/8) and ATP-binding cassette sub-family B member 1a or 1b (Abcb1a/b) by up to 8 times in the duodenum mucosa but not in the liver. RSV also significantly downregulated the expression of intestinal Niemann-Pick C1-Like 1 (Npc1l1). Knock-down of liver X receptor alpha (LXRα) but not Sirt1 by siRNA significantly blocked RSV-induced cholesterol excretion in Caco-2 cells. In conclusion, RSV could decrease circulating cholesterol levels through enhancing TICE and limiting cholesterol absorption via selective activation of intestinal LXRα.

Marine furanocembranoids-inspired macrocycles enabled by Pd-catalyzed unactivated C(sp3)-H olefination mediated by donor/donor carbenes.

Biomimetic modularization and function-oriented synthesis of structurally diversified natural product-like macrocycles in a step-economical fashion is highly desirable. Inspired by marine furanocembranoids, herein, we synthesize diverse alkenes substituted furan-embedded macrolactams via a modular biomimetic assembly strategy. The success of this assembly is the development of crucial Pd-catalyzed carbene coupling between ene-yne-ketones as donor/donor carbene precursors and unactivated Csp3‒H bonds which represents a great challenge in organic synthesis. Notably, this method not only obviates the use of unstable, explosive, and toxic diazo compounds, but also can be amenable to allenyl ketones carbene precursors. DFT calculations demonstrate that a formal 1,4-Pd shift could be involved in the mechanism. Moreover, the collected furanocembranoids-like macrolactams show significant anti-inflammatory activities against TNF-α, IL-6, and IL-1ß and the cytotoxicity is comparable to Dexamethasone.

Salt Stress Modulates the Landscape of Transcriptome and Alternative Splicing in Date Palm (Phoenix dactylifera L.).

Date palm regards as a valuable genomic resource for exploring the tolerance genes due to its ability to survive under the sever condition. Although a large number of differentiated genes were identified in date palm responding to salt stress, the genome-wide study of alternative splicing (AS) landscape under salt stress conditions remains unknown. In the current study, we identified the stress-related genes through transcriptomic analysis to characterize their function under salt. A total of 17,169 genes were differentially expressed under salt stress conditions. Gene expression analysis confirmed that the salt overly sensitive (SOS) pathway genes, such as PdSOS2;1, PdSOS2;2, PdSOS4, PdSOS5, and PdCIPK11 were involved in the regulation of salt response in date palm, which is consistent with the physiological analysis that high salinity affected the Na+/K+ homeostasis and amino acid profile of date palm resulted in the inhibition of plant growth. Interestingly, the pathway of "spliceosome" was enriched in the category of upregulation, indicating their potential role of AS in date palm response to salt stress. Expectedly, many differentially alternative splicing (DAS) events were found under salt stress conditions, and some splicing factors, such as PdRS40, PdRSZ21, PdSR45a, and PdU2Af genes were abnormally spliced under salt, suggesting that AS-related proteins might participated in regulating the salt stress pathway. Moreover, the number of differentially DAS-specific genes was gradually decreased, while the number of differentially expressed gene (DEG)-specific genes was increased with prolonged salt stress treatment, suggesting that AS and gene expression could be distinctively regulated in response to salt stress. Therefore, our study highlighted the pivotal role of AS in the regulation of salt stress and provided novel insights for enhancing the resistance to salt in date palm.

Associations between serum total, free and bioavailable testosterone and non-alcoholic fatty liver disease in community-dwelling middle-aged and elderly women.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is considered both a cause and consequence of the metabolic syndrome (MetS). While emerging evidence has indicated that testosterone is associated with MetS, the relationship between testosterone and NAFLD in women remains unclear. Therefore, this study investigated the associations between serum testosterone levels and NAFLD prevalence risk in a community-based cross-sectional study. METHODS: A total of 2117 adult women were included in the analysis. Serum total testosterone (TT) was measured by chemiluminescence immunoassay, and other testosterone-related indices, such as concentrations and percentages of calculated free testosterone (cFT) and bioavailable testosterone (BioT), and free androgen index (FAI), were also calculated. NAFLD was diagnosed by clinical criteria. Logistic regression was used to explore these associations. RESULTS: There were significant differences in TT, FAI, cFT and BioT between women with and without NAFLD (all P<0.001). Multivariate logistic-regression analyses demonstrated that both absolute concentrations and percentages of cFT and BioT were positively associated with NAFLD risk prevalence in all models. Adjusted ORs (95% CI) for quartile 4 vs quartile 1 of % cFT and % BioT were 5.94 (4.29-8.22) and 5.21 (3.79-7.17) in model 2, and 4.35 (3.07-6.18) and 3.58 (2.55-5.03) in model 3 (all P<0.001 for trend). In addition, quartiles of TT, FAI, cFT and BioT were significantly correlated with degree of hepatic steatosis. ROC analysis also showed that % cFT and % BioT were more accurate for predicting NAFLD prevalence than was TT. CONCLUSION: Serum cFT and BioT were positively associated with NAFLD risk, and elevated levels of cFT and BioT could be independent risk factors of NAFLD prevalence in middle-aged and elderly women.

Anthocyanin supplementation at different doses improves cholesterol efflux capacity in subjects with dyslipidemia-a randomized controlled trial.

BACKGROUND/OBJECTIVES: Numerous clinical trials have confirmed that supplementation with purified anthocyanins has favorable effects on metabolic diseases, but the dose-response of dyslipidemia to anthocyanin supplementation remains unclear. This study aimed to investigate the effect of anthocyanin supplementation in different doses on lipid profile. SUBJECTS/METHODS: We randomly assigned 176 dyslipidemic subjects aged 35-70 to three purified anthocyanin groups (40 mg/day, n = 45; 80 mg/day, n = 42; 320 mg/day, n = 43) and a placebo group (n = 46). Anthropometric parameters, serum lipid profiles, and cholesterol efflux capacity (CEC) were measured at baseline, and at the end of 6 and 12 weeks. RESULTS: After 12 weeks of supplementation, significant differences in CEC (P = 0.033), high-density lipoprotein cholesterol (HDL-C) (P = 0.043), and apolipoprotein A-I (ApoA-I) (P = 0.022) were observed between four groups. Compared with placebo, 320 mg/day anthocyanin significantly increased CEC (35.8%, 95% CI: 11.5-60.2%; P = 0.004), HDL-C (0.07 mmol/L, 95% CI: 0.01-0.14; P = 0.003), and ApoA-I (0.07 g/L, 95% CI: 0.01-0.12; P = 0.008). Linear trend analysis showed that anthocyanin supplementation has a strong dose-response relationship with CEC (P = 0.002), HDL-C (P = 0.038), and ApoA-I (P = 0.023). Moreover, the enhancement of CEC showed positive correlations with the increase in HDL-C (r = 0.215, P < 0.01) and APOA-I (r = 0.327, P < 0.01). CONCLUSIONS: Anthocyanin supplementation at 0-320 mg/day for 12 weeks enhances CEC in a dose-response manner in dyslipidemic subjects. Anthocyanin supplementation doses of 80-320 mg/day can improve serum HDL-C levels and HDL-induced CEC.

Associations between plasma ceramides and mortality in patients with coronary artery disease.

BACKGROUND AND AIMS: The relationship between ceramides and the risk of mortality among patients with coronary artery disease (CAD) is currently relatively sparse. This prospective study aimed to clarify whether plasma ceramides are associated with greater risks of cardiovascular and all-cause mortality among CAD patients. METHODS: Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was used to measure plasma ceramides, C16:0, C18:0, C24:0, and C24:1, in 1704 CAD patients. Cox regression models were used to estimate the association between ceramides and the risk of cardiovascular and all-cause mortality. RESULTS: During the median 9.3-year follow-up, 396 all-cause deaths occurred, of which 253 were cardiovascular deaths. Plasma C16:0, C18:0 and C24:1 ceramides and their ratios with C24:0 ceramide were significantly associated with increased risk of cardiovascular and all-cause mortality. After multivariable adjusted, for 1-SD increases of C16:0/C24:0, C18:0/C24:0, and C24:1/C24:0 ratios, the risk of cardiovascular mortality increased by 27%, 35%, and 21%, and the risk of all-cause mortality increased by 29%, 28%, and 24%, respectively. Patients with higher ceramide risk score had 1.81-fold (95%CI, 1.24-2.64) and 1.95-fold (95%CI, 1.43-2.65) risk of cardiovascular and all-cause mortality, respectively, compared to patients with lower ceramide risk score. The risks of cardiovascular and all-cause mortality increased by 9% for 1-point increment in the ceramide risk score. Subgroup analyses did not substantially modify the results. CONCLUSIONS: Our study documented that distinct ceramides were significantly associated with the risks of cardiovascular and all-cause mortality in CAD patients. Further studies are warranted to determine the clinical diagnostic value of distinct ceramides in identifying patients at risk of mortality.

Pd-Catalyzed Decarboxylative Olefination: Stereoselective Synthesis of Polysubstituted Butadienes and Macrocyclic P-glycoprotein Inhibitors.

The efficient and stereoselective synthesis of polysubstituted butadienes, especially the multifunctional butadienes, represents a great challenge in organic synthesis. Herein, we wish to report a distinctive Pd(0) carbene-initiated decarboxylative olefination approach that enables the direct coupling of diazo esters with vinylethylene carbonates (VECs), vinyl oxazolidinones, or vinyl benzoxazinones to afford alcohol-, amine-, or aniline-containing 1,3-dienes in moderate to high yields and with excellent stereoselectivity. This protocol features operational simplicity, mild reaction conditions, a broad substrate scope, and gram-scalability. Notably, a structurally unique allylic Pd(II) intermediate was isolated and characterized. DFT calculation and control experiments demonstrated that a rare Pd(0) carbene intermediate could be involved in this reaction. Moreover, the polysubstituted butadienes as novel building blocks were unprecedentedly assembled into macrocycles, which efficiently inhibited the P-glycoprotein and dramatically reversed multidrug resistance in cancer cells by 190-fold.

A modular biomimetic strategy for the synthesis of macrolide P-glycoprotein inhibitors via Rh-catalyzed C-H activation.

One of the key challenges to overcome multidrug resistance (MDR) in cancer is the development of more effective and general strategies to discover bioactive scaffolds. Inspired by natural products, we describe a strategy to achieve this goal by modular biomimetic synthesis of scaffolds of (Z)-allylic-supported macrolides. Herein, an Rh(III)-catalyzed native carboxylic acid-directed and solvent-free C-H activation allylation with high stereoselectivity and chemoselectivity is achieved. The generated poly-substituted allylic alcohol as a multifunctional and biomimetic building block is crucial for the synthesis of (Z)-allylic-supported macrolides. Moreover, the unique allylic-supported macrolides significantly potentiate the sensitivity of tumor cells to cytotoxic agents such as vinorelbine and doxetaxel by reversing p170-glycoprotein-mediated MDR. Our findings will inspire the evolution of synthetic chemistry and open avenues for expedient and diversified synthesis of bioactive macrocyclic molecules.

Anthocyanin supplementation improves anti-oxidative and anti-inflammatory capacity in a dose-response manner in subjects with dyslipidemia.

BACKGROUND: Anthocyanins, one of the major plant bioactive substances, possess anti-oxidative and anti-inflammatory capacity. However, their dose-response relationship has remained unclear. The present study investigated the dose-response relationship of anthocyanins with oxidative stress and inflammation in subjects with dyslipidemia. DESIGN: and Participants: A total of 169 participants with dyslipidemia were randomly assigned to placebo (n = 43), anthocyanins 40 mg/day (n = 44), 80 mg/day (n = 40), or 320 mg/day (n = 42) groups. Urine 8-iso-prostaglandin F2α (8-iso-PGF2α), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malonaldehyde (MDA), total superoxide dismutase (T-SOD), UA (uric acid), interleukin (IL)-6, IL-10, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) were measured at baseline, at 6 weeks, and at 12 weeks. RESULTS: Anthocyanin supplementation (320 mg/day) for 6 weeks significantly improved T-SOD versus baseline (P < 0.05). A slight reduction in serum IL-6, TNF-α, and urine 8-iso-PGF2α from the baseline was observed at 12 weeks in the group receiving 40 mg/day anthocyanins. Anthocyanins (80 mg/day) significantly reduced serum IL-6 (-20%), TNF-α (-11%) and urine 8-iso-PGF2α (-27%) versus baseline (P < 0.05). Moreover, 320 mg/day anthocyanin supplementation reduced serum IL-6 (-40%), TNF-α (-21%), MDA (-20%) and urine 8-iso-PGF2α (-37%) and 8-OHdG (-36%) than 80 mg/day and 40 mg/day anthocyanins, P value < 0.05. Anthocyanin supplementation has dose-response relationships with decreased inflammatory cytokines IL-6, TNF-α and oxidative stress biomarkers 8-iso-PGF2α, 8-OHdG and MDA (P for trend, <0.05). Furthermore, a strong positive correlation was observed between the changes in the urine 8-iso-PGF2α , 8-OHdG levels and serum IL-6 levels in subjects from anthocyanin groups after 12 weeks of treatment. CONCLUSIONS: Supplementation of anthocyanins for 12 weeks positively improved the anti-oxidative and anti-inflammatory capacity in a dose-response manner in individuals with dyslipidemia.

Impact of smoke-free legislation on acute myocardial infarction and stroke mortality: Tianjin, China, 2007-2015.

BACKGROUND: Smoke-free legislation is an effective way to protect the population from the harms of secondhand smoke and has been implemented in many countries. On 31 May 2012, Tianjin became one of the few cities in China to implement smoke-free legislation. We investigated the impact of smoke-free legislation on mortality due to acute myocardial infarction (AMI) and stroke in Tianjin. METHODS: An interrupted time series design adjusting for underlying secular trends, seasonal patterns, population size changes and meteorological factors was conducted to analyse the impact of the smoke-free law on the weekly mortality due to AMI and stroke. The study period was from 1 January 2007 to 31 December 2015, with a 3.5-year postlegislation follow-up. RESULTS: Following the implementation of the smoke-free law, there was a decline in the annual trends of AMI and stroke mortality. An incremental 16% (rate ratio (RR): 0.84; 95% CI: 0.83 to 0.85) decrease per year in AMI mortality and a 2% (RR: 0.98; 95% CI: 0.97 to 0.99) annual decrease in stroke mortality among the population aged ≥35 years in Tianjin was observed. Immediate postlegislation reductions in mortality were not statistically significant. An estimated 10 000 (22%) AMI deaths were prevented within 3.5 years of the implementation of the law. CONCLUSION: The smoke-free law in Tianjin was associated with reductions in AMI mortality. This study reinforces the need for large-scale, effective and comprehensive smoke-free laws at the national level in China.

Hypouricemic and nephroprotective roles of anthocyanins in hyperuricemic mice.

Hyperuricemia (HUA) is a universal metabolic disorder characterized by a high level of uric acid in the serum. Anthocyanins (ACNs) are a group of natural flavonoids that have shown favourable bioactivities in the metabolic syndrome but the effect on uric acid metabolism remains underexplored. The present study investigated the hypouricemic effects of ACNs in a mice model and further studied the potential mechanisms. ICR mice based on a high-yeast diet were administered potassium oxonate (PO, 280 mg per kg body weight) and inosine (400 mg per kg body weight) to induce a hyperuricemia model, meanwhile, ACNs were supplemented by gavage. The mice were sacrificed after 3 weeks of treatment. ACN administration significantly reduced serum uric acid (SUA), blood urea nitrogen (BUN) and serum creatinine (Scr) levels and suppressed xanthine oxidase (XOD) activity in mice serum and liver. In addition, ACNs down-regulated the expression of hepatic XOD, caspase-1, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) and regulated the expression of renal urate transporters URAT1, GLUT9, ABCG2, OAT1, OAT3, OCT1, OCT2, OCTN1 and OCTN2. According to histological analysis, ACN treatment exhibited hepatoprotective and nephroprotective effects in hyperuricemic mice. In conclusion, ACNs reduced urate production and promoted uric acid excretion from the renal system, which suggests the potential of ACNs for the future treatment of HUA.