Structure and function of Mycobacterium tuberculosis EfpA as a lipid transporter and its inhibition by BRD-8000.3.

EfpA, the first major facilitator superfamily (MFS) protein identified in Mycobacterium tuberculosis (Mtb), is an essential efflux pump implicated in resistance to multiple drugs. EfpA-inhibitors have been developed to kill drug-tolerant Mtb. However, the biological function of EfpA has not yet been elucidated. Here, we present the cryo-EM structures of EfpA complexed with lipids or the inhibitor BRD-8000.3 at resolutions of 2.9 Å and 3.4 Å, respectively. Unexpectedly, EfpA forms an antiparallel dimer. Functional studies reveal that EfpA is a lipid transporter and BRD-8000.3 inhibits its lipid transport activity. Intriguingly, the mutation V319F, known to confer resistance to BRD-8000.3, alters the expression level and oligomeric state of EfpA. Based on our results and the observation of other antiparallel dimers in the MFS family, we propose an antiparallel-function model of EfpA. Collectively, our work provides structural and functional insights into EfpA's role in lipid transport and drug resistance, which would accelerate the development of antibiotics against this promising drug target.

Effects of different fats on postprandial appetite responses: a randomised crossover trial.

Overconsumption of fat is considered a major driver of the prevalence of obesity globally. While fat type and emulsification have been suggested to play roles in appetite control, very limited data exist. This study aimed to investigate the impacts of type and emulsification of fat on postprandial appetite responses. Sixteen healthy subjects participated in a 4-arm, randomised, crossover study. The net iAUC of hunger visual analogue scales (VAS) (mean ± SE) was observed higher with emulsified fat (-512 ± 137 cm × 300 min) than with non-emulsified fat (-785 ± 133 cm × 300 min) (p < 0.05), but the difference became insignificant over time. Compared to olive oil, coconut oil resulted in higher fullness VAS iAUC (olive oil: 1369 ± 306 cm × 600 min; coconut oil: 1786 ± 311 cm × 600 mi, p < 0.05). Findings from this study support the potential effects of fat in appetite regulation.

Skin carotenoid status and plasma carotenoids: biomarkers of dietary carotenoids, fruits and vegetables for middle-aged and older Singaporean adults.

Skin carotenoid status (SCS) measured by resonance Raman spectroscopy (RRS) may serve as an emerging alternative measurement for dietary carotenoid, fruit and vegetable (FV) intake although its application had not been assessed in a middle-aged and older population in Asia. This cross-sectional study aims to concurrently examine the use of SCS and plasma carotenoids to measure FV and carotenoid intake in a middle-aged and older population, taking into consideration potential socio-demographic and nutritional confounders. The study recruited 103 middle-aged and older adults (mean age: 58 years) in Singapore. Dietary carotenoids and FV, plasma carotenoid concentration and SCS were measured using 3-d food records, HPLC and a biophotonic scanner which utilised RRS, respectively. Adjusted for statistically defined socio-demographic covariates sex, age, BMI, prescription medication and cigarette smoking, plasma carotenoids and SCS showed positive associations with dietary total carotenoids (ßplasma: 0·020 (95 % CI 0·000, 0·040) µmol/l/mg, P = 0·05; ßskin: 265 (95 % CI 23, 506) arbitrary units/mg, P = 0·03) and FV (ßplasma: 0·076 (95 % CI 0·021, 0·132) µmol/l per FV serving, P = 0·008; ßskin: 1036 (95 % CI 363, 1708) arbitrary units/FV serving, P = 0·003). The associations of SCS with dietary carotenoid and FV intake were null with the inclusion of dietary PUFA, fibre and vitamin C as nutritional covariates (P > 0·05). This suggests a potential influence of these nutritional factors on carotenoid circulation and deposition in the skin. In conclusion, SCS, similar to plasma carotenoids, may serve as a biomarker for both dietary carotenoid and FV intake in a middle-aged and older Singaporean population.

Skin carotenoids status as a potential surrogate marker for cardiovascular disease risk determination in middle-aged and older adults.

BACKGROUND AND AIMS: Upon consumption, carotenoids, which may attenuate cardiovascular disease (CVD) risk, diffuse from the blood and accumulate in the skin. This study aimed to assess the associations between dietary, plasma, and skin carotenoids with CVD risk indicators and to examine the mediational role of plasma carotenoids in the relationship between skin carotenoids status (SCS) and CVD risk. METHODS AND RESULTS: Dietary, plasma, and skin carotenoids were assessed in a cross-sectional study from a community in Singapore (n = 103) aged 50 to 75 y. Multiple linear regression and binary logistics regression models were used to examine the associations between the carotenoids status with classical CVD risk factors and composite CVD risk indicators. After controlling for covariates, SCS and plasma carotenoids were inversely associated with systolic blood pressure (skin: P < 0.001; plasma: P < 0.05) and diastolic blood pressure (skin: P < 0.001; plasma: P < 0.005). Additionally, each increment of 1000 in SCS was associated with an odds ratio of 0.924 (P < 0.01) for metabolic syndrome diagnosis and 0.945 (P < 0.05) for moderate to high CVD risk classification. Associations between SCS and composite CVD risk indicators were null when adjusted for the corresponding plasma carotenoids, indicating complete mediation. Dietary carotenoids, however, showed no relationship with the CVD risk indicators. CONCLUSION: Carotenoids bioavailability may be important for cardiovascular protection. SCS, driven by the corresponding plasma carotenoids, could be a potential noninvasive surrogate marker for CVD risk determination in middle-aged and older adults. CLINICAL TRIAL REGISTRATION: NCT03554954, https://clinicaltrials.gov/. TRIAL REGISTRATION DATE: 13 June 2018.

Effects of fatty acids composition in a breakfast meal on the postprandial lipid responses: a systematic review and meta-analysis of randomised controlled trials.

Replacement of food rich in saturated fatty acids (SFAs) with unsaturated fatty acids (UFAs) is a well-known dietary strategy to reduce the risk of cardiovascular disease while its impact on postprandial blood lipids is less examined. This study assessed the effects of fatty acids composition on the postprandial triglycerides and cholesterol responses. Seventeen randomised controlled trials were identified and pooled analysis results revealed that consumption of a UFAs-rich or an SFAs-rich breakfast meal did not acutely affect postprandial triglycerides and cholesterol responses. However, subgroup analysis observed that triglycerides incremental area under the curve was lower with an SFAs-rich meal (SMD: -0.36; 95% CI: -0.57, -0.15) over a less than 8 h duration, while was higher (SMD: 0.59; 95% CI: 0.05, 1.23) over a longer postprandial duration. It suggests that the postprandial duration is of importance when evaluating the effects of fatty acids composition on blood lipid responses.

Chemical Compositions of Lianqiao (Forsythia suspensa) Extracts and Their Potential Health Benefits.

This study evaluated the fruits of Forsythia suspensa (Lianqiao), an important economic crop, for the chemical components of its water and ethanol extracts, inhibitory effects on SARS-CoV-2 virus spike protein binding to ACE2, inhibition of ACE2 activity, and capacity to scavenge free radicals. A total of 42 compounds were tentatively identified in the extracts via HPLC-MS/MS analysis. The water extract showed a greater ACE2 inhibition but a weaker inhibition on SARS-CoV-2 spike protein binding to ACE2 than the ethanol extract on a per-botanical-weight-concentration basis. The phenolic content was found to be greater in the water extract at 45.19 mg GAE/g dry botanical weight than in the ethanol extract (6.89 mg GAE/g dry botanical). Furthermore, the water extract had greater scavenging capacities against HO●, DPPH●, and ABTS●+ at 448.48, 66.36, and 121.29 µmol TE/g dry botanical, respectively, as compared to that of the ethanol extract (154.04, 3.55, and 33.83 µmol TE/g dry botanical, respectively). These results warrant further research into, and the development of, the potential COVID-19-preventive applications of Lianqiao and its extracts.

Tomato seed extract promotes health of the gut microbiota and demonstrates a potential new way to valorize tomato waste.

The current effort to valorize waste byproducts to increase sustainability and reduce agricultural loss has stimulated interest in potential utilization of waste components as health-promoting supplements. Tomato seeds are often discarded in tomato pomace, a byproduct of tomato processing, yet these seeds are known to contain an array of compounds with biological activity and prebiotic potential. Here, extract from tomato seeds (TSE), acquired from pomace, was evaluated for their ability to effect changes on the gut microbiota using an ex vivo strategy. The results found that TSE significantly increased levels of the beneficial taxa Bifidobacteriaceae in a donor-independent manner, from a range of 18.6-24.0% to 27.0-51.6% relative abundance following treatment, yet the specific strain of Bifidobacteriaceae enhanced was inter-individually variable. These structural changes corresponded with a significant increase in total short-chain fatty acids, specifically acetate and propionate, from an average of 13.3 to 22.8 mmol/L and 4.6 to 7.4 mmol/L, respectively. Together, these results demonstrated that TSE has prebiotic potential by shaping the gut microbiota in a donor-independent manner that may be beneficial to human health. These findings provide a novel application for TSE harvested from tomato pomace and demonstrate the potential to further valorize tomato waste products.

Reply to Finsterer et al.

This letter acknowledges Finsterer and colleagues' insightful comments on pesticide use in fruits and vegetables and impact on eye health. Pesticides can harm eyes through various exposures. Adverse effects occur due to direct entry into ocular tissues, with absorption through eye components. While the potential of organic diets to reduce pesticide exposure is acknowledged, the original paper's cited studies lack clarity on whether organic diet interventions were used. Future systematic reviews comparing organic and nonorganic diets could provide further insights.

Effect of xanthophyll-rich food and supplement intake on visual outcomes in healthy adults and those with eye disease: a systematic review, meta-analysis, and meta-regression of randomized controlled trials.

CONTEXT: Xanthophyll intake is known to improve eye health; however, its benefits on visual outcomes have not been systematically studied, particularly in a population with eye diseases. OBJECTIVE: A systematic review, meta-analysis, and meta-regression were conducted to investigate the effect of xanthophyll intake on visual outcomes, and further subgroup analysis was performed on the basis of eye disease status. DATA SOURCES: The PubMed, Scopus, Embase, CINAHL, Cochrane, and Web of Science databases were searched, and relevant randomized controlled trials were identified. DATA EXTRACTION: For systematic review, meta-analysis, and meta-regression, 43, 25, and 21 articles were selected, respectively. DATA ANALYSIS: Xanthophyll intake enhanced macular pigment optical density (MPOD) for both heterochromatic flicker photometry (weighted mean difference [WMD], 0.05; 95% confidence interval [CI], 0.03-0.07) and autofluorescence imaging (WMD, 0.08; 95%CI, 0.05-0.11) measurements and decreased photostress recovery time (WMD, -2.35; 95%CI, -4.49 to -0.20). While enhancement in visual acuity logarithm of the minimum angle of resolution was observed in response to the xanthophyll-rich food and supplement intake only for patients with eye disease (WMD, -0.04; 95%CI, -0.07 to -0.01). Meta-regression showed a positive correlation between change in MPOD (heterochromatic flicker photometry) and the corresponding change in serum lutein levels (regression coefficient = 0.068; P = 0.00). CONCLUSION: Intake of xanthophyll-rich food or supplements can improve eye health. Additional improvement in visual acuity was observed in patients with eye disease. A positive association between MPOD and serum lutein level, while absent with dietary xanthophyll intake, suggests the importance of bioavailability when examining the effect of xanthophyll on eye health. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42021295337.

Effects of dietary fat type and emulsification on carotenoid absorption: a randomized crossover trial.

BACKGROUND: Although emerging evidence has suggested that the type and emulsification of dietary fat may be important to carotenoid absorption, these effects have not yet been validated in a human trial. OBJECTIVES: This study aimed to examine the effects of dietary fat type and emulsification on the bioaccessibility and bioavailability of carotenoids from a carotenoid-rich salad. METHODS: An identical salad was used for the in vitro and the human trial. This was paired with 28 g of one of the following 4 different fats: 1) nonemulsified olive oil, 2) emulsified olive oil, 3) nonemulsified coconut oil, and 4) emulsified coconut oil. The bioaccessibility of total carotenoids (TCs) was assessed by a simulated in vitro digestion model. Sixteen subjects consumed salad with 4 test fats in random order, and plasma triglyceride and carotenoid (lutein, zeaxanthin, α-carotene, ß-carotene, and lycopene) concentrations were determined hourly for 10 h following the consumption. The absorption of TC and individual carotenoids was evaluated by the positive incremental AUC (iAUC) of plasma carotenoid concentrations. RESULTS: The bioaccessibility of TC was greater with olive oil (24.0%) than with coconut oil (14.9%), and with the oil being emulsified (23.5%) rather than that being nonemulsified (15.4%). Similarly, the positive iAUC1-10h of TC, α-carotene, and lycopene were 55.2%, 110.8%, and 45.8%, respectively, higher with olive oil than with coconut oil. Emulsified fat induced 40.0% greater positive iAUC1-10h of TC than nonemulsified fat. CONCLUSIONS: The type and emulsification of dietary fat are both essential to carotenoid absorption. Findings from this study may provide scientific support for designing excipient emulsions as potential dietary strategies to optimize the absorption of fat-soluble compounds. This study was registered at clinicaltrials.gov as NCT04323826.

Chemical Composition of Thyme (Thymus vulgaris) Extracts, Potential Inhibition of SARS-CoV-2 Spike Protein-ACE2 Binding and ACE2 Activity, and Radical Scavenging Capacity.

Water and ethanol extracts of dried thyme (Thymus vulgaris) were analyzed for chemical composition, inhibition of the SARS-CoV-2 spike protein-ACE2 interaction, inhibition of ACE2 activity, and free radical scavenging capacity. Thirty-two compounds were identified in water extract (WE) and 27 were identified in ethanol extract (EE) of thyme through HPLC-MS. The WE (33.3 mg/mL) and EE (3.3 mg/mL) of thyme inhibited the spike protein-ACE2 interaction by 82.6 and 86.4%, respectively. The thyme WE at 5 mg/mL inhibited ACE2 activity by 99%, and the EE at 5 mg/mL inhibited ACE2 by 65.8%. Total phenolics were determined to be 38.9 and 8.8 mg of GAE/g in WE and EE, respectively. The HO• scavenging capacities were 1121.1 and 284.4 µmol of TE/g in WE and EE, respectively. The relative DPPH• scavenging capacities were 126.3 µmol TE/g in WE and 28.2 µmol TE/g in EE. The ABTS•+ scavenging capacities were 267.1 µmol TE/g in WE and 96.7 µmol TE/g in EE. The results suggested that the thyme extract could be potentially used to prevent SARS-CoV-2 infection and mitigate the complications from the infection.

Manganese regulation of COPII condensation controls circulating lipid homeostasis.

Precise control of circulating lipids is instrumental in health and disease. Bulk lipids, carried by specialized lipoproteins, are secreted into the circulation, initially via the coat protein complex II (COPII). How the universal COPII machinery accommodates the abundant yet unconventional lipoproteins remains unclear, let alone its therapeutic translation. Here we report that COPII uses manganese-tuning, self-constrained condensation to selectively drive lipoprotein delivery and set lipid homeostasis in vivo. Serendipitously, adenovirus hijacks the condensation-based transport mechanism, thus enabling the identification of cytosolic manganese as an unexpected control signal. Manganese directly binds the inner COPII coat and enhances its condensation, thereby shifting the assembly-versus-dynamics balance of the transport machinery. Manganese can be mobilized from mitochondria stores to signal COPII, and selectively controls lipoprotein secretion with a distinctive, bell-shaped function. Consequently, dietary titration of manganese enables tailored lipid management that counters pathological dyslipidaemia and atherosclerosis, implicating a condensation-targeting strategy with broad therapeutic potential for cardio-metabolic health.

Chemical Composition of Rosemary (Rosmarinus officinalis L.) Extract and Its Inhibitory Effects on SARS-CoV-2 Spike Protein-ACE2 Interaction and ACE2 Activity and Free Radical Scavenging Capacities.

This study evaluated the chemical composition of rosemary water extract (RWE) and its influence on mechanisms by which the SARS-CoV-2 virus enters into cells as a potential route for reducing the risk of COVID-19 disease. Compounds in RWE were identified using UHPLC-MS/MS. The inhibitory effect of RWE was then evaluated on binding between the SARS-CoV-2 spike protein (S-protein) and ACE2 and separately on ACE2 activity/availability. Additionally, total phenolic content (TPC) and free radical scavenging capacities of RWE against HO•, ABTS•+, and DPPH• were assessed. Twenty-one compounds were tentatively identified in RWE, of which tuberonic acid hexoside was identified for the first time in rosemary. RWE dose of 33.3 mg of rosemary equivalents (RE)/mL suppressed the interaction between S-protein and ACE2 by 72.9%, while rosmarinic and caffeic acids at 3.3 µmol/mL suppressed the interaction by 36 and 55%, respectively. RWE at 5.0, 2.5, and 0.5 mg of RE/mL inhibited ACE2 activity by 99.5, 94.5, and 68.6%, respectively, while rosmarinic acid at 0.05 and 0.01 µmol/mL reduced ACE2 activity by 31 and 8%, respectively. RWE had a TPC value of 72.5 mg GAE/g. The results provide a mechanistic basis on which rosemary may reduce the risk of SARS-CoV-2 infection and the development of COVID-19.

Effects of dietary fats on the bioaccessibility and bioavailability of carotenoids: a systematic review and meta-analysis of in vitro studies and randomized controlled trials.

CONTEXT: Dietary fats are one of the well-known stimulators of carotenoid absorption, but the effects of the quantity and the type of dietary fats on carotenoid absorption have not yet been studied systematically. OBJECTIVE: This review aimed to analyze data from both in vitro studies and randomized controlled trials (RCTs) to examine the effects of dietary fats on the bioaccessibility and bioavailability of carotenoids. DATA SOURCES: A systematic search of 5 databases (Scopus, PubMed, Embase, CINAHL and the Cochrane Library) was conducted. STUDY SELECTION: In vitro studies and RCTs were selected according to the PICOS criteria and were reviewed independently by 2 investigators. DATE EXTRACTION: Key study characteristics from the eligible in vitro studies and RCTs were extracted independently by 2 investigators using a standardized table. RESULTS: A total of 27 in vitro studies and 12 RCTs were included. The meta-regression of in vitro studies showed that the bioaccessibility of carotenoids, except for lycopene, was positively associated with the concentration of dietary fats. The meta-analysis of RCTs showed that the bioavailability of carotenoids was enhanced when a higher quantity of dietary fats was co-consumed. Moreover, fats rich in unsaturated fatty acids resulted in greater improvement in carotenoid bioavailability (SMD 0.90; 95%CI, 0.69-1.11) as compared with fats rich in saturated fatty acids (SMD 0.27; 95%CI, 0.08-0.47). CONCLUSIONS: Co-consuming dietary fats, particularly those rich in unsaturated fatty acids, with carotenoid-rich foods can improve the absorption of carotenoids. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42020188539.

Energy Storage Application of All-Organic Polymer Dielectrics: A Review.

With the wide application of energy storage equipment in modern electronic and electrical systems, developing polymer-based dielectric capacitors with high-power density and rapid charge and discharge capabilities has become important. However, there are significant challenges in synergistic optimization of conventional polymer-based composites, specifically in terms of their breakdown and dielectric properties. As the basis of dielectrics, all-organic polymers have become a research hotspot in recent years, showing broad development prospects in the fields of dielectric and energy storage. This paper reviews the research progress of all-organic polymer dielectrics from the perspective of material preparation methods, with emphasis on strategies that enhance both dielectric and energy storage performance. By dividing all-organic polymer dielectrics into linear polymer dielectrics and nonlinear polymer dielectrics, the paper describes the effects of three structures (blending, filling, and multilayer) on the dielectric and energy storage properties of all-organic polymer dielectrics. Based on the above research progress, the energy storage applications of all-organic dielectrics are summarized and their prospects discussed.

The Roles of Carotenoid Consumption and Bioavailability in Cardiovascular Health.

Carotenoids are natural pigments generally with a polyene chain consisting of 9-11 double bonds. In recent years, there has been increasing research interest in carotenoids because of their protective roles in cardiovascular diseases (CVDs). While the consumption of carotenoids may have a beneficial effect on CVDs, the literature shows inconsistencies between carotenoid consumption and reductions in the risk of CVDs. Therefore, this review aims to provide a summary of the association between dietary carotenoid intake and the risk of CVDs from published epidemiological studies. Meanwhile, to further elucidate the roles of carotenoid intake in CVD protection, this review outlines the evidence reporting the effects of carotenoids on cardiovascular health from randomized controlled trials by assessing classical CVD risk factors, oxidative stress, inflammatory markers and vascular health-related parameters, respectively. Given the considerable discrepancies among the published results, this review underlines the importance of bioavailability and summarizes the current dietary strategies for improving the bioavailability of carotenoids. In conclusion, this review supports the protective roles of carotenoids against CVDs, possibly by attenuating oxidative stress and mitigating inflammatory response. In addition, this review suggests that the bioavailability of carotenoids should be considered when evaluating the roles of carotenoids in CVD protection.

Encapsulation of Lutein via Microfluidic Technology: Evaluation of Stability and In Vitro Bioaccessibility.

Inadequate intake of lutein is relevant to a higher risk of age-related eye diseases. However, lutein has been barely incorporated into foods efficiently because it is prone to degradation and is poorly bioaccessible in the gastrointestinal tract. Microfluidics, a novel food processing technology that can control fluid flows at the microscale, can enable the efficient encapsulation of bioactive compounds by fabricating suitable delivery structures. Hence, the present study aimed to evaluate the stability and the bioaccessibility of lutein that is encapsulated in a new noodle-like product made via microfluidic technology. Two types of oils (safflower oil (SO) and olive oil (OL)) were selected as a delivery vehicle for lutein, and two customized microfluidic devices (co-flow and combination-flow) were used. Lutein encapsulation was created by the following: (i) co-flow + SO, (ii) co-flow + OL, (iii) combination-flow + SO, and (iv) combination-flow + OL. The initial encapsulation of lutein in the noodle-like product was achieved at 86.0 ± 2.7%. Although lutein's stability experienced a decreasing trend, the retention of lutein was maintained above 60% for up to seven days of storage. The two types of device did not result in a difference in lutein bioaccessibility (co-flow: 3.1 ± 0.5%; combination-flow: 3.6 ± 0.6%) and SO and OL also showed no difference in lutein bioaccessibility (SO: 3.4 ± 0.8%; OL: 3.3 ± 0.4%). These results suggest that the types of oil and device do not affect the lutein bioaccessibility. Findings from this study may provide scientific insights into emulsion-based delivery systems that employ microfluidics for the encapsulation of bioactive compounds into foods.

A monoclonal antibody targeting the dimer interface of epidermal growth factor receptor (EGFR).

Epidermal growth factor receptor (EGFR) is an attractive target for the treatment of epithelial cancers. However, EGFR antagonists have low clinical response rates and frequently induce resistance mainly caused by the hypermutation of the extracellular and intracellular domains and the heterodimerization of EGFR. Dimerization plays a key role in the activation of the EGFR family of receptors. Thus, targeting the highly conserved dimer interface of EGFR maybe an attractive strategy for improving the clinical response of anti-EGFR therapies. In this work, we report a monoclonal antibody (mAb) called Antidimer 5G9 that targets the ß-hairpin within the dimer interface of EGFR, which is 100% homologous with mouse EGFR. Antidimer 5G9 belongs to the isotype IgG1 and bound with an affinity constant of 1.837×109L/mol. Just as designed and expected, Antidimer 5G9 could recognize and bind to human EGFRs or mouse EGFRs on the surface of human breast cancer cells of the MDA-MB-231 cell line or mouse Lewis lung cancer cells (LLC), effectively inhibiting growth and inducing apoptosis in the targeted cells. This work lays the foundation for further studies investigating the feasibility of this strategy for targeting the dimer interface of EGFR and developing novel anti-EGFR drugs.