Alveolar Macrophages Inherently Express Programmed Death-1 Ligand 1 for Optimal Protective Immunity and Tolerance.

Macrophages play a central role in lung physiology and pathology. In this study, we show in mice that alveolar macrophages (AMs), unlike other macrophage types (interstitial, peritoneal, and splenic macrophages), constitutively express programmed death-1 ligand 1 (PD-L1), thereby possessing a superior phagocytic ability and the capacity to repress CTLs by cis- and trans-interacting with CD80 and programmed death-1 (PD-1), respectively. This extraordinary ability of AMs assures optimal protective immunity and tolerance within the lung. These findings uncover a unique characteristic of AMs and an innate immune function of PD-L1 and CD80 and therefore help in the understanding of lung physiology, diseases, and PD-L1/PD-1-based immunotherapy.

Pharmacological Activities and Synthesis of Esculetin and Its Derivatives: A Mini-Review.

Esculetin, synonymous with 6,7-dihydroxycoumarin, is the main active ingredient of the traditional Chinese medicine Cortex Fraxini. The twig skin or trunk bark of Cortex Fraxini are used by herb doctors as a mild, bitter liver and gallbladder meridians' nontoxic drug as well as dietary supplement. Recently, with a variety of novel esculetin derivatives being reported, the molecular mechanism research as well as clinical application of Cortex Fraxini and esculetin are becoming more attractive. This mini-review will consolidate what is known about the biological activities, the mechanism of esculetin and its synthetic derivatives over the past decade in addition to providing a brief synopsis of the properties of esculetin.

Oncovirus Kaposi sarcoma herpesvirus (KSHV) represses tumor suppressor PDLIM2 to persistently activate nuclear factor κB (NF-κB) and STAT3 transcription factors for tumorigenesis and tumor maintenance.

Kaposi sarcoma herpesvirus (KSHV) is the most common cause of malignancies among AIDS patients. However, how KSHV induces tumorigenesis remains largely unknown. Here, we demonstrate that one important mechanism underlying the tumorigenesis of KSHV is through transcriptional repression of the tumor suppressor gene PDZ-LIM domain-containing protein 2 (PDLIM2). PDLIM2 expression is repressed in KSHV-transformed human umbilical vascular endothelial cells as well as in KSHV-associated cancer cell lines and primary tumors. Importantly, PDLIM2 repression is essential for KSHV-induced persistent activation of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) and subsequent tumorigenesis and tumor maintenance. Our mechanistic studies indicate that PDLIM2 repression by KSHV involves DNA methylation. Notably, the epigenetic repression of PDLIM2 can be reversed by 5-aza-2-deoxycytidine and vitamin D to suppress KSHV-associated cancer cell growth. These studies not only improve our understanding of KSHV pathogenesis but also provide immediate therapeutic strategies for KSHV-mediated cancers, particularly those associated with AIDS.

Critical and distinct roles of cell type-specific NF-κB2 in lung cancer.

Different from the well-studied canonical NF-κB member RelA, the role of the noncanonical NF-κB member NF-κB2 in solid tumors, and lung cancer in particular, is poorly understood. Here we report that in contrast to the tumor-promoting role of RelA, NF-κB2 intrinsic to lung epithelial and tumor cells had no marked effect on lung tumorigenesis and progression. On the other hand, NF-κB2 limited dendritic cell number and activation in the lung but protected lung macrophages and drove them to promote lung cancer through controlling activation of noncanonical and canonical NF-κB, respectively. NF-κB2 was also required for B cell maintenance and T cell activation. The antitumor activity of lymphocyte NF-κB2 was dominated by the protumor function of myeloid NF-κB2; thus, NF-κB2 has an overall tumor-promoting activity. These studies reveal a cell type-dependent role for NF-κB2 in lung cancer and help understand the complexity of NF-κB action and lung cancer pathogenesis for better design of NF-κB-targeted therapy against this deadliest cancer.

Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2.

Background: Immune checkpoint inhibitors (ICIs) and their combination with other therapies such as chemotherapy, fail in most cancer patients. We previously identified the PDZ-LIM domain-containing protein 2 (PDLIM2) as a bona fide tumor suppressor that is repressed in lung cancer to drive cancer and its chemo and immunotherapy resistance, suggesting a new target for lung cancer therapy improvement. Methods: Human clinical samples and data were used to investigate PDLIM2 genetic and epigenetic changes in lung cancer. Using an endogenous mouse lung cancer model faithfully recapitulating refractory human lung cancer and a clinically feasible nano-delivery system, we investigated the therapeutic efficacy, action mechanism, and safety of systemically administrated PDLIM2 expression plasmids encapsulated in nanoparticles (nanoPDLIM2) and its combination with PD-1 antibody and chemotherapeutic drugs. Results: PDLIM2 repression in human lung cancer involves both genetic deletion and epigenetic alteration. NanoPDLIM2 showed low toxicity, high tumor specificity, antitumor activity, and greatly improved the efficacy of anti-PD-1 and chemotherapeutic drugs, with complete tumor remission in most mice and substantial tumor reduction in the remaining mice by their triple combination. Mechanistically, nanoPDLIM2 increased major histocompatibility complex class I (MHC-I) expression, suppressed multi-drug resistance 1 (MDR1) induction and survival genes and other tumor-related genes expression in tumor cells, and enhanced lymphocyte tumor infiltration, turning the cold tumors hot and sensitive to ICIs and rendering them vulnerable to chemotherapeutic drugs and activated tumor-infiltrating lymphocytes (TILs) including those unleashed by ICIs. Conclusions: These studies established a clinically applicable PDLIM2-based combination therapy with great efficacy for lung cancer and possibly other cold cancers.

Effect of Plasma-Activated Water (PAW) on the Postharvest Quality of Shepherd's Purse (Capsella bursa-pastoris).

Plasma-activated water (PAW) treatment is an effective technique for the quality retention of fresh vegetables with cold atmospheric plasma using controllable parameters. This study investigated the effect of PAW on the postharvest quality of shepherd's purse (Capsella bursa-pastoris). The results displayed that PAW treatment with an activation time of 5, 10, 15, and 20 min reduced the yellowing rate and weight loss of the shepherd's purse during 9 days of storage. Compared with untreated samples, PAW treatment at different times reduced the number of total bacteria, coliform, yeast, and mold by 0.18-0.94, 0.59-0.97, 0.90-1.18, and 1.03-1.17 Log CFU/g after 9 days of storage, respectively. Additionally, the treatments with PAW-5 and PAW-10 better preserved ascorbic acid, chlorophyll, total phenol, and total flavonoid contents. They also maintained the higher antioxidant and CAT activity and inhibited the formation of terpenes, alcohols, and nitrogen oxide compounds of the shepherd's purse at the end of storage. The microstructural result illustrated that the cells of the shepherd's purse treated with PAW-5 and PAW-10 were relatively intact, with a small intercellular space after storage. This study demonstrated that PAW treatment effectively improved the postharvest quality of shepherd's purse.

Identification of carotenoids from fruits and vegetables with or without saponification and evaluation of their antioxidant activities.

This study investigates the composition and form of carotenoids in typical fruits and vegetables obtained through saponification or non-saponification and evaluates the correlation between carotenoids and antioxidant capacity. The results showed that the content of the total carotenoids in non-saponified broccoli was the highest, reaching 1505.93 ± 71.99 µg/g d.w. The content of the total carotenoids in pumpkin flesh and broccoli after saponification was reduced by 71.82% and 52.02%, respectively. The content of lutein in spinach decreased by 24.4% after saponification, but the content of ß-carotene increased compared to non-saponification. After saponification, the total antioxidant activities of apple peel, radish peel, radish flesh, and maize were significantly increased by 30.26%, 91.74%, 425.30%, and 242.88%, respectively. Saponification also improved the antioxidant activities of carotenoids in maize under six different antioxidant assays. The highest correlation was found between the total amount of carotenoids and oxygen radical absorbance capacity (R = 0.945), whereas the correlation coefficients among reducing power, 2,2-diphenyl-1-picrylhydrazyl, 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid), hydroxyl and superoxide radical scavenging activity, and total carotenoids' content were 0.935, 0.851, 0.872, 0.885, and 0.777, respectively, all showing significant correlations. The study demonstrates that saponification can increase the total carotenoid content and antioxidation for apple peel, radish peel, radish flesh, and maize. Moreover, carotenoids were significantly positively correlated with most in vitro antioxidant assays. This study provides a theoretical basis for improving the postharvest added value of fruits and vegetables and rationally utilizing their byproducts.

Can Green Technological Innovation Reduce Hazardous Air Pollutants?-An Empirical Test Based on 283 Cities in China.

Based on the panel data of 283 cities in China from 2009 to 2018, this paper analyzes the effect of urban green scientific and technological innovation enhancement on hazardous air pollutants using the GS2SLS method, which simultaneously controls for model endogeneity and spatial spillover effects and reveals the transmission mechanism of urban green scientific and technological innovation level. It was found that (1) There is a significant spatial spillover effect of hazardous air pollutants between regions, both in China as a whole and in the eastern, central, and western parts of the country, and the spatial spillover effect of hazardous air pollutants is significantly greater in the eastern and central parts of China than in the western parts. (2) Green technological innovation has a significant inhibitory effect on hazardous air pollutants in cities in eastern and central China. An extended study found that the improvement in green technology levels in innovative cities has a better effect on controlling hazardous air pollutants than in non-innovative cities. (3) The energy- saving and green economy effects have a mediating influence on the effect of green technological innovation on hazardous air pollutants in cities, and the simultaneous occurrence of these two effects in green technological innovation serves to enhance the transmission of hazardous air pollutants in order to facilitate the long-term management of haze.

PDLIM2 repression by ROS in alveolar macrophages promotes lung tumorigenesis.

One of the most fundamental and challenging questions in the field of cancer is how immunity is transformed from tumor immunosurveillance to tumor-promoting inflammation. Here, we identified the tumor suppressor PDZ-LIM domain-containing protein 2 (PDLIM2) as a checkpoint of alveolar macrophages (AMs) important for lung tumor suppression. During lung tumorigenesis, PDLIM2 expression in AMs is downregulated by ROS-activated transcription repressor BTB and CNC homology 1 (BACH1). PDLIM2 downregulation leads to constitutive activation of the transcription factor STAT3, driving AM protumorigenic polarization/activation and differentiation from monocytes attracted from the circulation to suppress cytotoxic T lymphocytes and promote lung cancer. PDLIM2 downregulation also decreases AM phagocytosis. These findings establish ROS/BACH1/PDLIM2/STAT3 as a signaling pathway driving AMs for lung tumor promotion.

Effects of pre-drying treatments combined with explosion puffing drying on the physicochemical properties, antioxidant activities and flavor characteristics of apples.

The purpose of this research was to study the effect of hot air drying, microwave vacuum drying and freeze drying combined with explosion puffing drying (HDEPD, MDEPD and FDEPD) on physicochemical properties, antioxidant activities and flavor characteristics of apples. The results showed that MDEPD and FDEPD products had better color and textural properties, exhibited a homogeneous porous structure. MDEPD and FDEPD better preserved scavenging abilities of DPPH, hydroxyl radical and FRAP, retained values of TFC and TPC. Aroma characteristics and taste properties of apples obviously changed with different drying methods, and drying qualities of products could be classified in terms of volatile compounds and taste profiles. Two principal components were able to describe 90.12% and 69.43% of the total volatile compound variance and total taste profile variance, respectively. Three main clusters of dried apples were identified, MDEPD and FDEPD can be used to enhance drying qualities of apple products.

Effect of methyl jasmonate on carotenoids biosynthesis in germinated maize kernels.

This study investigated effects of different concentrations of methyl jasmonate (MeJA) on carotenoids accumulation, radical scavenging activity and proline content in germinated maize kernels. MeJA treatment promoted carotenoids accumulation, radical scavenging activity and proline accumulation, while salicyl hydroxamic acid (SHAM) reduced carotenoids accumulation. There was a significant increase of 42.5% in lutein content when treated with 0.5 µM MeJA. Furthermore, the transcriptional expression of seven carotenogenic genes were explored by MeJA and SHAM. The results showed that 0.5 µM MeJA significantly increased the gene expression levels of PSY, PDS, ZDS, LCYB, LCYE, BCH1, CYP97C, and their transcript levels, which were strongly associated with carotenoids content. Treatment of MeJA affected the carotenoids biosynthesis gene and led to the accumulation of carotenoids. These new findings would help to develop innovative approach for enrichment of lutein in germinated maize kernels for further development of functional food materials.

A comparative evaluation of nutritional properties, antioxidant capacity and physical characteristics of cabbage (Brassica oleracea var. Capitate var L.) subjected to different drying methods.

Cabbag has been considered as one of attractive raw materials for dehydrated vegetables owing to high nutrient value. However, information about how drying methods affect the physicochemical properties of cabbage is limited. In present study, segmented cabbages were subjected to freeze drying (FD), hot air drying (HAD), microwave vacuum drying (MVD), vacuum drying (VD), MVD combined with HAD (MVD + HAD) and VD (MVD + VD). Dehydrated cabbages were compared in terms of nutritional components, antioxidant activity, microstructure, texture and so on. Results demonstrated that HAD conducted a worse effect, with loss rate of nutritional components >45%. However, two combined methods performed higher retention for nutritional compositions, better antioxidant activity and lower energy consumption than individual HAD. Furthermore, MVD + HAD products exhibited higher rehydration capacity and more uniform honeycomb porous structure but lower hardness compared to HAD. This conclusion would be fundamental for choosing more appropriate drying methods to obtain desirable quality.

Effect of UV-B radiation and a supplement of CaCl2 on carotenoid biosynthesis in germinated corn kernels.

This study investigated effects of UV-B radiation and CaCl2 on the enhancement of carotenoid content in germinated corn kernels. UV-B radiation and CaCl2 treatments were effective for promoting both carotenoid content and antioxidant activity. Furthermore, the carotenoid content was greater when under the combined treatments of UV-B radiation and CaCl2. Activities of superoxide dismutase and peroxidase were enhanced but malondialdehyde content was weakened by UV-B radiation plus CaCl2 compared to the UV-B radiation only. The mRNA expression of PSY, PDS, ZDS, LCYB, LCYE, BCH1, CYP97C genes involved in the carotenoid biosynthesis pathway showed different patterns in UV-B radiation and CaCl2 treatments. This reveals that the UV-B radiation can increase carotenoid content and antioxidant enzyme activity. Moreover, CaCl2 can further improve carotenoid content and reduce photooxidative damage caused by UV-B radiation.

Polypeptide - decorated nanoliposomes as novel delivery systems for lutein.

Lutein (LUT) is a bioactive food compound found in various vegetables and plays a critical role in the promotion of health and well-being. However, lutein is an unstable molecule which has a very low bioavailability caused by its poor solubility in aqueous media, and is poorly absorbed when administered orally. To enhance the stability, release and bioactivity of lutein, poly-l-lysine (PLL) decorated nanoliposomes (PLL-LUT-NLP) were developed as novel delivery systems for lutein. The mean particle size of PLL-LUT-NLP was found to be in the range 264-367 nm with a low polydispersity index (PDI < 0.4). The zeta potential changed from -38.6 mV in undecorated nanoliposomes to -27.9 mV in PLL-decorated nanoliposomes. Furthermore, the lutein entrapment efficiency (EE%) of PLL-LUT-NLP was found to be highest in nanoliposomes decorated with 0.06% (w/v) PLL. PLL could protect lutein in nanoliposomes from degradation and promote the lutein release from the nanoliposomes in gastrointestinal fluid conditions. Additionally, the PLL-decorated nanoliposomes maintained the antioxidant activity of the lutein, and the antiproliferative activity was more significant than that of undecorated nanoliposomes in inhibiting the proliferation of human tumor cells. These results suggest that PLL-decorated nanoliposomes have potential to be used for efficient delivery of lutein and further improve its bioavailability.

Thermal degradation kinetics of all-trans and cis-carotenoids in a light-induced model system.

Thermal degradation kinetics of lutein, zeaxanthin, ß-cryptoxanthin, ß-carotene was studied at 25, 35, and 45°C in a model system. Qualitative and quantitative analyses of all-trans- and cis-carotenoids were conducted using HPLC-DAD-MS technologies. Kinetic and thermodynamic parameters were calculated by non-linear regression. A total of 29 geometrical isomers and four oxidation products were detected, including all-trans-, keto compounds, mono-cis- and di-cis-isomers. Degradations of all-trans-lutein, zeaxanthin, ß-cryptoxanthin, and ß-carotene were described by a first-order kinetic model, with the order of rate constants as kß-carotene>kß-cryptoxanthin>klutein>kzeaxanthin. Activation energies of zeaxanthin, lutein, ß-cryptoxanthin, and ß-carotene were 65.6, 38.9, 33.9, and 8.6kJ/moL, respectively. cis-carotenoids also followed with the first-order kinetic model, but they did not show a defined sequence of degradation rate constants and activation energies at different temperatures. A possible degradation pathway of four carotenoids was identified to better understand the mechanism of carotenoid degradation.

Protective Effects of Blueberry Anthocyanins against H2O2-Induced Oxidative Injuries in Human Retinal Pigment Epithelial Cells.

Blueberry anthocyanins are considered protective of eye health because of their recognized antioxidant properties. In this study, blueberry anthocyanin extract (BAE), malvidin (Mv), malvidin-3-glucoside (Mv-3-glc), and malvidin-3-galactoside (Mv-3-gal) all reduced H2O2-induced oxidative stress by decreasing the levels of reactive oxygen species and malondialdehyde and increasing the levels of superoxide dismutase, catalase, and glutathione peroxidase in human retinal pigment epithelial cells. BAE and the anthocyanin standards enhanced cell viability from 63.69 ± 3.36 to 86.57 ± 6.92% (BAE), 115.72 ± 23.41% (Mv), 98.15 ± 9.39% (Mv-3-glc), and 127.97 ± 20.09% (Mv-3-gal) and significantly inhibited cell apoptosis (P < 0.01 for all). Mitogen-activated-protein-kinase pathways, including ERK1/2 and p38, were involved in the bioactivities. In addition, the anthocyanins decreased vascular-endothelial-cell-growth-factor levels and activated Akt-signal pathways. These combined results supported the hypothesis that blueberry anthocyanins could inhibit the induction and progression of age-related macular degeneration (AMD) through antioxidant mechanisms.

Evaluation of the impact of food matrix change on the in vitro bioaccessibility of carotenoids in pumpkin (Cucurbita moschata) slices during two drying processes.

The food matrix is a limiting factor in determining the bioaccessibility of carotenoids. The impact of food matrix change on the bioaccessibility of carotenoids during drying processes is still unknown. The effect of intermittent microwave vacuum-assisted drying (IMVD) and hot air drying (HAD) on the in vitro liberation and micellization of carotenoids in pumpkin slices was studied. This variable depended on the changes of the matrix driven by the drying process. Different changes in the cell morphology and carotenoid distribution of pumpkin slices during the two processing methods were observed. For IMVD, cell wall degradation and complete chromoplast organelle disruption contributed to the improvement in the liberation and micellization of carotenoids. In the HAD-dried sample, large pigment aggregates hindered the liberation of carotenoids. The carotenoid level in the micellar fraction appeared to be lower than that in the aqueous supernatant during the two processes, suggesting that the new obstacles formed during processing and/or digestion hindered the incorporation of carotenoids in mixed micelles.

Light-induced oxidation and isomerization of all-trans-ß-cryptoxanthin in a model system.

The oxidation and isomerization of all-trans-ß-cryptoxanthin as affected by iodine-catalysed illumination and non-iodine-catalysed illumination were studied. Seven cis-isomers and two oxidation products were separated by HPLC method using a C30 column. The identification and structural elucidation of the compounds were determined by HPLC-DAD-APCI-MS. Five compounds were identified in details for the first time, namely, ß-ß-carotene-3-one, 5,6-epoxy-ß-ß-carotene-3-one, 13,15-di-cis-, 9,13-di-cis- and 9,9'-di-cis-ß-cryptoxanthin. Sum of 13- and 13'-cis-ß-cryptoxanthin was the major cis-isomer of ß-cryptoxanthin formed, accounting for 59.0% and 30.6%, respectively. The formation of di-cis isomers may prefer in the present of iodine. 13,15-di-cis-ß-cryptoxanthin was the major di-cis-isomer of the iodine-catalysed photo-isomerization.

Analysis of (all-E)-lutein and its (Z)-isomers during illumination in a model system.

Light induced-isomerization of (all-E)-lutein in organic solvent and starch model systems was investigated. Lutein and its (Z)-isomers were separated by HPLC using a C30 column and gradient mobile phase based on methanol-methyl-tert-butyl ether-water in 24min. (All-E)-lutein and twelve (Z)-isomers of lutein, in addition a small amount of (all-E)-zeaxanthin and (9Z, 9'Z)-zeaxanthin were identified by HPLC-DAD-APCI-MS. Five di-(Z)-luteins were identified for the first time, namely, (9Z, 9'Z)-, (9Z, 13Z)/(9 Z, 13'Z)-, (13Z, 15Z)- and (9Z, 15Z)-lutein and (9Z, 9'Z)-zeaxanthin. A mixture of (9Z)-lutein and of (9'Z)-lutein was the main product of the iodine-catalyzed photo-isomerization. (9Z, 13Z)/(9Z, 13'Z)-lutein were the major di-(Z)-isomers of lutein formed. The susceptibility of lutein to degradation was much less under dark storage than under lighted storage in starch model system. Isomerization and degradation of lutein and its (Z)-isomers proceeded simultaneously in all the model systems.