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Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an in situ nano-vaccine (CpG@Man-P/Tra/Gel) targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer. The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib (Tra) and nano-adjuvant CPG@Man-P, which generated abundant in situ depot of whole-cell tumor antigens and formed in situ nano-vaccines with CpG@Man-P. Benefiting from mannose (Man) modification, the nano-vaccines targeted to LNs, promoted the uptake of antigens by DCs, further inducing the maturation of DCs and activation of T cells. Moreover, CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response in vivo. Notably, combined with PD-1 blocking, the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer.

A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8+ T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

A special microenvironment called the “pre-metastatic niche” is thought to help primary tumor cells migrate to new tissues and invade them, in part because the normal barrier function of the vascular endothelium is compromised. While the primary tumor itself can promote the creation of such niches by secreting pro-metastatic factors, the underlying molecular mechanisms are still poorly understood. Here, we show that the injection of primary tumor-secreted pro-metastatic factors from B16F10 melanoma or 4T1 breast cancer cells into healthy mice can induce the destruction of the vascular endothelial glycocalyx, which is a polysaccharide coating on the vascular endothelial lumen that normally inhibits tumor cell passage into and out of the circulation. However, when human umbilical vein endothelial cultures were treated in vitro with these secreted pro-metastatic factors, no significant destruction of the glycocalyx was observed, implying that this destruction requires a complex in vivo microenvironment. The tissue section analysis revealed that secreted pro-metastatic factors could clearly upregulate macrophage-related molecules such as CD11b and tumor necrosis factor-α (TNF-α) in the heart, liver, spleen, lung, and kidney, which is associated with the upregulation and activation of heparanase. In addition, macrophage depletion significantly attenuated the degradation of the vascular endothelial glycocalyx induced by secreted pro-metastatic factors. This indicates that the secreted pro-metastatic factors that destroy the vascular endothelial glycocalyx rely primarily on macrophages. Our findings suggest that the formation of pre-metastatic niches involves degradation of the vascular endothelial glycocalyx, which may hence be a useful target for developing therapies to inhibit cancer metastasis.

Objective. Fetal growth restriction (FGR) is a significant contributor to negative pregnancy and postnatal developmental outcomes. Currently, the exact pathological mechanism of FGR remains unknown. This study aims to utilize multiomics sequencing technology to investigate potential relationships among mRNA, gut microbiota, and metabolism in order to establish a theoretical foundation for diagnosing and understanding the molecular mechanisms underlying FGR. Methods. In this study, 11 healthy pregnant women and nine pregnant women with FGR were divided into Control group and FGR group based on the health status. Umbilical cord blood, maternal serum, feces, and placental tissue samples were collected during delivery. RNA sequencing, 16S rRNA sequencing, and metabolomics methods were applied to analyze changes in umbilical cord blood circulating mRNA, fecal microbiota, and metabolites. RT-qPCR, ELISA, or western blot were used to detect the expression of top 5 differential circulating mRNA in neonatal cord blood, maternal serum, or placental tissue samples. Correlation between differential circulating mRNA, microbiota, and metabolites was analyzed by the Spearman coefficient. Results. The top 5 mRNA genes in FGR were altered with the downregulation of TRIM34, DEFA3, DEFA1B, DEFA1, and QPC, and the upregulation of CHPT1, SMOX, FAM83A, GDF15, and NAPG in newborn umbilical cord blood, maternal serum, and placental tissue. The abundance of Bacteroides, Akkermansia, Eubacterium_coprostanoligenes_group, Phascolarctobacterium, Parasutterella, Odoribacter, Lachnospiraceae_UCG_010, and Dielma were significantly enriched in the FGR group. Metabolites such as aspartic acid, methionine, alanine, L-tryptophan, 3-methyl-2-oxovalerate, and ketoleucine showed notable functional alterations. Spearman correlation analysis indicated that metabolites like methionine and alanine, microbiota (Tyzzerella), and circulating mRNA (TRIM34, SMOX, FAM83A, NAPG) might play a role as mediators in the communication between the gut and circulatory system interaction in FGR. Conclusion. Metabolites (METHIONINE, alanine) as well as microbiota (Tyzzerella) and circulating mRNA (TRIM34, SMOX, FAM83A, NAPG) were possible mediators that communicated the interaction between the gut and circulatory systems in FGR.

In this study, a stable aqueous solution of paprika oleoresin (PO, the natural colorant extracted from the fruit peel of Capsicum annuum L) was constructed. The solubility of PO in an alkline aqueous solution (pH 10.95–11.10) increased rapidly. However, the aqueous solution of PO (pH 12.00) was unstable, obvious stratification was observed, and the color retention rate was only 52.99% after 28 days of storage. Chicken egg yolk low-density lipoprotein (LDL) was added combined with ultrasonic treatment to improve the stability of LDL-PO solution. The method could decrease the turbidity by 17.5 %, reduce the average particle size of the LDL-PO solution (13.9%), and enhance the interaction and combination of LDL and PO. The prepared PO aqueous solution was used in yogurt, egg white gel, fish balls and soymilk, and it could significantly improve the color of products and provided potential health benefits.

Rheumatoid arthritis is a systemic inflammatory disease that can lead to articular cartilage destruction and periarticular bone erosion, thus ultimately compromising joint integrity and function. Anti-inflammatory drugs and biological agents are commonly used to treat rheumatoid arthritis, but they cannot selectively target inflamed joints, because of their systemic mechanisms, short half-lives and low bioavailability. Consequently, these agents must be used at high doses and delivered frequently, thereby increasing costs and the risk of adverse effects. Drug delivery systems, such as nanoparticles, liposomes and micelles, can significantly prolong drug half-life in the body and enable targeted delivery into the joints. In this review, we comprehensively describe the pathogenesis and clinical diagnosis of rheumatoid arthritis, and summarize recent advances in targeted therapeutic strategies, particularly nano-targeting systems for rheumatoid arthritis.

Sows’ maternal behavior is important for improving piglet survival and growth; thus, breeding for good mothering sows is necessary for pig production. However, there is little research on the genetic mechanism of maternal behavior. In this study, a comparative analysis of piglets’ growth traits between good and bad maternal behavior groups and a genome-wide association study (GWAS) was performed to elucidate the impact of sows’ maternal behavior on piglet growth and identify candidate genes and markers of sow’s maternal behaviors. Comparing the growth traits of piglets between good and bad sows’ maternal behavior groups, the results showed that the growth traits of piglets from sows with good maternal behavior were better than those from sows with bad maternal behavior and especially for the multiparous sows group, this comparative difference was significant. For the intensive study of the genetic mechanisms of sows’ maternal behavior, a total of 452 sows were genotyped using the Illumina Porcine 50K SNP Chip, and 4 traits, including biting piglets (BP), crushing piglets (CP), trampling piglets (TP) and screaming test (ST), were examined. Using a GWAS, 20 single nucleotide polymorphisms (SNPs) were found to be associated with these traits. Within 1 Mb upstream and downstream of the significant SNPs screened, 138 genes were obtained. After pathway enrichment and gene annotation, HIP1, FZD9 and HTR7 were identified as important candidate genes affecting sows’ maternal behaviors. These findings preliminarily elucidate the genetic basis of sows’ maternal behavior traits and provide candidate genes and markers for molecular breeding in pigs.

Egg-yolk low-density lipoprotein (LDL) has a natural liposome structure. Using ultrasound-assisted pH-shifting (pH 12), a naturally safe and stable aqueous solution of vitamin D3 (VD3) was constructed employing LDL as the carrier. Images from electron microscopy showed that pH-shifting remodeled LDL molecules, resulting in a dramatic reduction in particle size (∼50%) and an increase in specific surface area, which reduced the turbidity (27.7%) and provided new interfaces for VD3 loading. Fluorescence analyses showed that the binding of VD3 to LDL under pH-shifting was strong, involved quenching, and the binding constant was 6.19 × 104 M−1. Thermogravimetric analysis and Fourier transform-infrared spectroscopy showed that pH-shifting hydrolyzed the esters in LDL to fatty acid salts, and the maximum weight loss of LDL occurred from 381.9 °C to 457.0 °C. Ultrasonic treatment enhanced the binding of LDL and VD3 (binding constant increased to 2.56 × 107 M−1), reduced the particle size, and increased the ζ-potential of the complex between LDL and VD3, thereby resulting in the improvement of solution stability and storage stability of VD3. Ultrasound-assisted pH-shifting could remodel LDL to construct a stable aqueous solution of VD3, which showed the potential of LDL as a carrier for lipid-soluble components.

BackgroundBrain and central nervous system (CNS) cancers represent a major source of cancer burden in China and the United States. Comparing the two countries' epidemiological features for brain and CNS cancers can help plan interventions and draw lessons.MethodsData were extracted from the Global Burden of Disease repository. The average annual percentage change (AAPC) and relative risks of cancer burdens were calculated using joinpoint regression analysis and age-period-cohort (APC) models, respectively. Moreover, a Bayesian APC model was employed to predict the disease burden over the next decade.ResultsFrom 1990 to 2019, the number of incidences, deaths, and disability-adjusted life-years (DALYs) increased in China and the US, with a larger increase in China. Age-standardized incidence rates in China and the United States have shown an increasing trend over the past three decades, with AAPCs of 0.84 and 0.16%, respectively. However, the rates of age-standardized mortality and age-standardized DALYs decreased in both countries, with a greater decrease in China. Overall, age trends in cancer burden were similar for males and females, with two peaks in the childhood and elderly groups, respectively. The period and cohort effects on incidence showed an overall increasing trend in China and limited change in the US. However, the period effects for mortality and DALY were decreasing in both countries, while the cohort effects tended to increase and then decrease. Moreover, we predicted that the cancer burdens would continue to rise in China over the next decade.ConclusionThe burden of brain and CNS cancers is substantial and will continue to increase in China. Comprehensive policy and control measures need to be implemented to reduce the burden.

Nano- and microemulsions are colloidal systems that are widely used in various fields of biomedicine, including wound and burn healing, cosmetology, the development of antibacterial and antiviral drugs, oncology, etc. The stability of these systems is governed by the balance of molecular interactions between nanodomains. Microemulsions as a colloidal form play a special important role in stability. The microemulsion is the thermodynamically stable phase from oil, water, surfactant and co-surfactant which forms the surface of drops with very small surface energy. The last phenomena determines the shortage time of all fluid dispersions including nanoemulsions and emulgels. This review examines the theory and main methods of obtaining nano- and microemulsions, particularly focusing on the structure of microemulsions and methods for emulsion analysis. Additionally, we have analyzed the main preclinical and clinical studies in the field of wound healing and the use of emulsions in cancer therapy, emphasizing the prospects for further developments in this area.

N-hydroxy-pipecolic acid (NHP) is a hydroxylated product of pipecolic acid and an important systemic acquired resistance signal molecule. However, the biosynthesis of NHP does not have a natural metabolic pathway in microorganisms. Here, we designed and constructed a promising artificial pathway in Escherichia coli for the first time to produce NHP from biomass-derived lysine. This biosynthesis route expands the lysine catabolism pathway and employs six enzymes to sequentially convert lysine into NHP. This artificial route involves six functional enzyme coexpression: lysine α-oxidase from Scomber japonicus (RaiP), glucose dehydrogenase from Bacillus subtilis (GDH), Δ1-piperideine-2-carboxylase reductase from Pseudomonas putida (DpkA), lysine permease from E. coli (LysP), flavin-dependent monooxygenase (FMO1), and catalase from E. coli (KatE). Moreover, different FMO1s are used to evaluate the performance of the produce NHP. A titer of 111.06 mg/L of NHP was yielded in shake flasks with minimal medium containing 4 g/L of lysine. By this approach, NHP has so far been produced at final titers reaching 326.42 mg/L by 48 h in a 5-L bioreactor. To the best of our knowledge, this is the first NHP process using E. coli and the first process to directly synthesize NHP by microorganisms. This study lays the foundation for the development and utilization of renewable resources to produce NHP in microorganisms.

Backfat thickness (BFT) is an important carcass composition trait and regarded as a breeding focus. Our initial transcriptome analysis of pig BFT identified GLI pathogenesis-related 1 (GLIPR1) as one of the promising candidate genes. This study was conducted to identify the expression profiles, polymorphisms, and genetic effects of the GLIPR1 gene on BFT in pigs. The expression of the GLIPR1 gene existed in every detected tissue, and there was a significantly higher expression in spleen and adipose tissue than others (p < 0.05). At the different ages of pig, the expression of the GLIPR1 gene was low at an early age, increased with growth, and reached the highest level at 180 days. Genetic polymorphism analysis was detected in 553 individuals of the Large White × Minzhu F2 population. Four SNPs in the promoter significantly associated with 6–7 rib BFT (p < 0.05) were predicted to alter the transcription factor binding sites (TFBS), and the mutations of g.38758089 T>G and g.38758114 G>C were predicted to change the TFs associated with the regulation of adipogenesis. Haplotypes were formed by the detected SNPs, and one block showed a strong association with BFT (p < 0.05). In summary, our results indicate that the expression profiles and genetic variants of GLIPR1 affected the BFT of pigs. To our knowledge, this study is the first to demonstrate the biological function and genetic effects of the GLIPR1 gene on the BFT of pig and provide genetic markers to optimize breeding for BFT in pigs.

Cell surface thiols can be targeted by thiol-reactive groups of various materials such as peptides, nanoparticles, and polymers. Here, we used the maleimide group, which can rapidly and covalently conjugate with thiol groups, to prepare surface-modified liposomes (M-Lip) that prolong retention of doxorubicin (Dox) at tumor sites, enhancing its efficacy. Surface modification with the maleimide moiety had no effect on the drug loading efficiency or drug release properties. Compared to unmodified Lip/Dox, M-Lip/Dox was retained longer at the tumor site, it was taken up by 4T1 cells to a significantly greater extent, and exhibited stronger inhibitory effect against 4T1 cells. The in vivo imaging results showed that the retention time of M-Lip at the tumor was significantly longer than that of Lip. In addition, M-Lip/Dox also showed significantly higher anticancer efficacy and lower cardiotoxicity than Lip/Dox in mice bearing 4T1 tumor xenografts. Thus, the modification strategy with maleimide may be useful for achieving higher efficient liposome for tumor therapy.

Zingiber mioga (Thunb.) Rosc. is an important plant species in tropical Asia widely used for decoration, and in traditional food and medicine. In this study, we reported for the first time the complete chloroplast genome sequence of Z. mioga. The assembled chloroplast genome was 159,868 bp long with a typical quadripartite structure consisting of two reverse repeated regions of 26,652 bp in length, separated by a large single-copy (89,431 bp) and a small single-copy (17,133 bp) region. We annotated 113 genes including 78 protein-coding, 31 tRNA and 4 rRNA genes. Phylogenetic analysis with 27 other species showed that Z. mioga clustered with Z. officinale and Z. spectabile, all belonging to the Zingiberaceae family of the Zingiberales order. The results of this study will facilitate the breeding process and conservation of the species.

Caffeine and related purine alkaloids are common ingredients of many stimulating drinks. Studies have shown that lower concentrations of caffeine have a protective role in aging-related disorders. However, the associated mode of action of caffeine and its related methylxanthines is still not clear. In this study, we demonstrated that caffeine and theophylline promote longevity in Caenorhabditis elegans. Lifespan studies with the wild type, DAF-16 and SKN-1 mutant strains indicated that the methylxanthines-mediated lifespan extension in C. elegans was independent of DAF-16/FOXO and SKN-1. All the tested methylxanthines could protect C. elegans against acute oxidative stress. At early stages of life, an increase of ROS (reactive oxygen species) induced the translocation of DAF-16 and SKN-1, resulting in upregulation of several antioxidant genes, for example, sod-3p::GFP, gst-4p::GFP, gcs-1p::GFP; and downregulation of hsp-16.2p::GFP. RT-PCR corroborates the upregulation of gst-4 and skn-1 genes. The expression of DAF-16 decreased although its nuclear translocation was induced. Keywords: Caenorhabditis elegans, Pro-oxidant effect, Caffeine, Theophylline, Theobromine, DAF-16/FOXO, SKN-1

The tiger milk mushroom, Lignosus rhinocerus (LR), exhibits antioxidant properties, as shown in a few in vitro experiments. The aim of this research was to study whether three LR extracts exhibit antioxidant activities in Caenorhabditis elegans. In wild-type N2 nematodes, we determined the survival rate under oxidative stress caused by increased intracellular ROS concentrations. Transgenic strains, including TJ356, TJ375, CF1553, CL2166, and LD1, were used to detect the expression of DAF-16, HSP-16.2, SOD-3, GST-4, and SKN-1, respectively. Lifespan, lipofuscin, and pharyngeal pumping rates were assessed. Three LR extracts (ethanol, and cold and hot water) protected the worms from oxidative stress and decreased intracellular ROS. The extracts exhibited antioxidant properties through the DAF-16/FOXO pathway, leading to SOD-3 and HSP-16.2 modification. However, the expression of SKN-1 and GST-4 was not changed. All the extracts extended the lifespan. They also reduced lipofuscin (a marker for aging) and influenced the pharyngeal pumping rate (another marker for aging). The extracts did not cause dietary restriction. This novel study provides evidence of the functional antioxidant and anti-aging properties of LR. Further studies must confirm that they are suitable for use as antioxidant supplements.

Carbon materials as versatile fillers have drawn increasing attention in thermal conductive polymer composites, however, the thermal conductivity (TC) regulation of them remains challenging. Herein, the tunable lattice thermal conductivity is reported for glucose derived graphitic carbon nanoparticles (GCPs) and their polymer composites. Both the in-plane (La) and out-of-plane (Lc) coherence lengths of GCPs increase with carbonization temperature in the range of 700 °C to 1300 °C. The intrinsic TC of GCPs film is directly extracted from the dependence of the Raman G peak frequency on the excitation laser power and the first order temperature coefficient. It is found that the in-plane lattice TC increases exponentially with both of the increasing La and decreasing defect concentration. The GCPs are then used as highly processible fillers to fabricate thermoset composites based on reactive benzoxazine (BA-a). The total TC of the poly(BA-a)/GCPs are found increase monotonically from 0.27 W·m-1·K-1 to 0.34 W·m-1·K-1 with the increasing graphitization levels of GCPs, and a clear signature of thermal percolation threshold at 6 vol% GCPs loadings is also observed.

Background: Multidrug resistance (MDR) can develop in cancer cells after treatment with anticancer drugs, mainly due to the overexpression of the ATP-binding cassette (ABC) transporters. We analyzed the ability of two pungent-tasting alkaloids—capsaicin and piperine from Capsicum frutescens and Piper nigrum, respectively—to reverse multidrug resistance in the cancer cell lines Caco-2 and CEM/ADR 5000, which overexpress P-glycoprotein (P-gp) and other ABC transporters. Methods: The MTT assay was first used to determine the cytotoxicity of doxorubicin, the alkaloids, and digitonin alone, and then their combinations. Furthermore, rhodamine (Rho) 123 and calcein-AM were used to detect the effects of alkaloids on the activity of P-gp. Results: Capsaicin and piperine synergistically enhanced the cytotoxicity of doxorubicin in Caco-2 and CEM/ADR 5000 cells. Furthermore, capsaicin and piperine increased the intracellular accumulation of the fluorescent P-glycoprotein (P-gp) substrates rhodamine and calcein and inhibited their efflux from the MDR cell lines. Conclusion: Our study has demonstrated that capsaicin and piperine are P-gp substrates and have potential chemosensitizing activity, which might be interesting for the development of novel modulators of multidrug resistance.