New Insights of Biological Functions of Natural Polyphenols in Inflammatory Intestinal Diseases.

The intestine is critically crucial for nutrient absorption and host defense against exogenous stimuli. Inflammation-related intestinal diseases, including enteritis, inflammatory bowel disease (IBD), and colorectal cancer (CRC), are heavy burdens for human beings due to their high incidence and devastating clinical symptoms. Current studies have confirmed that inflammatory responses, along with oxidative stress and dysbiosis as critical pathogenesis, are involved in most intestinal diseases. Polyphenols are secondary metabolites derived from plants, which possess convincible anti-oxidative and anti-inflammatory properties, as well as regulation of intestinal microbiome, indicating the potential applications in enterocolitis and CRC. Actually, accumulating studies based on the biological functions of polyphenols have been performed to investigate the functional roles and underlying mechanisms over the last few decades. Based on the mounting evidence of literature, the objective of this review is to outline the current research progress regarding the category, biological functions, and metabolism of polyphenols within the intestine, as well as applications for the prevention and treatment of intestinal diseases, which might provide ever-expanding new insights for the utilization of natural polyphenols.

Glycine regulates mucosal immunity and the intestinal microbial composition in weaned piglets.

Glycine is an amino acid with a diverse array of health benefits regarding metabolism, immunity, and development. The aim of this study was to test the hypothesis that glycine supplementation alters the intestinal microbial composition and improves the intestinal mucosal immunity of weaned piglets. One hundred and twenty-eight weaned piglets divided into 4 groups were fed with a corn- and soybean meal-based diet supplemented with 0 (control), 0.5, 1, or 2% glycine for 7 days. The intestinal microbiota and tissue samples from the control and the 2% glycine-supplemented piglets were collected for determination of the composition of microbial community and the intestinal mucosal barrier function. Piglets fed with diet containing 2% glycine, instead of 0.5% or 1% glycine, presented elevated average daily gain and feed conversion ratio, as compared with the control. 2% glycine enhanced the abundance of mucins in the jejunum and ileum and mRNA level of porcine ß-defensin (pBD) 2 and pBD-3, as well as the protein level of secretory immunoglobulin A (sIgA) in the jejunum. The mRNA expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6, and the protein level of phosphorylated p38 mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), nuclear factor (NF)-κB p65, and claudin-2 in the jejunum were lower in the 2% glycine group than that in the control. In addition, an elevated ratio of CD4+/CD8+ T lymphocytes was observed in the jejunum of piglets receiving diet supplemented with 2% glycine. The colon content of piglets fed with 2% glycine exhibited a reduction in abundance of pathogenic bacteria (Escherichia-Shigella, Clostridium, and Burkholderiales) and an increase in short-chain fatty acid-producing bacteria (Blautia, Lachnospiraceae, Anaerostipes, and Prevotella) in comparison with the control. We conclude that dietary supplementation with 2% glycine improves the intestinal immunological barrier function and the microbial composition, therefore, contributing to the growth performance of weaned piglets.

Protective effects of glycine against lipopolysaccharide-induced intestinal apoptosis and inflammation.

Intestinal dysfunction is commonly observed in humans and animals. Glycine (Gly) is a functional amino acid with anti-inflammatory and anti-apoptotic properties. The objective of this study was to test the protective effects of Gly against lipopolysaccharide (LPS)-induced intestinal injury. 28 C57BL/6 mice with a body weight (BW) of 18 ± 2 g were randomly assigned into four groups: CON (control), GLY (orally administered Gly, 5 g/kg BW/day for 6 days), LPS (5 mg/kg BW on day 7, i. p.), and GLY + LPS (Gly pretreatment and LPS administration). Histological alterations, inflammatory responses, epithelial cell apoptosis, and changes of the intestinal microbiota were analyzed. Results showed that, compared with the CON group, mice in the LPS treatment group showed decreased villus height, increased crypt depth, and decreased ratio of villus height to crypt depth, which were significantly attenuated by Gly. Neither LPS nor Gly treatment altered morphology of the distal colon tissues. LPS increased the apoptosis of jejunum and colon epithelial cells and protein abundance of cleaved caspase3 in the jejunum, which were markedly abrogated by Gly. LPS also elevated the mRNA levels of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MYD88), pro-inflammatory cytokines, and chemokines in the jejunum and colon. These alterations were significantly suppressed by Gly. In addition, Gly supplementation attenuated infiltration of CD4+, CD8+ T-lymphocytes, CD11b+ and F4/80+ macrophages in the colon. Furthermore, Gly increased the relative abundance of Mucispirillum, Lachnospiraceae-NK4A136-group, Anaerotruncus, Faecalibaculum, Ruminococcaceae-UCG-014, and decreased the abundance of Bacteroides at genus level. Supplementation with Gly might be a nutritional strategy to ameliorate LPS-induced intestinal injury in mice.

Coupling Chlorin-Based Photosensitizers and Histone Deacetylase Inhibitors for Photodynamic Chemotherapy.

Photodynamic therapy combined with chemotherapy is a promising strategy to improve the antitumor efficacy. On the basis of coupling the chlorin-based photosensitizer pyropheophorbide a (Pyro) and histone deacetylase inhibitors (HDACis) to fabricate dual-mode antitumor molecules, a series of dual-mode antitumor prodrug molecules were synthesized and assessed for antitumor activity in vitro and in vivo. The data demonstrated that compound 4, with the most favorable phototoxicity and dark toxicity, could significantly inhibit the cell migration and upregulate the expression of acetyl-H3 protein, functioning as a photosensitizer and HDACi, respectively. Furthermore, compared with talaporfin, Pyro, and SAHA, compound 4 demonstrated the best inhibitory effect on tumor growth and metastasis in tumor-bearing mice; therefore, represented by compound 4, this pharmacophore coupling strategy is much more promising and effective than the pharmacophore fusion strategy for fabricating photodynamic and chemotherapeutical dual-mode molecules.

Lactobacillus johnsonii Attenuates Citrobacter rodentium-Induced Colitis by Regulating Inflammatory Responses and Endoplasmic Reticulum Stress in Mice.

BACKGROUND: Probiotics are beneficial in intestinal disorders. However, the benefits of Lactobacillus johnsonii in experimental colitis remain unknown. OBJECTIVES: This study aimed to investigate the benefits of L. johnsonii against Citrobacter rodentium-induced colitis. METHODS: Thirty-six 5-wk-old female C57BL/6J mice were randomly assigned to 3 groups (n = 12): control (Ctrl) group, Citrobacter rodentium treatment (CR) group (2 × 109 CFU C. rodentium), and Lactobacillus johnsonii and Citrobacter rodentium cotreatment (LJ + CR) group (109 CFU L. johnsonii with C. rodentium). Colon length, mucosal thickness, proinflammatory cytokine genes, and endoplasmic reticulum stress were tested. RESULTS: The CR group had greater spleen weight, mucosal thickness, and Ki67+ cells (0.4-4.7 times), and a 23.8% shorter colon length than the Ctrl group, which in the LJ + CR group were 22.4%-77.6% lower and 30% greater than in the CR group, respectively. Relative to the Ctrl group, serum proinflammatory cytokines and immune cell infiltration were greater by 0.3-1.6 times and 6.2-8.8 times in the CR group, respectively; relative to the CR group, these were 19.9%-61.9% and 69.5%-84.2% lower in the LJ + CR group, respectively. The mRNA levels of lysozyme (Lyz) and regenerating islet-derived protein III were 22.7%-36.5% lower and 1.5-2.7 times greater in the CR group than in the Ctrl group, respectively, whereas they were 22.2%-25.7% greater and 57.2%-76.9% lower in the LJ + CR group than in the CR group, respectively. Cell apoptosis was 11.9 times greater in the CR group than in the Ctrl group, and 87.4% lower in the LJ + CR group than in the CR group. Consistently, the protein abundances of C/EBP homologous protein (CHOP), cleaved caspase 1 and 3, activating transcription factor 6α (ATF6A), and phospho-inositol-requiring enzyme 1α (P-IRE1A) were 0.3-2.1 times greater in the CR group and 31.1%-60.4% lower in the LJ + CR group. All these indexes did not differ between the Ctrl and LJ + CR groups, except for CD8+ T lymphocytes and CD11b+ and F4/80+ macrophages (1-1.5 times greater in LJ + CR) and mRNA concentration of Lyz2 (20.1% lower in LJ + CR). CONCLUSIONS: L. johnsonii supplementation is a promising nutritional strategy for preventing C. rodentium-induced colitis in mice.

Water-Soluble Flexible Organic Frameworks That Include and Deliver Proteins.

Four water-soluble hydrazone-based three-dimensional (3D) flexible organic frameworks FOF-1-4 have been synthesized from a semirigid tetracationic tetraaldehyde and four flexible dihydrazides. 1H NMR spectroscopy indicated the quantitative formation of FOF-1-4 in D2O, while dynamic light scattering experiments revealed that, depending on the concentration, these porous frameworks display hydrodynamic diameters ranging from 50 to 120 nm. The porosity of the frameworks is confirmed by ethanol vapor adsorption experiments of the solid samples as well as the high loading capacity for a 2.3 nm porphyrin guest in water. The new water-soluble frameworks exhibit low cytotoxicity and form inherent pores with diameters of 5.3 or 6.7 nm, allowing rapid inclusion of proteins such as bovine serum albumin and green and orange fluorescent proteins, and efficient delivery of the proteins into normal and cancer cells. Flow cytometric analysis reveals percentages of the delivered cells up to 99.8%.

Glycine Attenuates LPS-Induced Apoptosis and Inflammatory Cell Infiltration in Mouse Liver.

BACKGROUND: Liver dysfunction impairs immunological homeostasis. Glycine (Gly) has been reported to have antioxidative and anti-inflammatory effects and to regulate apoptosis in various models. OBJECTIVES: The aim of the present study was to determine whether Gly could attenuate LPS-induced liver injury. METHODS: In Experiment 1, 48 6-week-old male C57BL/6 mice were randomly assigned into one of 4 groups: CON (control), GLY [orally administered Gly, 5 g · kg body weight (BW)-1 · d-1 for 6 d], LPS (5 mg/kg BW, intraperitoneally administered), and GLY + LPS (Gly supplementation, and on day 7 LPS treatment). In Experiment 2, mice were untreated, pretreated with Gly as above, or pretreated with Gly + l-buthionine sulfoximine (BSO) (0.5 g/kg BW, intraperitoneally administered every other day) for 6 d. On day 7, mice were injected with LPS as above. Histological alterations, activities of antioxidative enzymes, apoptosis, and immune cell infiltration were analyzed. RESULTS: In Experiment 1, compared with CON, LPS administration resulted in increased karyolysis and karyopyknosis in the liver by 8- to 10-fold, enhanced serum activities of alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) by 1- to 1.8-fold, and increased hepatic apoptosis by 5.5-fold. Furthermore, LPS exposure resulted in increased infiltration of macrophages and neutrophils in the liver by 3.2- to 7.5-fold, elevated hepatic concentrations of malondialdehyde and hydrogen peroxide (H2O2), and elevated myeloperoxidase (MPO) activity by 1.5- to 6.3-fold. In Experiment 2, compared with the LPS group, mice in the GLY + LPS group had fewer histological alterations (68.5%-75.9%); lower serum ALT, AST, and LDH activities (24.3%-64.7%); and lower hepatic malondialdehyde and H2O2 concentrations (46.1%-80.2%), lower MPO activity (39.2%), immune cell infiltration (52.3%-85.3%), and apoptosis (69.6%), which were abrogated by BSO. Compared with the GLY + LPS group, mice in the GLY + BSO + LPS group had lower hepatic activities of catalase, superoxide dismutase, and glutathione peroxidase by 33.5%-48.5%; increased activation of NF-κB by 2.3-fold; and impaired nuclear factor (erythroid-derived 2)-like 2 signaling by 38.9%. CONCLUSIONS: Gly is a functional amino acid with an ability to protect the liver against LPS-induced injury in mice.

Maternal L-proline supplementation enhances fetal survival, placental development, and nutrient transport in mice†.

L-Proline (proline) in amniotic fluid was markedly increased during pregnancy in both pigs and sheep. However, in vivo data to support a beneficial effect of proline on fetal survival are not available. In this study, pregnant C57BL/6J mice were fed a purified diet supplemented with or without 0.50% proline from embryonic day 0.5 (E0.5) to E12.5 or term. Results indicated that dietary supplementation with proline to gestating mice enhanced fetal survival, reproductive performance, the concentrations of proline, arginine, aspartic acid, and tryptophan in plasma and amniotic fluid, while decreasing the concentrations of ammonia and urea in plasma and amniotic fluid. Placental mRNA levels for amino acid transporters, including Slc36a4, Slc38a2, Slc38a4, Slc6a14, and Na+/K+ ATPase subunit-1α (Atp1a1), fatty acid transporter Slc27a4, and glucose transporters Slc2a1 and Slc2a3, were augmented in proline-supplemented mice, compared with the control group. Histological analysis showed that proline supplementation enhanced labyrinth zone in the placenta of mice at E12.5, mRNA levels for Vegf, Vegfr, Nos2, and Nos3, compared with the controls. Western blot analysis showed that proline supplementation increased protein abundances of phosphorylated (p)-mTORC1, p-ribosomal protein S6 kinase (p70S6K), and p-eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), as well as the protein level of GCN2 (a negative regulator of mTORC1 signaling). Collectively, our results indicate a novel functional role of proline in improving placental development and fetal survival by enhancing placental nutrient transport, angiogenesis, and protein synthesis.

Maternal L-proline supplementation during gestation alters amino acid and polyamine metabolism in the first generation female offspring of C57BL/6J mice.

We recently reported that dietary supplementation with L-proline (proline) during gestation improved embryonic survival in C57BL/6J mice. The objective of the present study was to test the hypothesis that the effect of maternal proline supplementation on embryonic survival can be carried forward to the first generation female offspring. In the F0 generation, pregnant dams were fed a purified diet supplemented with 0 (control) or 5 g proline/kg diet. The F1 female adult offsprings were bred to fertile males. Fetal survival at embryonic day (E)12.5 and reproductive outcomes at term birth were recorded. The concentrations of amino acids, ammonia, and urea in plasma and amniotic fluid, as well as concentrations of polyamines in placental tissues and amniotic fluid at E12.5 were determined. Results showed that the F1 generation female offspring from proline-supplemented dams had higher (P < 0.05) concentrations of glutamate and taurine in plasma; of putrescine and spermidine in placental tissues; and of glycine, taurine, and spermidine in amniotic fluid at E12.5, as compared with F1 generation female offsprings from dams without proline supplementation. Concentration of proline in the plasma of offspring mice from proline-supplemented dams were lower (P < 0.05), as compared with the control group. No differences in fetal survival, reproductive outcomes, or concentrations of ammonia and urea in plasma and amniotic fluid were observed between the two groups of F1 female offspring. Collectively, our results indicate that the benefits of maternal proline supplementation during gestation on improving embryonic survival and fetal growth in F0 females are not transmitted to their F1 generation females.

l-Glutamine Attenuates Apoptosis in Porcine Enterocytes by Regulating Glutathione-Related Redox Homeostasis.

Background: Programmed cell death plays a fundamental role in intestinal development and mucosal homeostasis. Dysregulation of these processes is associated with an impaired intestinal-mucosal barrier, reduced nutrient absorption, and initiation and progression of intestinal diseases. 4-Hydroxy-2-nonenal (4-HNE), a product of lipid peroxidation, is commonly used to induce oxidative stress in cells. l-Glutamine is known to protect cells from apoptosis. However, the underlying mechanisms are largely unknown. Objective: This study was conducted to test the hypothesis that l-glutamine attenuates 4-HNE-induced apoptosis by modulating glutathione (GSH) and thioredoxin (TXN) antioxidant systems and the expression of genes involved in 4-HNE metabolism in enterocytes. Methods: Intestinal porcine epithelial cell line 1 (IPEC-1) cells were cultured with or without 4-HNE (30 µmol/L) in the presence of 0.05 or 0.25 mmol l-glutamine/L (a physiological concentration in the lumen of the small intestine) for indicated time periods. Cell viability, abundances of apoptotic proteins, mitochondrial membrane depolarization, production of reactive oxygen species (ROS) and GSH, and expression of genes involved in the biosynthesis of GSH, thioredoxin, and 4-HNE metabolism were determined. Results: Compared with basal medium containing 0.05 mmol l-glutamine/L, 4-HNE enhanced apoptosis by 19.6% (P < 0.05) in a caspase-3-dependent manner. This effect was accompanied by elevated intracellular ROS production (39.5% and 85.3% for 2- and 4-h treatment, respectively), increased mitochondrial depolarization by 80%, and decreased intracellular GSH concentrations by 17.7%. These effects of 4-HNE were reduced by 0.25 mmol l-glutamine/L. Further study showed that the protective effect of l-glutamine was associated with the enhanced expression of genes involved in GSH production (including GCLC, GCLM, GSR, CBS, and CTH) by 3.9-14-fold, as well as genes involved in 4-HNE metabolism [e.g., glutathione S-transferase A (GSTA)1 and GSTA4] by 1.9-7.2-fold. The mRNA levels for ADH5, AKR1C1, AKR1A1, and TXNRD1 were enhanced 1.4-8.8-fold by 4-HNE but were not changed in cells co-treated with 4-HNE and l-glutamine. Conclusion: These findings indicate that l-glutamine attenuates 4-HNE-induced apoptosis by regulating GSH-related redox homeostasis and enhancing GSTA-mediated metabolism in enterocytes.

Construction of ThermoMaze.

Physiological changes during awake immobility-related brain states remain one of the great unexplored behavioral states. Controlling periods of awake immobility is challenging because restraining the animal is stressful and is accompanied by altered physiological states. Here, we describe the ThermoMaze, a behavioral paradigm that allows for the collection of large amounts of physiological data while the animal rests at distinct experimenter-determined locations. We found that the paradigm generated long periods of immobility and did not alter the brain temperature. We combined the ThermoMaze with electrophysiology recordings in the CA1 region of the hippocampus and found a location-specific distribution of sharp-wave ripple events. We describe the construction of the ThermoMaze with the intention that it helps enable large-scale data recordings on immobility-related brain states. Key features • Controlling periods of awake immobility in rodents. • Electronic-friendly analog of the Morris water maze.

A dual-prodrug nanogel combining Vorinostat and Pyropheophorbide a for a high efficient photochemotherapy.

The challenges posed by intractable relapse and metastasis in cancer treatment have led to the development of various forms of photodynamic therapy (PDT). However, traditional drug delivery systems, such as virus vectors, liposomes, and polymers, often suffer from issues like desynchronized drug release, carrier instability, and drug leakage during circulation. To address these problems, we have developed a dual-prodrug nanogel (PVBN) consisting of Pyro (Pyropheophorbide a) and SAHA (Vorinostat) bound to BSA (Bovine Serum Albumin), which facilitates synchronous and spontaneous drug release in situ within the lysosome. Detailed results indicate that PVBN-treated tumor cells exhibit elevated levels of ROS and Acetyl-H3, leading to necrosis, apoptosis, and cell cycle arrest, with PDT playing a dominant role in the synergistic therapeutic effect. Furthermore, the anti-tumor efficacy of PVBN was validated in melanoma-bearing mice, where it significantly inhibited tumor growth and pulmonary metastasis. Overall, our dual-prodrug nanogel, formed by the binding of SAHA and Pyro to BSA and releasing drugs within the lysosome, represents a novel and promising strategy for enhancing the clinical efficacy of photochemotherapy.

ThermoMaze: A behavioral paradigm for readout of immobility-related brain events.

Brain states fluctuate between exploratory and consummatory phases of behavior. These state changes affect both internal computation and the organism's responses to sensory inputs. Understanding neuronal mechanisms supporting exploratory and consummatory states and their switching requires experimental control of behavioral shifts and collecting sufficient amounts of brain data. To achieve this goal, we developed the ThermoMaze, which exploits the animal's natural warmth-seeking homeostatic behavior. By decreasing the floor temperature and selectively heating unmarked areas, mice avoid the aversive state by exploring the maze and finding the warm spot. In its design, the ThermoMaze is analogous to the widely used water maze but without the inconvenience of a wet environment and, therefore, allows the collection of physiological data in many trials. We combined the ThermoMaze with electrophysiology recording, and report that spiking activity of hippocampal CA1 neurons during sharp-wave ripple events encode the position of the animal. Thus, place-specific firing is not confined to locomotion and associated theta oscillations but persist during waking immobility and sleep at the same location. The ThermoMaze will allow for detailed studies of brain correlates of immobility, preparatory-consummatory transitions and open new options for studying behavior-mediated temperature homeostasis.

Establishment of a TaqMan-based real-time quantitative PCR method for detection of exogenous fowl adenovirus type â , type â ¢ and avian leukosis virus in human cold adapted live attenuated influenza vaccines.

Cold adapted live attenuated influenza vaccines can effectively prevent human disease and death caused by influenza virus. Since chicken embryos are used as the culture substrate for the large-scale production of influenza vaccines, cold adapted live attenuated influenza vaccines may be contaminated by exogenous avian viruses. Rapid and sensitive methods such as TaqMan-based quantitative PCR are needed for the detection of exogenous avian viruses during cold adapted live attenuated influenza vaccines production. In this study, a TaqMan-based quantitative PCR method was established for the detection of three common exogenous avian viruses, including fowl adenovirus type I, type Ⅲ and avian leukosis virus. Avian virus-encoding plasmids purified in high-performance liquid chromatography were essential for sensitivity analysis. The sensitivity reached 1 copy per reaction for each of the avian virus plasmids. Standard curves showed a strong linear relationship. The TaqMan-based quantitative PCR method had high specificity and no cross-reactivity with other irrelevant viruses. Furthermore, the established TaqMan-based quantitative PCR can effectively detect 0.1 TCID50 of each avian virus without or with interference from the influenza virus nucleic acid. Ultimately, this method was used to test three master seed lots of monovalent cold adapted live attenuated influenza vaccine, and the results showed that no fowl adenovirus type I, type Ⅲ or avian leukosis virus contamination, which were consistent with serological methods. The TaqMan-based quantitative PCR method for the determination of extraneous avian viruses in cold adapted live attenuated influenza vaccines met the requirement for both conventional and emergency inspection on cold adapted live attenuated influenza vaccines.

Preconfigured dynamics in the hippocampus are guided by embryonic birthdate and rate of neurogenesis.

The incorporation of new information into the hippocampal network is likely to be constrained by its innate architecture and internally generated activity patterns. However, the origin, organization and consequences of such patterns remain poorly understood. In the present study we show that hippocampal network dynamics are affected by sequential neurogenesis. We birthdated CA1 pyramidal neurons with in utero electroporation over 4 embryonic days, encompassing the peak of hippocampal neurogenesis, and compared their functional features in freely moving adult mice. Neurons of the same birthdate displayed distinct connectivity, coactivity across brain states and assembly dynamics. Same-birthdate neurons exhibited overlapping spatial representations, which were maintained across different environments. Overall, the wiring and functional features of CA1 pyramidal neurons reflected a combination of birthdate and the rate of neurogenesis. These observations demonstrate that sequential neurogenesis during embryonic development shapes the preconfigured forms of adult network dynamics.

Association between intestinal microbiota and inflammatory bowel disease.

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), has emerged as a global disease with high incidence, long duration, devastating clinical symptoms, and low curability (relapsing immune response and barrier function defects). Mounting studies have been performed to investigate its pathogenesis to provide an ever-expanding arsenal of therapeutic options, while the precise etiology of IBD is not completely understood yet. Recent advances in high-throughput sequencing methods and animal models have provided new insights into the association between intestinal microbiota and IBD. In general, dysbiosis characterized by an imbalanced microbiota has been widely recognized as a pathology of IBD. However, intestinal microbiota alterations represent the cause or result of IBD process remains unclear. Therefore, more evidences are needed to identify the precise role of intestinal microbiota in the pathogenesis of IBD. Herein, this review aims to outline the current knowledge of commonly used, chemically induced, and infectious mouse models, gut microbiota alteration and how it contributes to IBD, and dysregulated metabolite production links to IBD pathogenesis.

Microneedle-based two-step transdermal delivery of Langerhans cell-targeting immunoliposomes induces a Th1-biased immune response.

Novel Coronavirus is affecting human's life globally and vaccines are one of the most effective ways to combat the epidemic. Transcutaneous immunization based on microneedle (MN) has attracted much attention because of its painlessness, rapidity, high efficiency and good compliance. In this study, CD11c monoclonal antibody-immunoliposomes (OVA@CD11c-ILP) actively targeting to Langerhans cells (LCs) were successfully prepared and were delivered by the microchannels of skin produced by MN to induce an immune response in vivo. OVA@CD11c-ILP could be targeted to LCs by conjugating CD11c monoclonal antibody to the surface of the ILP. OVA@CD11c-ILP promoted the maturation of dendritic cells (DCs) and the uptake and endocytosis of antigen by LCs. Moreover, OVA@CD11c-ILP immunization can significantly inhibit tumor growth and prolong overall survival. Furthermore, a higher antibody's titer ratio of IgG1/IgG2a indicated that the immune response stimulated by this immunization method was Th1-biased and the liposomes showed Th1-type adjuvant effect. In conclusion, the combination delivery system of immunoliposomes and microneedle can significantly improve the efficiency of antigen presentation and effectively activate cellular immune responses in the body, which is expected to be a promising transdermal immune strategy.

Lysosomal activable Vorinostat carrier-prodrug self-assembling with BPQDs enables photothermal oncotherapy to reverse tumor thermotolerance and metastasis.

Photothermal therapy (PTT) is becoming increasing prevalent in clinic for eradicating the primary tumor and improving cancer patients' compliance. However, photothermal resistance and distal metastasis still haunt the tumor treatment with PTT. Herein, on the basis that histone deacetylase acetylase inhibitor (HDACis) could activate the expression of anti-tumor gene and accelerate the differentiation and apoptosis of tumor cells, we propose that HDACis supplementing PTT could overcome those obstacles with appropriate drug-controlled release strategy. Thus, we fabricated a nano-complex of lysosomal activable vorinostat (SAHA) carrier-prodrug encapsulating black phosphorus quantum dots (BPQDs@PPS) to counter those challenges in PTT. With spherical morphology and favorable bio-safety, BPQDs@PPS could release BPQDs and Vorinostat spontaneously in lysosome, not only effectively inhibiting tumor growth, but also reversing tumor thermotolerance and metastasis within a PTT procedure. Especially, both western blot and immunofluorescence analysis validate that Vorinostat enables PTT to reverse tumor thermotolerance and distal metastasis by down-regulation of HSP70 and up-regulation of H3. Therefore, this research not only reveals the mechanism how HDACis supplement PTT in reversing tumor thermotolerance and metastasis, but also provides a promising prospect to upgrade clinical photothermal therapy.

Supramolecular organic frameworks improve the safety of clinically used porphyrin photodynamic agents and maintain their antitumor efficacy.

Despite that photodynamic therapy (PDT) has been applied for the treatment of cancer and skin diseases for more than two decades, all clinically used photodynamic agents (PDAs) suffer the drawback of skin phototoxicity of PDAs, which requires patients to avoid exposure to natural light for weeks after treatment, but has so far lacked effective suppression methods. Here, we report that three-dimensional diamondoid supramolecular organic frameworks (SOFs), that possess well-defined 2.1-nm porosity, can be used to suppress the skin phototoxicity of Photofrin, HiPorfin and Talaporfin, three porphyrin-based PDAs which clinically receive the most wide applications by injecting SOF after PDT, via an adsorption and retention mechanism. Fluorescence and dynamic light scattering experiments confirm that the SOFs have strong interaction with PDAs, and can adsorb PDAs at a micromolar concentration, whereas dialysis experiments support that the adsorption leads to an important retention effect. In vitro and in vivo experiments reveal that SOFs have high biocompatibility. Studies with healthy and tumor-bearing mouse models demonstrate that, when the PDAs are administrated at a dose comparable with the clinical one, SOF can remarkably suppress sunlight-induced skin phototoxicity, whereas the PDT efficacy of mice treated with SOF post-PDT is maintained. This work provides an efficient strategy for the improvement of the safety of clinically used PDAs.