Enzyme/ROS dual-sensitive nanoplatform with on-demand Celastrol release capacity for enhanced ulcerative colitis therapy by ROS scavenging, microbiota rebalancing, inflammation alleviating.

BACKGROUND: The oral administration of drugs for treating ulcerative colitis (UC) is hindered by several factors, including inadequate gastrointestinal stability, insufficient accumulation in colonic lesions, and uncontrolled drug release. METHODS: A multiple sensitive nano-delivery system comprising ß-cyclodextrin (CD) and 4-(hydroxymethyl)phenylboronic acid (PAPE) with enzyme/reactive oxygen species (ROS) sensitivity was developed to load celastrol (Cel) as a comprehensive treatment for UC. RESULTS: Owing to the positive charge in the site of inflamed colonic mucosa, the negatively charged nanomedicine (Cel/NPs) could efficiently accumulate. Expectedly, Cel/NPs showed excellent localization ability to colon in vitro and in vivo tests. The elevated concentration of ROS and intestinal enzymes in the colon microenvironment quickly break the CD, resulting in Cel release partially to rebalance microbiota and recover the intestinal barrier. The accompanying cellular internalization of residual Cel/NPs, along with the high concentration of cellular ROS to trigger Cel burst release, could decrease the expression of inflammatory cytokines, inhibit colonic cell apoptosis, promote the macrophage polarization, scavenge ROS, and regulate the TLR4/NF-κB signaling pathway, which certified that Cel/NPs possessed a notably anti-UC therapy outcome. CONCLUSIONS: We provide a promising strategy for addressing UC symptoms via an enzyme/ROS-sensitive oral platform capable of releasing drugs on demand.

Pickering Emulsion Stabilized by Hordein-Whey Protein Isolate Complex: Delivery System of Quercetin.

As a lipophilic flavonol, quercetin has low bioavailability, which limits its application in foods. This work aimed to prepare a hordein-based system to deliver quercetin. We constructed hordein-whey isolate protein fibril (WPIF) complexes (H-Ws) by anti-solvent precipitation method at pH 2.5. The TEM results of the complexes showed that spherical-like hordein particles were wrapped in WPIF clusters to form an interconnected network structure. FTIR spectra revealed that hydrogen bonds and hydrophobic interactions were the main driving forces for the complex formation. H-W1 (the mass ratio of hordein to WPIF was 1:1) with a three-phase contact angle of 70.2° was chosen to stabilize Pickering emulsions with oil volume fractions (φ) of 40-70%. CLSM images confirmed that the oil droplets were gradually embedded in the three-dimensional network structure of H-W1 with the increase in oil volume fraction. The emulsion with φ = 70% showed a tight gel structure. Furthermore, this emulsion exhibited high encapsulation efficiency (97.8%) and a loading capacity of 0.2%, demonstrating the potential to deliver hydrophobic bioactive substances. Compared with free quercetin, the bioaccessibility of the encapsulated quercetin (35%) was significantly improved. This study effectively promoted the application of hordein-based delivery systems in the food industry.

Tumor Microenvironment ROS/pH Cascade-Responsive Supramolecular Nanoplatform with ROS Regeneration Property for Enhanced Hepatocellular Carcinoma Therapy.

The low targeted drug delivery efficiency, including poor tumor accumulation and penetration and uncontrolled drug release, leads to the failure of cancer therapy. Herein, a multifunctional supramolecular nanoplatform loading triptolide (TPL/PBAETK@GA NPs) was fabricated via the host-guest interaction between glycyrrhetinic-acid-modified poly(ethylene glycol)-adamantanecarboxylic acid moiety and reactive oxygen species (ROS)/pH cascade-responsive copolymer poly(ß-amino esters)-thioketal (TK)-ß-cyclodextrin. TPL/PBAETK@GA NPs could accumulate in hepatocellular carcinoma (HCC) tissue effectively, mediated by nanoscale advantage and GA' recognition to specific receptors. The elevated concentration of ROS in tumor microenvironment (TME) quickly breaks the TK linkages, causing the detachment of shell (cyclodextrin) CD layer. Then, the accompanying negative-to-positive charge-reversal of NPs was realized via the PBAE moiety protonation under the slightly acidic TME, significantly enhancing the NPs' cellular internalization. Remarkably, the pH-responsive endo/lysosome escape of PBAE core triggered intracellular TPL burst release, promoting the cancer cell apoptosis, autophagy, and intracellular ROS generation, leading to the self-amplification of ROS in TME. Afterward, the ROS positive-feedback loop was generated to further promote size-shrinkage and charge-reversal of NPs. Both in vitro and in vivo tests verified that TPL/PBAETK@GA NPs produced a satisfactory anti-HCC therapy outcome. Collectively, this study offers a potential appealing paradigm to enhance TPL-based HCC therapy outcomes via multifunctionalized supramolecular nanodrugs.

Ameliorative Effect of Malvidin on Spleen Injury in LPS-Induced Sepsis.

Sepsis, one of the most destructive diseases in the world, is a syndrome of systemic inflammatory response caused by the invasion of pathogenic microorganisms such as bacteria into the body. Malvidin is one of the most widespread anthocyanins, and its significant antioxidant and anti-inflammatory activities have been widely reported. However, the effect of Malvidin on sepsis and related complications is still unclear. The present study aimed to determine the mechanisms of Malvidin's potential protection from lipopolysaccharide (LPS)-induced spleen injury model of sepsis. In the LPS-induced mouse spleen injury model of sepsis, pretreatment with Malvidin was performed to assess morphological damage in spleen tissue and to detect the expression of mRNA levels of serum necrosis factor α, interleukin 1ß and interleukin 6, and IL-10. Apoptosis was detected using the TUNEL technique, and the levels of oxidative stress-related oxidase and antioxidant enzymes were measured by kit to assess the effect of Malvidin on inflammation and oxidative stress associated with septic spleen injury. The results of this study indicated that Malvidin was be a potentially effective drug for the treatment of sepsis.

Retraction notice to "Betulinic acid downregulates expression of oxidative stress-induced lipoprotein lipase via PKC/ERK/c-Fos pathways in RAW264.7 macrophages" [Biochimie 119C (2015) 192-203].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Concerns raised by Dr. Sander Kersten in PubPeer pointed out that Figs. 6.1B and 6.2B of this paper were different figures but the legends and Western blots were identical; the quantification was also seen to be different between the two figures. Shortly afterwards, the authors asked to publish a corrigendum for part B of Fig. 6.1, including images of western blots and associated bar plots. Subsequently, the journal conducted an investigation and found evidence that there had been improper manipulation and duplication of images in Fig. 2 E, 6.2 B, 5 A and and 6.2 D, as shown by the reuse of several western blot bands with approximately 180° rotation in each case. After raising the complaint with the authors, the corresponding author agreed that the paper should be retracted. The authors apologise to the readers of the journal.

Reciprocal costimulatory molecules control the activation of mucosal type 3 innate lymphoid cells during engagement with B cells.

Innate lymphoid cells (ILCs) are the counterpart of T helper cells in the innate immune system and share multiple phenotypes with T helper cells. Inducible T-cell costimulator (ICOS) is recognized on T cells and participates in T-cell activation and T and B-cell engagement in lymphoid tissues. However, the role of ICOS in ILC3s and ILC3-involved interactions with the immune microenvironment remains unclear. Here, we found that ICOS expression on human ILC3s was correlated with the activated state of ILC3s. ICOS costimulation enhanced the survival, proliferation, and capacity of ILC3s to produce cytokines (IL-22, IL-17A, IFN-γ, TNF, and GM-CSF). Via synergistic effects of ICOS and CD40 signaling, B cells promoted ILC3 functions, and ILC3-induced T-cell-independent B-cell IgA and IgM secretion primarily required CD40 signaling. Hence, ICOS is essential for the nonredundant role of ILC3s and their interaction with adjacent B cells.

The relationship between autophagy and PD-L1 and their role in antitumor therapy.

Immune checkpoint blockade therapy is an important advance in cancer treatment, and the representative drugs (PD-1/PD-L1 antibodies) have greatly improved clinical outcomes in various human cancers. However, since many patients still experience primary resistance, they do not respond to anti-PD1/PD-L1 therapy, and some responders also develop acquired resistance after an initial response. Therefore, combined therapy with anti-PD-1/PD-L1 immunotherapy may result in better efficacy than monotherapy. In tumorigenesis and tumor development processes, the mutual regulation of autophagy and tumor immune escape is an intrinsic factor of malignant tumor progression. Understanding the correlation between the tumor autophagy pathway and tumor immune escape may help identify new clinical cancer treatment strategies. Since both autophagy and immune escape of tumor cells occur in a relatively complex microenvironmental network, autophagy affects the immune-mediated killing of tumor cells and immune escape. Therefore, comprehensive treatment targeting autophagy and immune escape to achieve "immune normalization" may be an important direction for future research and development. The PD-1/PD-L1 pathway is essential in tumor immunotherapy. High expression of PD-L1 in different tumors is closely related to poor survival rates, prognoses, and treatment effects. Therefore, exploring the mechanism of PD-L1 expression is crucial to improve the efficacy of tumor immunotherapy. Here, we summarize the mechanism and mutual relationship between autophagy and PD-L1 in antitumor therapy, which may help enhance current antitumor immunotherapy approaches.

Novel players in organogenesis and flavonoid biosynthesis in cucumber glandular trichomes.

Glandular trichomes (GTs) are outgrowths of plant epidermal cells that secrete and store specialized secondary metabolites that protect plants against biotic and abiotic stresses and have economic importance for human use. While extensive work has been done to understand the molecular mechanisms of trichome organogenesis in Arabidopsis (Arabidopsis thaliana), which forms unicellular, nonglandular trichomes (NGTs), little is known about the mechanisms of GT development or regulation of secondary metabolites in plants with multicellular GTs. Here, we identified and functionally characterized genes associated with GT organogenesis and secondary metabolism in GTs of cucumber (Cucumis sativus). We developed a method for effective separation and isolation of cucumber GTs and NGTs. Transcriptomic and metabolomic analyses showed that flavonoid accumulation in cucumber GTs is positively associated with increased expression of related biosynthesis genes. We identified 67 GT development-related genes, the functions of 7 of which were validated by virus-induced gene silencing. We further validated the role of cucumber ECERIFERUM1 (CsCER1) in GT organogenesis by overexpression and RNA interference transgenic approaches. We further show that the transcription factor TINY BRANCHED HAIR (CsTBH) serves as a central regulator of flavonoid biosynthesis in cucumber GTs. Work from this study provides insight into the development of secondary metabolite biosynthesis in multicellular GTs.

Identification and Functional Characterization of CsMYCs in Cucumber Glandular Trichome Development.

Glandular trichomes (GTs), specialized structures formed by the differentiation of plant epidermal cells, are known to play important roles in the resistance of plants to external biotic and abiotic stresses. These structures are capable of storing and secreting secondary metabolites, which often have important agricultural and medicinal values. In order to better understand the molecular developmental mechanisms of GTs, studies have been conducted in a variety of crops, including tomato (Solanum lycopersicum), sweetworm (Artemisia annua), and cotton (Gossypium hirsutum). The MYC transcription factor of the basic helix-loop-helix (bHLH) transcription factor family has been found to play an important role in GT development. In this study, a total of 13 cucumber MYC transcription factors were identified in the cucumber (Cucumis sativus L.) genome. After performing phylogenetic analyses and conserved motifs on the 13 CsMYCs in comparison to previously reported MYC transcription factors that regulate trichome development, seven candidate MYC transcription factors were selected. Through virus-induced gene silencing (VIGS), CsMYC2 is found to negatively regulate GT formation while CsMYC4, CsMYC5, CsMYC6, CsMYC7, and CsMYC8 are found to positively regulate GT formation. Furthermore, the two master effector genes, CsMYC2 and CsMYC7, are observed to have similar expression patterns indicating that they co-regulate the balance of GT development in an antagonistic way.

Partial immune responses in Sichuan bream (Sinibrama taeniatus) after starvation.

Background: Food deprivation is a severe stress across multiple fields and it might be a challenge to immune system. Methods: In the present study, adult male Sinibrama taeniatus were deprived of feed for 7 to 28 days. We explored the effects of starvation on immunity in S. taeniatus through hematological analysis, antioxidant capacity analysis, detection of the content or activity of immune factors in plasma, and transcriptomic analysis. Results: The results indicated that biometric indexes significantly decreased in the fish after starvation, the proportion of thrombocyte, neutrophil and monocyte increased and, conversely, the proportion of lymphocyte decreased. The antioxidant indexes (SOD and CAT) and innate immune parameters (LZM, C3) were upregulated in fish suffering from a short period of starvation, while adaptive immune parameter (IgM) conversely declined. The transcriptome analysis revealed the changes of various metabolic regulatory pathways involved in fatty acids and amino acids, as well as the immune responses and antioxidant capacity. Conclusions: Taken together, this research in the present study suggested an induced innate immunity while a partly suppressed adaptive immunity under a short period starvation.

Liensinine attenuates inflammation and oxidative stress in spleen tissue in an LPS-induced mouse sepsis model. / 莲心碱可减轻LPSè¯±å¯¼çš„å°é¼ è„“æ¯’ç—‡æ¨¡åž‹ä¸­è„¾è„ç»„ç»‡ç‚Žç—‡å’Œæ°§åŒ–åº”æ¿€ååº”.

Sepsis is a complex syndrome caused by multiple pathogens and involves multiple organ failure, particularly spleen dysfunction. In 2017, the worldwide incidence was 48.9 million sepsis cases and 11 million sepsis-related deaths were reported (Rudd et al., 2020). Inflammation, oxidative stress, and apoptosis are the most common pathologies seen in sepsis. Liensinine (LIE) is a bisbenzylisoquinoline-type alkaloid extracted from the seed embryo of Nelumbo nucifera. Lotus seed hearts have high content of LIE which mainly has antihypertensive and antiarrhythmic pharmacological effects. It can exert anti-carcinogenic activity by regulating cell, inflammation, and apoptosis signaling pathways (Manogaran et al., 2019). However, its protective effect from sepsis-induced spleen damage is unknown. In this research, we established a mouse sepsis model induced by lipopolysaccharide (LPS) and investigated the protective effects of LIE on sepsis spleen injury in terms of inflammatory response, oxidative stress, and apoptosis.

Low levels of tenofovir in breast milk support breastfeeding in HBV-infected mothers treated with tenofovir disoproxil fumarate.

OBJECTIVE: Tenofovir disoproxil fumarate (TDF) is recommended for the prevention of mother-to-infant transmission of the hepatitis B virus (HBV). This study investigated the safety of infants whose mothers continued to receive TDF while breastfeeding. PATIENTS AND METHOD: Thirty women taking TDF daily from the second or third trimester of pregnancy to three months postpartum were enrolled. Tenofovir (TFV) concentrations in breast milk were determined and compared with those in umbilical cord (UC) blood and amniotic fluid. Infant growth parameters were assessed at birth, and at 3, 6, and 12 months. TFV uptake experiments were conducted in vitro to elucidate the mechanisms of TFV exposure via breast milk. RESULTS: TFV concentrations in breast milk ranged from 1.4 to 11.7 ng/mL within 24 h after dosing in the third month postpartum. The median trough concentration of TFV in breast milk was 3.7 (interquartile range, 2.6-6.2) ng/mL, which is lower than that in UC blood (median = 53.5 ng/mL) and amniotic fluid (median = 531.0 ng/mL). The low permeability of TFV in MCF-10A cells may explain the minimal exposure to TFV in breast milk. Body weights, body lengths, and head circumferences of the breastfed infants were comparable to the national standards for physical development. CONCLUSION: Infant exposure to TFV from breast milk is much lower than the exposure from placental transfer and swallowing from amniotic fluid. The physical growth parameters of all infants in this study were normal. The findings indicate that breastfeeding is safe for infants of HBV-infected mothers who continue to receive TDF through three months postpartum.

Biased mutations and gene losses underlying diploidization of the tetraploid broomcorn millet genome.

Broomcorn millet (Panicum miliaceum L.) is one of the earliest domesticated crops, and is a valuable resource to secure food diversity and combat drought stresses under the global warming scenario. However, due to the absence of extant diploid progenitors, the polyploidy genome of broomcorn millet remains poorly understood. Here, we report the chromosome-scale genome assembly of broomcorn millet. We divided the broomcorn millet genome into two subgenomes using the genome sequence of Panicum hallii, a diploid relative of broomcorn millet. Our analyses revealed that the two subgenomes diverged at ~4.8 million years ago (Mya), while the allotetraploidization of broomcorn millet may have occurred about ~0.48 Mya, suggesting that broomcorn millet is a relatively recent allotetraploid. Comparative analyses showed that subgenome B was larger than subgenome A in size, which was caused by the biased accumulation of long terminal repeat retrotransposons in the progenitor of subgenome B before polyploidization. Notably, the accumulation of biased mutations in the transposable element-rich subgenome B led to more gene losses. Although no significant dominance of either subgenome was observed in the expression profiles of broomcorn millet, we found the minimally expressed genes in P. hallii tended to be lost during diploidization of broomcorn millet. These results suggest that broomcorn millet is at the early stage of diploidization and that mutations likely occurred more on genes that were marked with lower expression levels.

The effect of HPV DNA and p16 status on the prognosis of patients with hypopharyngeal carcinoma: a meta-analysis.

OBJECTIVE: To evaluate whether the presence of human papillomavirus (HPV) DNA and p16 might be associated with better prognosis in patients with hypopharyngeal carcinoma (HPC), especially on overall survival (OS) and disease-free survival (DFS). METHOD: PubMed, the Cochrane Library, the Web of Science and EMBASE were searched from inception to April 2021 to search for HPV DNA- and p16-related prognostic articles on HPC. Meta-analysis was performed on the selected articles according to the inclusion and exclusion criteria. Publication bias was assessed for the included studies with Egger's test. All studies were analyzed by using Stata 16.0 statistical software. RESULTS: A total of 18 studies were included, including 12 HPV DNA studies and 11 p16 studies. Meta-analysis showed that HPV DNA positivity was a strong prognostic factor for improved OS in patients with HPC, with a pooled hazard ratio (HR) of 0.61 (95% CI, 0.54-0.69), but there was no statistically significant difference in DFS (HR, 0.60; 95% CI, 0.31-1.16). Patients with p16-positive tumors had better OS (HR, 0.66; 95% CI, 0.49-0.89) and DFS (HR, 0.59; 95% CI, 0.44-0.78) than patients with p16-negative tumors. CONCLUSIONS: This study suggests that the presence of HPV DNA leads to better OS in patients with HPC, and the presence of p16 also corresponds to better OS and DFS. Our results provide up-to-date evidence to clinicians and researchers. Larger studies adjusting for prognostic factors are needed in subsequent studies.

A pH-sensitive supramolecular nanosystem with chlorin e6 and triptolide co-delivery for chemo-photodynamic combination therapy.

The combination of Ce6, an acknowledged photosensitizer, and TPL, a natural anticancer agent, has been demonstrated as a useful strategy to reinforce the tumor growth suppression, as well as decrease the systemic side effects compared with their monotherapy. However, in view of the optimal chemo-photodynamic combination efficiency, there is still short of the feasible nanovehicle to steadily co-deliver Ce6 and TPL, and stimuli-responsively burst release drugs in tumor site. Herein, we described the synergistic antitumor performance of a pH-sensitive supramolecular nanosystem, mediated by the host-guest complexing between ß-CD and acid pH-responsive amphiphilic co-polymer mPEG-PBAE-mPEG, showing the shell-core structural micelles with the tight ß-CD layer coating. Both Ce6 and TPL were facilely co-loaded into the spherical supramolecular NPs (TPL+Ce6/NPs) by one-step nanoprecipitation method, with an ideal particle size (156.0 nm), acid pH-responsive drug release profile, and enhanced cellular internalization capacity. In view of the combination benefit of photodynamic therapy and chemotherapy, as well as co-encapsulation in the fabricated pH-sensitive supramolecular NPs, TPL+Ce6/NPs exhibited significant efficacy to suppress cellular proliferation, boost ROS level, lower MMP, and promote cellular apoptosis in vitro. Particularly, fluorescence imaging revealed that TPL+Ce6/NPs preferentially accumulated in the tumor tissue area, with higher intensity than that of free Ce6. As expected, upon 650-nm laser irradiation, TPL+Ce6/NPs exhibited a cascade of amplified synergistic chemo-photodynamic therapeutic benefits to suppress tumor progression in both hepatoma H22 tumor-bearing mice and B16 tumor-bearing mice. More importantly, lower systemic toxicity was found in the tumor-bearing mice treated with TPL+Ce6/NPs. Overall, the designed supramolecular TPL+Ce6/NPs provided a promising alternative approach for chemo-photodynamic therapy in tumor treatment.

Explorations on risk profiles for overweight and obesity in 9501 preschool-aged children.

BACKGROUND: Childhood obesity places a major burden on global public health. We aimed to identify and characterize potential factors, both individually and jointly, in association with overweight and obesity in Chinese preschool-aged children. METHODS: We cross-sectionally recruited 9501 preschool-aged children from 30 kindergartens in Beijing and Tangshan. Overweight and obesity are defined according to the World Health Organization (WHO), International Obesity Task Force (IOTF), and China criteria. RESULTS: After multivariable adjustment, eating speed, sleep duration, birthweight, and paternal body mass index (BMI) were consistently and significantly associated with childhood overweight and obesity under three growth criteria at a significance level of 5%. Additional fast food intake frequency, maternal BMI, gestational weight gain (GWG) and maternal pre-pregnancy BMI were significant factors for overweight (WHO criteria) and obesity (both IOTF and China criteria). Importantly, there were significant interactions between parental obesity and eating speed for childhood obesity. Finally, for practical reasons, risk nomogram models were constructed for childhood overweight and obesity based on significant factors under each criterion, with good prediction accuracy. CONCLUSION: Our findings indicated a synergistic association of lifestyle, fetal and neonatal, and family-related factors with the risk of experiencing overweight and obesity among preschool-aged children.

[Mechanisms and application of triptolide against breast cancer].

Overtaking lung cancer,breast cancer is now the most commonly diagnosed cancer seriously threatening people's health and life. As the main effective component of Tripterygium wilfordii,triptolide( TP) has attracted increasing attention due to its multitarget and multi-pathway anti-tumor activity. Recent studies have revealed that breast cancer-sensitive TP enables the inactivation of breast cancer cells by inducing tumor cell apoptosis and autophagy,interfering in tumor cell metastasis,resisting drug resistance,arresting tumor cell cycle,and influencing tumor microenvironment. It has been recognized as a promising clinical antitumor agent by virtue of its widely accepted therapeutic efficacy. This paper reviewed the anti-breast cancer action and its molecular mechanisms of TP on the basis of the relevant literature in the past ten years,and proposed application strategies in view of the inadequacy of TP to provide a reference for further research on the application of TP in the treatment of breast cancer.

Novel CD44-targeting and pH/redox-dual-stimuli-responsive core-shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis.

BACKGROUND: The toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited the clinical application. Thus, we fabricated a CD44-targeting and tumor microenvironment pH/redox-sensitive nanosystem composed of hyaluronic acid-vitamin E succinate and poly (ß-amino esters) (PBAEss) polymers to enhance the TPL-mediated suppression of breast cancer proliferation and lung metastasis. RESULTS: The generated TPL nanoparticles (NPs) had high drug loading efficiency (94.93% ± 2.1%) and a desirable average size (191 nm). Mediated by the PBAEss core, TPL/NPs displayed a pH/redox-dual-stimuli-responsive drug release profile in vitro. Based on the hyaluronic acid coating, TPL/NPs exhibited selective tumor cellular uptake and high tumor tissue accumulation capacity by targeting CD44. Consequently, TPL/NPs induced higher suppression of cell proliferation, blockage of proapoptotic and cell cycle activities, and strong inhibition of cell migration and invasion than that induced by free TPL in MCF-7 and MDA-MB-231 cells. Importantly, TPL/NPs also showed higher efficacy in shrinking tumor size and blocking lung metastasis with decreased systemic toxicity in a 4T1 breast cancer mouse model at an equivalent or lower TPL dosage compared with that of free TPL. Histological immunofluorescence and immunohistochemical analyses in tumor and lung tissue revealed that TPL/NPs induced a high level of apoptosis and suppressed expression of matrix metalloproteinases, which contributed to inhibiting tumor growth and pulmonary metastasis. CONCLUSION: Collectively, our results demonstrate that TPL/NPs, which combine tumor active targeting and pH/redox-responsive drug release with proapoptotic and antimobility effects, represent a promising candidate in halting breast cancer progression and metastasis while minimizing systemic toxicity.

Calcium pectinate and hyaluronic acid modified lactoferrin nanoparticles loaded rhein with dual-targeting for ulcerative colitis treatment.

Herein, dual-bioresponsive of Rhein (RH) in promoting colonic mucous damage repair and controlling inflammatory reactions were combined by the dual-targeting (intestinal epithelial cells and macrophages) oral nano delivery strategy for effective therapy of ulcerative colitis (UC). Briefly, two carbohydrates, calcium pectinate (CP) and hyaluronic acid (HA) were used to modify lactoferrin (LF) nanoparticles (NPs) to encapsulate RH (CP/HA/RH-NPs). CP layer make CP/HA/RH-NPs more stable and protect against the destructive effects of the gastrointestinal environment and then release HA/RH-NPs to colon lesion site. Cellular uptake evaluation confirmed that NPs could specifically target and enhance the uptake rate via LF and HA ligands. in vivo experiments revealed that CP/HA/RH-NPs significantly alleviated inflammation by inhibiting the TLR4/MyD88/NF-κB signaling pathway and accelerated colonic healing. Importantly, with the help of CP, this study was the first to attempt for LF as a targeting nanomaterial in UC treatment and offers a promising food-based nanodrug in anti-UC.

Gastroprotective Effects of Periplaneta americana L. Extract Against Ethanol-Induced Gastric Ulcer in Mice by Suppressing Apoptosis-Related Pathways.

Although Periplaneta americana L. and its modern preparation, Kangfuxin liquid, have been extensively applied for ulcerative diseases in gastrointestinal tract (e.g., gastric ulcer (GU) and ulcerative colitis, the effective components and potential mechanisms) remain unclear. In accordance with the accumulating research evidences, the relieving/exacerbating of GU is noticeably correlated to focal tissue programmed cell death. Herein, gastro-protective effects of the effective Periplaneta americana L. extract (PAE) fraction were assessed in vitro and in vivo, involving in programmed cell death-related signaling channels. To screen the effective PAE fraction exerting gastroprotective effects, several PAE fractions were gained based on a wide range of ethanol solution concentration, and they were assessed on ethanol-induced ulcer mice. Based on HPLC investigation with the use of nucleosides, the chemical composition of screened effective PAE, extracted by 20% ethanol, was analyzed in terms of quality control. Based on CCK-8 assay, the protective effects on GES-1 cells, impaired by ethanol, of PAE were assessed. After 3 days pre-treatment with PAE (200, 400, 800 mg/kg), the gastric lesions were assessed by tissue morphology, and periodic acid-schiff (PAS) staining, as well as hematoxylin and eosin (H&E) based histopathology-related investigation. The levels for inflammation cytokines (IL1-ß, TNF-α, IL-18, PGE2, and IL-6), antioxidant indices (SOD and MDA) were examined via ELISA. In the meantime, based on Western Blotting assay, the expression levels of some programmed cell death-related protein targets (NLRP3, caspase-1, NF-κB p65, MyD88, and TLR4) were analyzed. As revealed from the results, PAE is capable of alleviating gastric mucosa impairment, suppressing the inflammatory cytokines, and down-regulating the MyD88/NF-κB channels. Accordingly, 20% ethanol extract of Periplaneta americana L. would contribute its gastroprotective effects, thereby providing the evidence that its anti-GU mechanisms correlated with inhibiting programmed cell death channel.