Curcumin suppresses colorectal cancer by induction of ferroptosis via regulation of p53 and solute carrier family 7 member 11/glutathione/glutathione peroxidase 4 signaling axis.

Driven by iron-dependent lipid peroxidation, ferroptosis is regulated by p53 and solute carrier family 7 member 11 (SLC7A11)/glutathione/glutathione peroxidase 4 (GPX4) axis in colorectal cancer (CRC). This study aimed to investigate the influence of curcumin (CUR) on ferroptosis in CRC. The efficacies of CUR on the malignant phenotype of CRC cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, wound healing, and clonogenic assays. The effects of CUR on ferroptosis of CRC cells were evaluated by transmission electron microscopy, lactate dehydrogenase release assay, Fe2+ staining, and analyses of reactive oxygen species, lipid peroxide, malondialdehyde, and glutathione levels. CUR's targets in ferroptosis were predicted by network pharmacological study and molecular docking. With SW620 xenograft tumors, the efficacy of CUR on CRC was investigated, and the effects of CUR on ferroptosis were assessed by detection of Fe2+, malondialdehyde, and glutathione levels. The effects of CUR on expressions of p53, SLC7A11, and GPX4 in CRC cells and tumors were analyzed by quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. CUR suppressed the proliferation, migration, and clonogenesis of CRC cells and xenograft tumor growth by causing ferroptosis, with enhanced lactate dehydrogenase release and Fe2+, reactive oxygen species, lipid peroxide, and malondialdehyde levels, but attenuated glutathione level in CRC. In silico study indicated that CUR may bind p53, SLC7A11, and GPX4, consolidated by that CUR heightened p53 but attenuated SLC7A11 and GPX4 mRNA and protein levels in CRC. CUR may exert an inhibitory effect on CRC by inducing ferroptosis via regulation of p53 and SLC7A11/glutathione/GPX4 axis.

A Novel Nomogram to Predict Prognosis in Elderly Early-Stage Hepatocellular Carcinoma Patients After Ablation Therapy.

Purpose: Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Early diagnosis is crucial for improving prognosis. Elderly HCC patients often have underlying liver diseases such as chronic hepatitis and cirrhosis, leading to impaired liver function and suboptimal liver reserve. Radiofrequency ablation (RFA) has rapidly become one of the most important methods for treating early-stage hepatocellular carcinoma (EHCC) due to its advantages, including minimal trauma, short operation time, less intraoperative bleeding, quick postoperative recovery, cost-effectiveness, and few postoperative-complications. However, the prognostic model for early recurrence after local ablation in elderly EHCC patients has not been widely evaluated. We have developed a prognostic model for the recurrence of local RFA in elderly EHCC patients. This is expected to provide a new early warning system for preventing early recurrence in elderly EHCC patients, prolonging patient's life, and improving overall quality of life. Methods: In this study, we included 661 EHCC patients who underwent local ablation, dividing them into a Primary cohort and a Validation cohort in a 7:3 ratio. We characterized the cohorts and utilized the primary cohort to develop a prognostic nomogram model for recurrence after local ablation in elderly EHCC patients. Additionally, the validation cohort was used to assess the potential of the nomogram as a non-invasive biomarker for post-ablation recurrence in EHCC. Results: The user-friendly nomogram incorporates common clinical variables including gender, BCLC stage, tumor number, tumor size, red blood cell (RBC), gamma-glutamyl transferase (GGT), and prothrombin time activity (PTA). The nomogram constructed using the identified seven variables exhibits robust discriminatory capabilities, favorable predictive performance, and noteworthy clinical utility. Conclusion: We developed a user-friendly nomogram based on the BCLC stage classification, which may provide prognostic assessments for elderly EHCC patients at 1, 3, and 5 years post-RFA.

Machine learning-based characterization of the gut microbiome associated with the progression of primary biliary cholangitis to cirrhosis.

BACKGROUND: Primary biliary cholangitis (PBC) is associated closely with the gut microbiota. This study aimed to explore the characteristics of the gut microbiota after the progress of PBC to cirrhosis. METHOD: This study focuses on utilizing the 16S rRNA gene sequencing method to screen for differences in gut microbiota in PBC patients who progress to cirrhosis. Then, we divided the data into training and verification sets and used seven different machine learning (ML) models to validate them respectively, calculating and comparing the accuracy, F1 score, precision, and recall, and screening the dominant intestinal flora affecting PBC cirrhosis. RESULT: PBC cirrhosis patients showed decreased diversity and richness of gut microbiota. Additionally, there are alterations in the composition of gut microbiota in PBC cirrhosis patients. The abundance of Faecalibacterium and Gemmiger bacteria significantly decreases, while the abundance of Veillonella and Streptococcus significantly increases. Furthermore, machine learning methods identify Streptococcus and Gemmiger as the predominant gut microbiota in PBC patients with cirrhosis, serving as non-invasive biomarkers (AUC = 0.902). CONCLUSION: Our study revealed that PBC cirrhosis patients gut microbiota composition and function have significantly changed. Streptococcus and Gemmiger may become a non-invasive biomarker for predicting the progression of PBC progress to cirrhosis.

Obeticholic Acid Inhibit Mitochondria Dysfunction Via Regulating ERK1/2-DRP Pathway to Exert Protective Effect on Lipopolysaccharide-Induced Myocardial Injury.

Farnesoid X receptor (FXR) plays critical regulatory roles in cardiovascular physiology/pathology. However, the role of FXR agonist obeticholic acid (OCA) in sepsis-associated myocardial injury and underlying mechanisms remain unclear. C57BL/6J mice are treated with OCA before lipopolysaccharide (LPS) administration. The histopathology of the heart and assessment of FXR expression and mitochondria function are performed. To explore the underlying mechanisms, H9c2 cells, and primary cardiomyocytes are pre-treated with OCA before LPS treatment, and extracellular signal-regulated protein kinase (ERK) inhibitor PD98059 is used. LPS-induced myocardial injury in mice is significantly improved by OCA pretreatment. Mechanistically, OCA pretreatment decreased reactive oxygen species (ROS) levels and blocked the loss of mitochondrial membrane potential (ΔΨm) in cardiomyocytes. The expression of glutathione peroxidase 1 (GPX1), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2-related factor 2 (NRF-2) increased in the case of OCA pretreatment. In addition, OCA improved mitochondria respiratory chain with increasing Complex I expression and decreasing cytochrome C (Cyt-C) diffusion. Moreover, OCA pretreatment inhibited LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway. FXR agonist OCA inhibits LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway to protect mice against LPS-induced myocardial injury.

Antibacterial Activity of Plants in Cirsium: A Comprehensive Review.

As ethnic medicine, the whole grass of plants in Cirsium was used as antimicrobial. This review focuses on the antimicrobial activity of plants in Cirsium, including antimicrobial components, against different types of microbes and bacteriostatic mechanism. The results showed that the main antimicrobial activity components in Cirsium plants were flavonoids, triterpenoids and phenolic acids, and the antimicrobial ability varied according to the species and the content of chemicals. Among them, phenolic acids showed a strong antibacterial ability against Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecium. The antibacterial mechanisms include: (1) damaging the cell membrane, cell walls, mitochondria and nucleus of bacteria; (2) inhibiting the synthesis of proteins and nucleic acids; (3) suppressing the synthesis of enzymes for tricarboxylic acid cycle pathways and glycolysis, and then killing the bacteria via inhibition of energy production. Totally, most research results on antimicrobial activity of Cirsium plants are reported based on in vitro assays. The evidence from clinical data and comprehensive evaluation are needed.

Plant-derived nanovesicles: Further exploration of biomedical function and application potential.

Extracellular vesicles (EVs) are phospholipid bilayer vesicles actively secreted by cells, that contain a variety of functional nucleic acids, proteins, and lipids, and are important mediums of intercellular communication. Based on their natural properties, EVs can not only retain the pharmacological effects of their source cells but also serve as natural delivery carriers. Among them, plant-derived nanovesicles (PNVs) are characterized as natural disease therapeutics with many advantages such as simplicity, safety, eco-friendliness, low cost, and low toxicity due to their abundant resources, large yield, and low risk of immunogenicity in vivo. This review systematically introduces the biogenesis, isolation methods, physical characterization, and components of PNVs, and describes their administration and cellular uptake as therapeutic agents. We highlight the therapeutic potential of PNVs as therapeutic agents and drug delivery carriers, including anti-inflammatory, anticancer, wound healing, regeneration, and antiaging properties as well as their potential use in the treatment of liver disease and COVID-19. Finally, the toxicity and immunogenicity, the current clinical application, and the possible challenges in the future development of PNVs were analyzed. We expect the functions of PNVs to be further explored to promote clinical translation, thereby facilitating the development of a new framework for the treatment of human diseases.

ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis.

Strengthened glycolysis is crucial for the macrophage pro-inflammatory response during sepsis. Activating transcription factor 4 (ATF4) plays an important role in regulating glucose and lipid metabolic homeostasis in hepatocytes and adipocytes. However, its immunometabolic role in macrophage during sepsis remains largely unknown. In the present study, we found that the expression of ATF4 in peripheral blood mononuclear cells (PBMCs) was increased and associated with glucose metabolism in septic patients. Atf4 knockdown specifically decreased LPS-induced spleen macrophages and serum pro-inflammatory cytokines levels in mice. Moreover, Atf4 knockdown partially blocked LPS-induced pro-inflammatory cytokines, lactate accumulation and glycolytic capacity in RAW264.7. Mechanically, ATF4 binds to the promoter region of hexokinase II (HK2), and interacts with hypoxia inducible factor-1α (HIF-1α) and stabilizes HIF-1α through ubiquitination modification in response to LPS. Furthermore, ATF4-HIF-1α-HK2-glycolysis axis launches pro-inflammatory response in macrophage depending on the activation of mammalian target of rapamycin (mTOR). Importantly, Atf4 overexpression improves the decreased level of pro-inflammatory cytokines and lactate secretion and HK2 expression in LPS-induced tolerant macrophages. In conclusion, we propose a novel function of ATF4 as a crucial glycolytic activator contributing to pro-inflammatory response and improving immune tolerant in macrophage involved in sepsis. So, ATF4 could be a potential new target for immunotherapy of sepsis.

Antimicrobial activity in Asterceae: The selected genera characterization and against multidrug resistance bacteria.

Plants from the Asteraceae family are widely used as ethno medicines to treatment parasitic, malaria, hematemesis, pruritus, pyretic, anthelmintic, wound healing. The aim of this review is to provide an overview of Asteraceae plants antimicrobial activity. The most relevant results from the published studies are summarized and discussed. The species in genus of Artemisia, Echinacea, Centaurea, Baccharis, and Calendula showed antimicrobial activity. Most of these species are usually used as ethno medicines to treat infection, inflammation, and parasitics. The effective part or component for antimicrobial was essential oil and crude extract, and essential oil attracted more attention. It was also reported that nanoparticles coated with crude extract were effective against multidrug resistant bacteria. For multidrug resistant bacteria study, the species in Armtemisia were the most investigated, and Staphylococcus aureus and Escherichia coli were the most studied multidrug resistant strains. The antimicrobial activity was evaluated mainly based on the results of minimum inhibitory concentration (MIC). Few reports have been reported on minimum bactericide concentration (MBC) and its antibacterial mechanisms. According to the reported study results, some plants in Asteraceae have the potential to be developed as bacteriostatic agents and against multidrug resistant bacteria. However, most studies are still in vitro, further clinical and applied studies are needed.

Tumor stemness score to estimate epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs) characterization and to predict the prognosis and immunotherapy response in bladder urothelial carcinoma.

BACKGROUND: A growing number of investigations have suggested a close link between cancer stem cells (CSCs), epithelial-to-mesenchymal transition (EMT), and the tumor microenvironment (TME). However, the relationships between these physiological processes in bladder urothelial carcinoma (BLCA) remain unclear. METHODS: We first explored biomarkers of tumor stemness (TS) by single-cell sequencing analysis. Then, subtypes of bladder urothelial carcinoma (BLCA) were identified using clustering analysis based on TS biomarkers. The TS score was constructed using principal component analysis to quantify tumor stemness in BLCA. Then, meta-analysis was performed to measure the hazard ratio of the TS score in BLCA cohorts. Moreover, we evaluated the clinical value of the TS score for predicting the response to tumor immunotherapy using immunotherapy cohorts. Finally, we built an EMT cell model by treating T24 cells with TGF-ß and validated the relationship between the TS score and the EMT process in tumors by real-time quantitative PCR, cell invasion assays, and RNA-seq. In total, 3846 BLCA cells, 6 cell lines, 1627 BLCA samples, and 9858 samples from 32 other types of tumors were included in our study. RESULTS: Three TS clusters and two TS-related gene clusters were identified with differential EMT activity status, CSC features, and TME characteristics in BLCA. Then, a TS scoring system was established with 61 TS-related genes to quantify the TS. The prognostic value of the TS score was then confirmed in multiple independent cohorts. A high TS score was associated with high EMT activity, CSC characteristics, high stromal cell content, high TP53 mutation rate, poor prognosis, and high tumor immunotherapy tolerance. The cell line experiment and RNA-seq further validated that our TS score can reflect the EMT and CSC characterization of tumor cells. CONCLUSION: Overall, this research provides a better understanding of tumor invasion and metastasis mechanisms through an analysis of TS patterns with different EMT processes and CSC characteristics. The TS score provides an index for EMT and CSC research and helps clinicians develop treatment plans and predict outcomes for patients.

Evaluation of a high-sensitivity SARS-CoV-2 antigen test on the fully automated light-initiated chemiluminescent immunoassay platform.

OBJECTIVES: To describe a high-sensitivity SARS-CoV-2 antigen test that is based on the fully automated light-initiated chemiluminescent immunoassay (LiCA®), and to validate its analytical characteristics and clinical agreement on detecting SARS-CoV-2 infection against the reference molecular test. METHODS: Analytical performance was validated and detection limits were determined using different types of nucleocapsid protein samples. 798-pair anterior nasal swab specimens were collected from hospitalized patients and asymptomatic screening individuals. Agreement between LiCA® antigen and real-time reverse transcription polymerase chain reaction (rRT-PCR) was evaluated. RESULTS: Repeatability and within-lab precision were 1.6-2.3%. The C5∼C95 interval was -5.1-4.6% away from C50. Detection limits in average (SD) were 325 (±141) U/mL on the national reference panel, 0.07 (±0.04) TCID50/mL on active viral cultures, 0.27 (±0.09) pg/mL on recombinant nucleocapsid proteins and 1.07 (±1.01) TCID50/mL on inactivated viral suspensions, respectively. LiCA detected a median of 374-fold (IQR 137-643) lower levels of the viral antigen than comparative rapid tests. As reference to the rRT-PCR method, overall sensitivity and specificity were determined to be 97.5% (91.4-99.7%) and 99.9% (99.2-100%), respectively. Total agreement between both methods was 99.6% (98.7-99.9%) with Cohen's kappa 0.98 (0.96-1). A positive detection rate of 100% (95.4-100%) was obtained as Ct≤37.8. CONCLUSIONS: The LiCA® system provides an exceptionally high-sensitivity and fully automated platform for the detection of the SARS-CoV-2 antigen in nasal swabs. The assay may have high potential use for large-scale population screening and surveillance of COVID-19 as an alternative to the rRT-PCR test.

Anti-cervical cancer effects of Compound Yangshe granule through the PI3K/AKT pathway based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Yangshe granule is a characteristic Chinese preparation against cervical cancer used at Fudan University Shanghai Cancer Center, and it consists of Hedyotis Diffusae Herba, Solani Lyrati Herba, Rubiae Radix et Rhizoma, Echinopsis Radix, Angelicae Sinensis Radix, Codonopsis Radix and Atractylodis Macrocephalae Rhizoma. AIM OF THE STUDY: The objective of the current study was to investigate the preclinical efficacy of compound Yangshe granule against cervical cancer and elucidate the underlying mechanisms. MATERIALS AND METHODS: Antitumor effect of the preparation was investigated in U14 cells in vitro and subcutaneous xenograft mice in vivo. The underlying mechanisms were investigated by through network pharmacological analysis and identified by in vitro study. The components of compound Yangshe granule were collected from the Traditional Chinese Medicine Systems Pharmacology database, and the corresponding targets were predicted by the SwissTargetPrediction database. The targets involved in cervical cancer were collected from the GeneCards, Online Mendelian Inheritance in Man and DrugBank databases. A protein‒protein interaction network was constructed by using the String platform. The drug-disease-target network was plotted by Cytoscape software. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses were performed to investigate hub targets. RESULTS: After treatment with 0.5-10 mg/mL compound Yangshe granule, the survival rates of U14 cells gradually declined to 53.32% for 24 h, 23.62% for 48 h, and 12.81% for 72 h. The apoptosis rates of U14 cells gradually increased to 15.52% for 24 h, 23.87% for 48 h, and 65.01% for 72 h after treatment with 2-10 mg/mL compound Yangshe granule. After oral administration of compound Yangshe granule by xenograft mice, the tumor inhibition rates reached 52.27%, 74.62%, and 82.70% in the low, middle, and high dose groups, respectively. According to the network pharmacological analysis, quercetin, luteolin and naringenin were the most bioactive ingredients of the preparation. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that compound Yangshe granule may combat cervical cancer through the PI3K/AKT pathway. CONCLUSION: In summary, network pharmacology combined with biological experiments demonstrated that the main bioactive components including quercetin, luteolin and naringenin could inhibit the tumor growth by regulating the PI3K/AKT pathway and Bcl-2 family. Thus, compound Yangshe granule may be a promising adjuvant therapy for cervical cancer.

Respiratory immune status and microbiome in recovered COVID-19 patients revealed by metatranscriptomic analyses.

Coronavirus disease 2019 (COVID-19) is currently a severe threat to global public health, and the immune response to COVID-19 infection has been widely investigated. However, the immune status and microecological changes in the respiratory systems of patients with COVID-19 after recovery have rarely been considered. We selected 72 patients with severe COVID-19 infection, 57 recovered from COVID-19 infection, and 65 with non-COVID-19 pneumonia, for metatranscriptomic sequencing and bioinformatics analysis. Accordingly, the differentially expressed genes between the infected and other groups were enriched in the chemokine signaling pathway, NOD-like receptor signaling pathway, phagosome, TNF signaling pathway, NF-kappa B signaling pathway, Toll-like receptor signaling pathway, and C-type lectin receptor signaling pathway. We speculate that IL17RD, CD74, and TNFSF15 may serve as disease biomarkers in COVID-19. Additionally, principal coordinate analysis revealed significant differences between groups. In particular, frequent co-infections with the genera Streptococcus, Veillonella, Gemella, and Neisseria, among others, were found in COVID-19 patients. Moreover, the random forest prediction model with differential genes showed a mean area under the curve (AUC) of 0.77, and KCNK12, IL17RD, LOC100507412, PTPRT, MYO15A, MPDZ, FLRT2, SPEG, SERPINB3, and KNDC1 were identified as the most important genes distinguishing the infected group from the recovered group. Agrobacterium tumefaciens, Klebsiella michiganensis, Acinetobacter pittii, Bacillus sp. FJAT.14266, Brevundimonas naejangsanensis, Pseudopropionibacterium propionicum, Priestia megaterium, Dialister pneumosintes, Veillonella rodentium, and Pseudomonas protegens were selected as candidate microbial markers for monitoring the recovery of COVID patients. These results will facilitate the diagnosis, treatment, and prognosis of COVID patients recovering from severe illness.

Activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation.

BACKGROUND: Gut-resident macrophages (gMacs) supplemented by monocytes-to-gMacs differentiation play a critical role in maintaining intestinal homeostasis. Activating transcription factor 4 (ATF4) is involved in immune cell differentiation. We therefore set out to investigate the role of ATF4-regulated monocytes-to-gMacs differentiation in sepsis-induced intestinal injury. METHODS: Sepsis was induced in C57BL/6 wild type (WT) mice and Atf4- knockdown ( Atf4+/ - ) mice by cecal ligation and puncture or administration of lipopolysaccharide (LPS). Colon, peripheral blood mononuclear cells, sera, lung, liver, and mesenteric lymph nodes were collected for flow cytometry, hematoxylin and eosin staining, immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. RESULTS: CD64, CD11b, Ly6C, major histocompatibility complex-II (MHC-II), CX3CR1, Ly6G, and SSC were identified as optimal primary markers for detecting the process of monocytes-to-gMacs differentiation in the colon of WT mice. Monocytes-to-gMacs differentiation was impaired in the colon during sepsis and was associated with decreased expression of ATF4 in P1 (Ly6C hi monocytes), the precursor cells of gMacs. Atf4 knockdown exacerbated the impairment of monocytes-to-gMacs differentiation in response to LPS, resulting in a significant reduction of gMacs in the colon. Furthermore, compared with WT mice, Atf4+/- mice exhibited higher pathology scores, increased expression of inflammatory factor genes ( TNF-α, IL-1ß ), suppressed expression of CD31 and vascular endothelial-cadherin in the colon, and increased translocation of intestinal bacteria to lymph nodes and lungs following exposure to LPS. However, the aggravation of sepsis-induced intestinal injury resulting from Atf4 knockdown was not caused by the enhanced inflammatory effect of Ly6C hi monocytes and gMacs. CONCLUSION: ATF4, as a novel regulator of monocytes-to-gMacs differentiation, plays a critical role in protecting mice against sepsis-induced intestinal injury, suggesting that ATF4 might be a potential therapeutic target for sepsis treatment.

Natural cell based biomimetic cellular transformers for targeted therapy of digestive system cancer.

Digestive system cancer is the most common cause of cancer death in the world. Although cancer treatment options are increasingly diversified, the mortality rate of malignant cancer of the digestive system remains high. Therefore, it is necessary to explore effective cancer treatment methods. Recently, biomimetic nanoparticle delivery systems based on natural cells that organically integrate the low immunogenicity, high biocompatibility, cancer targeting, and controllable, versatile functionality of smart nanocarrier design with natural cells have been expected to break through the bottleneck of tumor targeted therapy. In this review, we focus on the dynamic changes and complex cellular communications that occur in vivo in natural cells based vehicles. Recent studies on the development of advanced targeted drug delivery systems using the dynamic behaviors such as specific surface protein affinity, morphological changes, and phenotypic polarization of natural cells are summarized. In addition to drug delivery mediated by dynamic behavior, functional "delivery" based on the natural cell themselves is also involved. Aiming to make the best use of the functions of cells, providing clues for the development of advanced drug delivery platforms.

αvß3 integrin-specific exosomes engineered with cyclopeptide for targeted delivery of triptolide against malignant melanoma.

BACKGROUND: Melanoma is the most malignant skin tumor and is difficult to cure with the alternative treatments of chemotherapy, biotherapy, and immunotherapy. Our previous study showed that triptolide (TP) exhibited powerful tumoricidal activity against melanoma. However, the clinical potential of TP is plagued by its poor aqueous solubility, short half-life, and biotoxicity. Therefore, developing an ideal vehicle to efficiently load TP and achieving targeted delivery to melanoma is a prospective approach for making full use of its antitumor efficacy. RESULTS: We applied exosome (Exo) derived from human umbilical cord mesenchymal stromal cells (hUCMSCs) and engineered them exogenously with a cyclic peptide, arginine-glycine-aspartate (cRGD), to encapsulate TP to establish a bionic-targeted drug delivery system (cRGD-Exo/TP), achieving synergism and toxicity reduction. The average size of cRGD-Exo/TP was 157.34 ± 6.21 nm, with a high drug loading of 10.76 ± 1.21%. The in vitro antitumor results showed that the designed Exo delivery platform could be effectively taken up by targeted cells and performed significantly in antiproliferation, anti-invasion, and proapoptotic activities in A375 cells via the caspase cascade and mitochondrial pathways and cell cycle alteration. Furthermore, the biodistribution and pharmacokinetics results demonstrated that cRGD-Exo/TP possessed superior tumor targetability and prolonged the half-life of TP. Notably, cRGD-Exo/TP significantly inhibited tumor growth and extended survival time with negligible systemic toxicity in tumor-bearing mice. CONCLUSION: The results indicated that the functionalized Exo platform provides a promising strategy for targeted therapy of malignant melanoma.

Fibroblast Growth Factor 19 Improves LPS-Induced Lipid Disorder and Organ Injury by Regulating Metabolomic Characteristics in Mice.

Sepsis is extremely heterogeneous pathology characterized by complex metabolic changes. Fibroblast growth factor 19 (FGF19) is a well-known intestine-derived inhibitor of bile acid biosynthesis. However, it is largely unknown about the roles of FGF19 in improving sepsis-associated metabolic disorder and organ injury. In the present study, mice were intravenously injected recombinant human FGF19 daily for 7 days followed by lipopolysaccharide (LPS) administration. At 24 hours after LPS stimuli, sera were collected for metabolomic analysis. Ingenuity pathway analysis (IPA) network based on differential metabolites (DMs) was conducted. Here, metabolomic analysis revealed that FGF19 pretreatment reversed the increase of LPS-induced fatty acids. IPA network indicated that altered linoleic acid (LA) and gamma-linolenic acid (GLA) were involved in the regulation of oxidative stress and mitochondrial function and were closely related to reactive oxygen species (ROS) generation. Further investigation proved that FGF19 pretreatment decreased serum malondialdehyde (MDA) levels and increased serum catalase (CAT) levels. In livers, FGF19 suppressed the expression of inducible NO synthase (iNOS) and enhanced the expression of nuclear factor erythroid 2-related factor 2 (NRF2) and hemeoxygenase-1 (HO-1). Finally, FGF19 pretreatment protected mice against LPS-induced liver, ileum, and kidney injury. Taken together, FGF19 alleviates LPS-induced organ injury associated with improved serum LA and GLA levels and oxidative stress, suggesting that FGF19 might be a promising target for metabolic therapy for sepsis.

Orally Deliverable Dual-Targeted Pellets for the Synergistic Treatment of Ulcerative Colitis.

PURPOSE: The effective treatment of ulcerative colitis (UC) poses substantial challenges, and the aetiopathogenesis of UC is closely related to infectious, immunological and environmental factors. Currently, there is a considerable need for the development of orally bioavailable dosage forms that enable the effective delivery of therapeutic drugs to local diseased lesions in the gastrointestinal tract. METHODS: Berberine (BBR) and Atractylodes macrocephala Koidz (AM) volatile oil, derived from the Chinese herbs Coptis chinensis Franch and Atractylodes macrocephala Koidz, have anti-inflammatory and immunomodulatory activities. In this study, we prepared colon-targeted pellets loaded with BBR and stomach-targeted pellets loaded with AM volatile oil for the synergistic treatment of UC. The Box-Behnken design and ß-cyclodextrin inclusion technique were used to optimize the enteric coating formula and prepare volatile oil inclusion compounds. RESULTS: The two types of pellets were spherical and had satisfactory physical properties. The pharmacokinetic results showed that the AUC and MRT values of the dual-targeted (DPs) pellets were higher than those of the control pellets. In addition, in vivo animal imaging confirmed that the DPs could effectively deliver BBR to the colon. Moreover, compared with sulfasalazine and monotherapy, DPs exerted a more significant anti-inflammatory effect by inhibiting the expression of inflammatory factors including IL-1ß, IL-4, IL-6, TNF-α and MPO both in serum and tissues and enhancing immunity by decreasing the production of IgA and IgG. CONCLUSION: The DPs play a synergistic anti-UC effect by exerting systemic and local anti-inflammatory and provide an effective oral targeted preparation for the treatment of UC.

Engineering Exosomes Endowed with Targeted Delivery of Triptolide for Malignant Melanoma Therapy.

Malignant melanoma is considered the most aggressive skin carcinoma with invasive growth patterns. Triptolide (TPL) possesses various biological and pharmacological activities involved in cancer treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce cancer cell apoptosis by binding to DR5 highly expressed on cancer cells. Exosomes are natural nanomaterials with low immunogenicity, nontoxicity, and excellent biocompatibility and have been extensively used as emerging delivery vectors for diverse therapeutic cargos. Herein, a delivery system based on TRAIL-engineered exosomes (TRAIL-Exo) for loading TPL for targeted therapy against malignant melanoma is proposed and systematically investigated. Our results showed that TRAIL-Exo/TPL could improve tumor targetability, enhance cellular uptake, inhibit proliferation, invasion, and migration, and induce apoptosis of A375 cells through activating the extrinsic TRAIL pathway and the intrinsic mitochondrial pathway in vitro. Moreover, intravenous injection of TRAIL-Exo/TPL significantly suppressed tumor progression and reduced the toxicity of TPL in the melanoma nude mouse model. Together, our research presents a novel strategy for high-efficiency exosome-based drug-delivery nanocarriers and provides an alternative dimension for developing a promising approach with synergistic therapeutic efficacy and targeting capacity for melanoma treatment.

Corrigendum to "Fibrinogen as a Prognostic Predictor in Pediatric Patients with Sepsis: A Database Study".

[This corrects the article DOI: 10.1155/2020/9153620.].

[6-Formylindolo[3,2-b]carbazole alleviates lipopolysaccharide-induced acute lung injury via suppressing endoplasmic reticulum stress].

OBJECTIVE: To investigate the effect and mechanism of 6-formylindolo[3,2-b]carbazole (FICZ) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. METHODS: Male C57BL/6J mice aged 8-12 weeks were divided into 4 groups with 8 mice in each group, according to the method of simple random sampling. Sepsis-induced ALI mice model was established by intraperitoneal injection of LPS 5 mg/kg (LPS group), and phosphate buffer saline (PBS) control group (PBS group) was injected with equal volume of PBS. The LPS+FICZ group was intervened by intraperitoneal injection of 1 µg FICZ 1 hour after LPS stimuli, while the FICZ control group (FICZ group) was given the same amount of FICZ 1 hour after intraperitoneal injection of PBS. Serum and lung tissue were collected 24 hours after LPS stimuli, and the pathological changes of lung tissue were analyzed by hematoxylin-eosin (HE) staining and wet/dry weight (W/D) ratio of lung tissue. The concentrations of inflammatory factors in serum and lung tissue were detected by enzyme linked immunosorbent assay (ELISA). The expression levels of endoplasmic reticulum stress signaling pathway related molecules were detected by real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) and Western blotting. RESULTS: Compared with PBS group, inflammatory cell infiltration, alveolar collapse and obvious alveolar exudative lesions had increased, lung tissue W/D ratio was significantly increased, serum interleukin-6 (IL-6) level, lung tissue IL-6 mRNA expression, and the mRNA expressions of glucose-regulated protein 78 (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), CCAAT/EBP homologous protein (CHOP), and the protein expressions of GRP78, PERK, activating transcription factor 6 (ATF6), CHOP in lung tissue were significantly increased in LPS group. However, the indexes of FICZ group were not affected. Compared with LPS group, LPS+FICZ group had less inflammatory cell infiltration, relatively intact alveolar structure. Lung W/D weight ratio in LPS+FICZ group was significantly decreased (5.38±0.10 vs. 6.60±0.30, P < 0.01), so as serum IL-6 (ng/L: 15.55±3.77 vs. 32.22±3.84) and lung IL-6 mRNA expression (2-ΔΔCt: 0.79±0.21 vs. 6.89±0.92, both P < 0.01). The mRNA expressions of GRP78, PERK and CHOP were also significantly decreased [GRP78 mRNA (2-ΔΔCt): 1.90±0.16 vs. 7.55±1.29, PERK mRNA (2-ΔΔCt): 1.68±0.20 vs. 4.54±0.89, CHOP mRNA (2-ΔΔCt): 1.13±0.24 vs. 4.44±1.13, all P < 0.05], and the protein expressions of GRP78, PERK, ATF6 and CHOP were significantly decreased (GRP78/GAPDH: 0.59±0.02 vs. 0.77±0.01, PERK/GAPDH: 0.48±0.03 vs. 1.04±0.05, ATF6/GAPDH: 0.51±0.03 vs. 0.65±0.01, CHOP/GAPDH: 0.91±0.05 vs. 1.11±0.07, all P < 0.05). CONCLUSIONS: FICZ protects LPS-induced ALI possibly via suppressing endoplasmic reticulum stress and reducing IL-6 expression in blood and lung tissue.