Tumor-derived exosomal PD-L1: a new perspective in PD-1/PD-L1 therapy for lung cancer.

Exosomes play a crucial role in facilitating intercellular communication within organisms. Emerging evidence indicates that a distinct variant of programmed cell death ligand-1 (PD-L1), found on the surface of exosomes, may be responsible for orchestrating systemic immunosuppression that counteracts the efficacy of anti-programmed death-1 (PD-1) checkpoint therapy. Specifically, the presence of PD-L1 on exosomes enables them to selectively target PD-1 on the surface of CD8+ T cells, leading to T cell apoptosis and impeding T cell activation or proliferation. This mechanism allows tumor cells to evade immune pressure during the effector stage. Furthermore, the quantification of exosomal PD-L1 has the potential to serve as an indicator of the dynamic interplay between tumors and immune cells, thereby suggesting the promising utility of exosomes as biomarkers for both cancer diagnosis and PD-1/PD-L1 inhibitor therapy. The emergence of exosomal PD-L1 inhibitors as a viable approach for anti-tumor treatment has garnered significant attention. Depleting exosomal PD-L1 may serve as an effective adjunct therapy to mitigate systemic immunosuppression. This review aims to elucidate recent insights into the role of exosomal PD-L1 in the field of immune oncology, emphasizing its potential as a diagnostic, prognostic, and therapeutic tool in lung cancer.

When will the Glomerular Filtration Rate in Former Preterm Neonates Catch up with Their Term Peers?

AIMS: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. METHODS: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFRbirth (GFR at birth), and an Emax model dependent on PNA (with GFRmax, PNA50 (PNA at which half of GFR max is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations. RESULT: In the GFR model, GFRbirth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA50, and current weight for GFRmax. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well. CONCLUSIONS: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.

Preparation, structure, and in-vitro hypoglycemic potential of debranched millet starch-fatty acid composite resistant starch.

Currently, the preparation methods and basic physicochemical properties of starch-FA complexes have been widely studied; however, no in-depth research on the regulatory mechanism of the digestive properties of debranched starch-unsaturated FA complexes has been conducted. Therefore, six fatty acids with different carbon chains and different degrees of unsaturation were complexed with de-branched millet starch in this research, using the microwave method. Microwave millet starch-linoleic acid complex (MPS-LOA) had the highest resistant starch (RS) content, and the structure and physicochemical properties of MPS-LOA were determined using various molecular techniques. The results indicate that MPS-LOA had a resistant starch (RS) content of 40.35% and the most notable fluorescence. The characteristic UV peaks of MPS-LOA were blue-shifted, and new IR peaks appeared. The crystalline structure changed to V-type crystals, the crystallinity increased, and the molecular weight decreased. The enthalpy and coagulability of MPS-LOA increased, and the swelling force decreased. Additionally, MPS-LOA showed enhanced α-glucosidase and α-amylase inhibition, and in-vitro hydrolysis kinetics analysis of MPS-LOA showed a hydrolysis index of 53.8 and an extended glycemic index (eGI)I of 54.6, indicating a low eGI food suitable for consumption by people with type II diabetes. These results provide a theoretical basis for the preparation of amylopectin- and starch-based foods with an anti-enzyme structure and a low glycemic index (GI).

The effects of quinoa bran dietary fiber on glucose and lipid metabolism and hepatic transcriptome in obese rats.

BACKGROUND: As a complex chronic metabolic disease, obesity not only affects the quality of human life but also increases the risk of various other diseases. Therefore, it is important to investigate the molecular mechanisms and therapeutic effects of dietary interventions that counteract obesity. RESULTS: In this study, we extracted soluble (SDF) and insoluble dietary fiber (IDF) from quinoa bran using an enzymatic method and further investigated their effects on lipid metabolism and blood lipid levels in obese rats. Quinoa bran dietary fiber showed significantly reduced body weight, blood glucose level, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels compared to those in the model group of obese rats. Aspartate aminotransferase and alanine aminotransferase levels were significantly lower in the IDF group, demonstrating that IDF improved liver injury more significantly than SDF, which was consistent with the analysis of liver tissue sections. IDF supplementation significantly improved the oxidation resistance of obese rats by decreasing malondialdehyde and increasing superoxide dismutase and glutathione peroxidase levels compared to the high-fat diet group levels. Transcriptome analysis showed that IDF caused hepatic changes in genes (Ehhadh, PPARα, FADS, CPT1, CPT2, SCD-1, Acadm, and CYP7A1) related to fatty acid degradation, and this result coincided with that of the gene expression validation result. CONCLUSION: Overall, our research offers crucial data for the logical development of dietary fiber from quinoa bran with nutritional purposes. © 2023 Society of Chemical Industry.

Maturation of Paracetamol Elimination Routes in Preterm Neonates Born Below 32 Weeks of Gestation.

PURPOSE: Despite being off-label, intravenous paracetamol (PCM) is increasingly used to control mild-to-moderate pain in preterm neonates. Here we aim to quantify the maturation of paracetamol elimination pathways in preterm neonates born below 32 weeks of gestation. METHODS: Datasets after single dose (rich data) or multiple doses (sparse data) of intravenous PCM dose (median (range)) 9 (3-25) mg/kg were pooled, containing 534 plasma and 44 urine samples of PCM and metabolites (PCM-glucuronide, PCM-sulfate, PCM-cysteine, and PCM-mercapturate) from 143 preterm neonates (gestational age 27.7 (24.0-31.9) weeks, birthweight 985 (462-1,925) g, postnatal age (PNA) 5 (0-30) days, current weight 1,012 (462-1,959) g. Population pharmacokinetic analysis was performed using NONMEM® 7.4. RESULTS: For a typical preterm neonate (birthweight 985 g; PNA 5 days), PCM clearance was 0.137 L/h, with glucuronidation, sulfation, oxidation and unchanged renal clearance accounting for 5.3%, 73.7%, 16.3% and 4.6%, respectively. Maturational changes in total PCM clearance and its elimination pathways were best described by birthweight and PNA. Between 500-1,500 g birthweight, total PCM clearance increases by 169%, with glucuronidation, sulfation and oxidation clearance increasing by 347%, 164% and 164%. From 1-30 days PNA for 985 g birthweight neonate, total PCM clearance increases by 167%, with clearance via glucuronidation and oxidation increasing by 551%, and sulfation by 69%. CONCLUSION: Birthweight and PNA are the most important predictors for maturational changes in paracetamol clearance and its glucuronidation, sulfation and oxidation. As a result, dosing based on bodyweight alone will not lead to consistent paracetamol concentrations among preterm neonates.

Characterization of manganized soluble dietary fiber complexes from tigernut meal and study of the suppressive activity of digestive enzymes in vitro.

In this study, manganized soluble dietary fiber (SDF-Mn(II)) was prepared from tigernut meal using a microwave solid-phase synthesis method with SDF. Microscopic morphological and structural analyses of SDF-Mn(II) were carried out using scanning electron microscopy, Fourier infrared spectroscopy, UV full-band scanning, X-ray diffraction, a thermal analyzer, gel permeation chromatography, and nuclear magnetic resonance, and its in vitro hypoglycemic activity was initially investigated. The results of these analyses revealed that the reaction of Mn(II) with SDF mainly involved hydroxyl and carbonyl groups, with the Nuclear magnetic resonance (NMR) analysis showing that specific covalent binding was produced and substitution was mainly carried out at the C6 position. Moreover, compared with SDF, the SDF-Mn(II) complex exhibited a porous structure, red-shifted, and color-enhancing effects on the UV characteristic peaks, significantly increased crystallinity and decreased molecular weight, and improved thermal stability; in addition, SDF-Mn(II) afforded significantly enhanced inhibition of α-amylase and α-glucosidase and possesses good in vitro digestive enzyme inhibition activity.

Genomic characterization of an Omono River virus isolated from Culex tritaeniorhynchus in eastern China.

Omono River virus (OMRV) is a newly reported, unclassified RNA virus in the family Totiviridae, which infects mosquitoes and bats. In this study, we report the isolation of an OMRV strain SD76 from Culex tritaeniorhynchus captured in Jinan city, China. The cytopathic effect was characterized by cell fusion on C6/36 cell line. Its complete genome was 7611 nucleotides in length, with 71.4-90.4% similarities with other OMRV strains. Phylogenetic analysis based on complete genomes showed all OMRV-like strains can be divided into 3 groups with between-group distances ranging from 0.254 to 0.293. These results revealed that the OMRV isolate had high genetic diversity with those identified previously, and enriched the genetic information of family Totiviridae.

Use of the prognostic nutrition index as a predictive biomarker in small-cell lung cancer patients undergoing immune checkpoint inhibitor treatment in the Chinese alpine region.

Background: Whether the prognostic nutritional index (PNI), which is suggested to reflect systemic inflammation and nutritional status of patients, could be used as an effective prognostic factor for small-cell lung cancer (SCLC) has not yet been clarified. The purpose of this study was to verify the prognostic value of the PNI in SCLC patients treated with programmed cell death ligand-1/programmed cell death 1 (PD-L1/PD-1) inhibitors in the alpine region of China. Methods: SCLC patients treated with PD-L1/PD-1 inhibitors monotherapy or combined with chemotherapy between March 2017 and May 2020 were included. Based on the values of serum albumin and total lymphocyte count, the study population was divided into two groups: high and low PNI. The Kaplan-Meier method was used to compute the median survival time and the log-rank test was used to compare the two groups. To evaluate the prognostic value of the PNI, univariable and multivariable analyses of progression-free survival (PFS) and overall survival (OS) were performed. The correlations between PNI and DCR or ORR were calculated by Point biserial correlation analysis. Results: One hundred and forty patients were included in this study, of which, 60.0% were high PNI (PNI > 49.43) and 40.0% were low PNI (PNI ≤ 49.43). Results indicated that the high PNI group had better PFS and OS than the low PNI group in the patients who received PD-L1/PD-1 inhibitors monotherapy (median PFS: 11.0 vs. 4.8 months, p < 0.001 and median OS: 18.5 vs. 11.0 months, p = 0.004). Similarly, better PFS and OS were associated with an increase in PNI level in the patients who accepted PD-L1/PD-1 inhibitors combined with chemotherapy (median PFS: 11.0 vs. 5.3 months, p < 0.001 and median OS: 17.9 vs. 12.6 months, p = 0.005). Multivariate Cox-regression model showed that high PNI was significantly related to better PFS and OS in patients who accepted PD-L1/PD-1 inhibitors monotherapy or combined with chemotherapy (PD-L1/PD-1 inhibitors monotherapy: PFS: HR = 0.23, 95% CI: 0.10-0.52, p < 0.001 and OS: HR = 0.13, 95% CI: 0.03-0.55, p = 0.006; PD-L1/PD-1 inhibitors combined with chemotherapy: PFS: HR = 0.34, 95% CI: 0.19-0.61, p < 0.001 and OS: HR = 0.53, 95% CI: 0.29-0.97, p = 0.040, respectively). Additionally, Point biserial correlation analysis between PNI and disease control rate (DCR) showed that PNI status was positively correlated with DCR in SCLC patients receiving PD-L1/PD-1 inhibitors or combined with chemotherapy (r = 0.351, p < 0.001; r = 0.285, p < 0.001, respectively). Concussions: PNI may be a promising biomarker of treatment efficacy and prognosis in SCLC patients treated with PD-L1/PD-1 inhibitors in the alpine region of China.

Exosomes and osteosarcoma drug resistance.

Osteosarcoma (OS) is a primary malignant tumor of bone characterized by the formation of bone tissue or immature bone by tumor cells. Because of its multi-drug resistance, even with the improvement of chemotherapy and the use of targeted drugs, the survival rate of osteosarcoma (OS) is still less than 60%, and it is easy to metastasize, which is a difficulty for many clinicians and researchers. In recent years, with the continuous research on exosomes, it has been found that exosomes play a role in the diagnosis, treatment and chemotherapy resistance of osteosarcoma due to their unique properties. Exosomes can reduce the intracellular accumulation of chemotherapeutic drugs by mediating drug efflux, thus inducing chemotherapeutic resistance in OS cells. Exosomal goods (including miRNA and functional proteins) carried by exosomes also show great potential in affecting the drug resistance of OS. In addition, miRNA carried by exosomes and exosomes exist widely in tumor cells and can reflect the characteristics of parent cells, so it can also be used as a biomarker of OS. At the same time, the development of nanomedicine has given a new hope for the treatment of OS. Exosomes are regarded as good natural nano-carriers by researchers because of their excellent targeted transport capacity and low toxicity, which will play an important role in the field of OS therapy in the future. This paper reviews the internal relationship between exosomes and OS chemotherapy resistance, discusses the broad prospects of exosomes in the field of diagnosis and treatment of OS, and puts forward some suggestions for the study of the mechanism of OS chemotherapy resistance.

Inhibition of miR-143-3p alleviates myocardial ischemia reperfusion injury via limiting mitochondria-mediated apoptosis.

MicroRNA (miR)-143-3p is a potential regulatory molecule in myocardial ischemia/reperfusion injury (MI/RI), wherein its expression and pathological effects remains controversial. Thus, a mouse MI/RI and cell hypoxia/reoxygenation (H/R) models were built for clarifying the miR-143-3p's role in MI/RI. Following myocardial ischemia for 30 min, mice underwent reperfusion for 3, 6, 12 and 24 h. It was found miR-143-3p increased in the ischemic heart tissue over time after reperfusion. Cardiomyocytes transfected with miR-143-3p were more susceptible to apoptosis. Mechanistically, miR-143-3p targeted B cell lymphoma 2 (bcl-2). And miR-143-3p inhibition reduced cardiomyocytes apoptosis upon H/R, whereas it was reversed by a specific bcl-2 inhibitor ABT-737. Of note, miR-143-3p inhibition upregulated bcl-2 with better mitochondrial membrane potential (Δψm), reduced cytoplasmic cytochrome c (cyto-c) and caspase proteins, and minimized infarction area in mice upon I/R. Collectively, inhibition of miR-143-3p might alleviate MI/RI via targeting bcl-2 to limit mitochondria-mediated apoptosis. To our knowledge, this study further clarifies the miR-143-3p's pathological role in the early stages of MI/RI, and inhibiting miR-143-3p could be an effective treatment for ischemic myocardial disease.

Effect of Fermentation Time on Molecular Structure and Physicochemical Properties of Corn Ballast Starch.

The effect of fermentation treatment on the surface morphology, crystal structure, molecular weight, chain length distribution, and physicochemical properties of corn starch was investigated using natural fermentation of corn ballast. The amylose content in corn ballast starch reduced at first after natural fermentation, then grew, following the same trend as solubility. There were certain erosion marks on the surfaces of fermented corn ballast starch granules. The crystalline structure of corn ballast starch remained the same, i.e., a typical A-type crystalline structure, at different fermentation times; however, the intensities of diffraction peaks were different. The weight-average molecular weight of starch first increased and then decreased after fermentation. The content of low-molecular-weight starch (peak 3) decreased from 25.59 to 24.7% and then increased to 25.76%, while the content of high-molecular-weight starch (peak 1) increased from 51.45 to 53.26%, and then decreased to 52.52%. The fermentation time showed a negative correlation with the viscosity of starch, and the pasting temperature first increased, and then decreased. Natural fermentation can be used as a technical means to produce corn starch products as a result of the experiments' findings, and future experiments will detect and analyze the bacterial structure of corn fermentation broth in order to better understand the molecular mechanism of natural fermentation affecting the structure and physicochemical properties of corn starch.

Prediction of glomerular filtration rate maturation across preterm and term neonates and young infants using inulin as marker.

Describing glomerular filtration rate (GFR) maturation across the heterogeneous population of preterm and term neonates and infants is important to predict the clearance of renally cleared drugs. This study aims to describe the GFR maturation in (pre)term neonates and young infants (PNA < 90 days) using individual inulin clearance data (CLinulin). To this end, published GFR maturation models were evaluated by comparing their predicted GFR with CLinulin retrieved from literature. The best model was subsequently optimized in NONMEM V7.4.3 to better fit the CLinulin values. Our study evaluated seven models and collected 381 individual CLinulin values from 333 subjects with median (range) birthweight (BWb) 1880 g (580-4950), gestational age (GA) 34 weeks (25-43), current weight (CW) 1890 g (480-6200), postnatal age (PNA) 3 days (0-75), and CLinulin 2.20 ml/min (0.43-17.90). The De Cock 2014 model (covariates: BWb and PNA) performed the best in predicting CLinulin, followed by the Rhodin 2009 model (covariates: CW and postmenstrual age). The final optimized model shows that GFR at birth is determined by BWb, thereafter the maturation rate of GFR is dependent on PNA and GA, with a higher GA showing an overall faster maturation. To conclude, using individual CLinulin data, we found that a model for neonatal GFR requires a distinction between prenatal maturation quantified by BWb and postnatal maturation. To capture postnatal GFR maturation in (pre)term neonates and young infants, we developed an optimized model in which PNA-related maturation was dependent on GA.

Pre- and Postnatal Maturation are Important for Fentanyl Exposure in Preterm and Term Newborns: A Pooled Population Pharmacokinetic Study.

BACKGROUND AND OBJECTIVE: Fentanyl is an opioid commonly used to prevent and treat severe pain in neonates; however, its use is off label and mostly based on bodyweight. Given the limited pharmacokinetic information across the entire neonatal age range, we characterized the pharmacokinetics of fentanyl across preterm and term neonates to individualize dosing. METHODS: We pooled data from two previous studies on 164 newborns with a median gestational age of 29.0 weeks (range 23.9-42.3), birthweight of 1055 g (range 390-4245), and postnatal age (PNA) of 1 day (range 0-68). In total, 673 plasma samples upon bolus dosing (69 patients; median dose 2.1 µg/kg, median 2 boluses per patient) or continuous infusions (95 patients; median dose 1.1 µg/kg/h for 30 h) with and without boluses were used for population pharmacokinetic modeling in NONMEM® 7.4. RESULTS: Clearance in neonates with birthweight of 2000 and 3000 g was 2.8- and 5.0-fold the clearance in a neonate with birthweight of 1000 g, respectively. Fentanyl clearance at PNA of 7, 14, and 21 days was 2.7-fold, 3.8-fold, and 4.6-fold the clearance at 1 day, respectively. Bodyweight-based dosing resulted in large differences in fentanyl concentrations. Depending on PNA and birthweight, fentanyl concentrations increased slowly after the start of therapy for both intermittent boluses and continuous infusion and reached a maximum concentration at 12-48 h. CONCLUSIONS: As both prenatal and postnatal maturation are important for fentanyl exposure, we propose a birthweight- and PNA-based dosage regimen. To provide rapid analgesia in the first 24 h of treatment, additional loading doses need to be considered.

Interference with the expression of S1PR1 or STAT3 attenuates valvular damage due to rheumatic heart disease.

Rheumatic heart disease (RHD) affects numerous individuals annually; however, its pathogenesis remains unclear. The sphingosine 1­phosphate receptor 1 (S1PR1) and signal transducer and activator of transcription 3 (STAT3) have recently been shown to be involved in valvular damage via the promotion of the differentiation of T helper 17 (Th17) cells during the development of RHD­induced valvular damage. The present study investigated whether altering the expression of S1PR1 or STAT3 attenuates valvular damage due to RHD. Inactivated group A streptococcus (GAS) was used to establish a rat model of RHD. Recombinant adeno­associated viral vectors carrying an S1PR1 overexpression sequence were used to overexpress S1PR1. STAT3 small interfering RNA (STAT3­siRNA) was used to inhibit STAT3 expression. Reverse transcription­quantitative PCR (RT­qPCR) was performed to detect the mRNA expression of S1PR1, STAT3, collagen type III α1 chain (Col3a1) and fibroblast­specific protein 1. Western blotting (WB) and immunohistochemistry were used to detect the levels of S1PR1, STAT3, phosphorylated (p­) STAT3, and retinoic acid­related orphan receptor Î³T (RORγt) proteins. Enzyme­linked immunosorbent assays (ELISAs) and immunohistochemistry were used to detect the levels of interleukin (IL)­6 and IL­17. Hematoxylin and eosin (H&E) staining and Sirius Red staining were performed to evaluate the degree of inflammation and fibrosis in the valvular tissues. S1PR1 expression was decreased in the valvular tissues of the rats with RHD. The levels of IL­6, IL­17 and p­STAT3 in the rats with RHD were increased. The degree of valvular inflammation and fibrosis in the rats with RHD was also increased. The overexpression of S1PR1 and the inhibition of STAT3 reduced the total p­STAT3 level, resulting in decreased levels of IL­6, IL­17 and RORγt, and a reduced degree of valvular inflammation and fibrosis. These results suggest that the expression of S1PR1 and STAT3 may be involved in valvular tissue damage due to RHD. Thus, strategies designed to interfere with the expression of S1PR1 or STAT3 may affect the expression of Th17 cell­related cytokines and may thus attenuate valvular damage due to RHD.

Inhibition of HMGB1 alleviates myocardial ischemia/reperfusion injury in diabetic mice via suppressing autophagy.

BACKGROUND: Diabetes aggravates myocardial ischemia/reperfusion (I/R) injury (MI/RI). The association between high mobility group box 1 protein (HMGB1) and autophagy in diabetic MI/RI remains unknown. Therefore, we investigated whether inhibiting HMGB1 can regulate autophagy in diabetic mice (DM) after I/R injury. METHODS: I/R models of C57BL/KsJ mice and db/db mice were established. Histological changes, infarct size (IS), HMGB1 protein, and autophagy-related proteins were detected after 24h of reperfusion. In DM treatment groups, anti-HMGB1 antibody (H-Ig) was injected via tail vein after reperfusion for 15min, and the above-mentioned experimental methods were performed at the end of reperfusion. RESULTS: Compared with the I/R group, the pathological myocardial damage and IS were significantly increased in the I/R (DM) group. Additionally, the levels of HMGB1, Beclin1, and LC3II/LC3I ratio were remarkably higher in the I/R (DM) group than those in the I/R group, while p62 level was lower. In the H-Ig (DM) group, injection of H-Ig significantly reduced the IS, as well as alleviated pathological myocardial damage. Moreover, Beclin1, LC3II/LC3I ratio, and p62 levels were notably reversed after this treatment. CONCLUSIONS: I/R-induced myocardium was aggravated by diabetes, which may be related to increased release of HMGB1 and activated autophagy. Inhibition of HMGB1 alleviates diabetic MIRI which was associated with reduced autophagy.

Effects of High-Temperature, High-Pressure, and Ultrasonic Treatment on the Physicochemical Properties and Structure of Soluble Dietary Fibers of Millet Bran.

OBJECTIVES: The effects of high-temperature, high-pressure, and ultrasonic treatment on the physicochemical properties and structure of soluble dietary fibers in millet bran were studied to provide a comprehensive reference for the utilization of millet bran. METHODS: Different physical methods were used to treat millet bran dietary fibers, and their microstructures and Fourier-transform infrared spectra before and after modification were compared. The physicochemical properties (water-holding capacity, swelling capacity, oil-holding capacity, fat-binding capacity, cation exchange capacity), total antioxidant capacity, and thermal characteristics were also analyzed. RESULTS: There were no significant changes in the chemical groups of millet bran's soluble dietary fibers after modification, but cracks appeared on the surface of the fibers and the structure became loose and porous. Fiber agglomeration was observed, as well as improved thermal stability. After modification, the water-holding capacity, swelling capacity, oil-holding capacity, fat-binding capacity, and cation exchange capacity of millet bran were improved. When compared to the original soluble dietary fibers, ultrasound-treated fibers showed the most substantial improvement in all four capabilities, with increases of 140, 50, 78.1, 65.7, and 37.8%, respectively, compared with the original soluble dietary fibers (P < 0.05). The total antioxidant capacity of the ultrasound-treated fibers was found to be higher than those of the fibers that underwent the other three treatments (P < 0.05). CONCLUSIONS: The physicochemical qualities and structural characteristics of the soluble dietary fibers in millet bran are affected by all three physical modification methods; however, the physicochemical properties of the ultrasound-treated fibers are most significantly improved.

Activation of activin/Smad2 and 3 signaling pathway and the potential involvement of endothelial­mesenchymal transition in the valvular damage due to rheumatic heart disease.

Rheumatic heart disease (RHD) is an autoimmune disease caused by rheumatic fever following group A hemolytic streptococcal infection and primarily affects the mitral valve. RHD is currently a major global health problem. However, the exact pathological mechanisms associated with RHD­induced cardiac valve damage remain to be elucidated. The endothelial­mesenchymal transition (EndMT) serves a key role in a number of diseases with an important role in cardiac fibrosis and the activin/Smad2 and 3 signaling pathway is involved in regulating the EndMT. Nevertheless, there are no studies to date, to the best of the authors' knowledge, investigating the association between RHD and EndMT. Thus, the aim of the current study was to investigate the potential role of EndMT in cardiac valve damage and assess whether activin/Smad2 and 3 signaling was activated during RHD­induced valvular injury in a rat model of RHD induced by inactivated Group A streptococci and complete Freund's adjuvant. Inflammation and fibrosis were assessed by hematoxylin and eosin and Sirius red staining. Serum cytokine and rheumatoid factor levels were measured using ELISA kits. Expression levels of activin/Smad2 and 3 signaling pathway­related factors [activin A, Smad2, Smad3, phosphorylated (p­)Smad2 and p­Smad3], EndMT­related factors [lymphoid enhancer factor­1 (LEF­1), Snail1, TWIST, zinc finger E­box­binding homeobox (ZEB)1, ZEB2, α smooth muscle actin (α­SMA) and type I collagen α 1 (COL1A1)], apoptosis­related markers (BAX and cleaved caspase­3) and valvular inflammation markers (NF­κB and p­NF­κB) were detected using reverse transcription­quantitative PCR and western blot analyses. Compared with the control group, the degree of valvular inflammation and fibrosis, serum levels of IL­6, IL­17, TNF­α and expression of apoptosis­related markers (BAX and cleaved caspase­3) and valvular inflammation marker (p­NF­κB), activin/Smad2 and 3 signaling pathway­related factors (activin A, p­Smad2 and p­Smad3), EndMT­related factors (LEF­1, Snail1, TWIST, ZEB 1, ZEB2, α­SMA and COL1A1) were significantly increased in the RHD group. These results suggested that the activin/Smad2 and 3 signaling pathway was activated during the development of valvular damage caused by RHD and that the EndMT is involved in RHD­induced cardiac valve damage.

Oridonin Attenuates Myocardial Ischemia/Reperfusion Injury via Downregulating Oxidative Stress and NLRP3 Inflammasome Pathway in Mice.

Oridonin (ORI), the major pharmacological component extracted from a traditional Chinese medicine, possesses a beneficial effect on myocardial ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanism by which ORI effects take place is not completely known. Thus, whether ORI works via downregulating oxidative stress and nod-like receptor protein-3 (NLRP3) inflammasome pathway was investigated in this study. Mice underwent surgery to induce myocardial I/R injury, and some were administered ORI (10 mg/kg/day) pretreatment, while others were not. The myocardial enzymes' levels, infarct area, and inflammatory injury were measured. The activation situation of oxidative stress and NLRP3 inflammasome was also detected. We found that ORI pretreatment significantly alleviated CK-MB and cTnI levels and infarct size induced by I/R. ORI mitigated the inflammatory injury by decreasing the pathological damage and lowering TNF-α, IL-1ß, and IL-18 levels. Moreover, the SOD1 and eNOS levels were significantly increased by ORI, while MDA and iNOS levels were relatively decreased. The oxidative stress was reversed using ORI pretreatment. Importantly, NLRP3 inflammasome pathway was also inhibited by ORI, as reflected by the lower protein levels of NLRP3, caspase-1, and IL-1ß. In conclusion, ORI alleviates myocardial injury induced by I/R via inhibiting the oxidative stress and NLRP3 inflammasome pathway.

Busulfan systemic exposure and its relationship with efficacy and safety in hematopoietic stem cell transplantation in children: a meta-analysis.

BACKGROUND: Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However, the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial. METHODS: Research on pertinent literature was carried out at PubMed, EMBASE, Web of science, the Cochrane Library and ClinicalTrials.gov. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cut-off value, which we set as 800, 900, 1000, 1125, 1350, and 1500 µM × min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events. RESULTS: Thirteen studies involving 548 pediatric patients (aged 0.3-18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 µM × min, the mean AUC value of < 900 µM × min significantly increased the incidence of graft failure (RR = 3.666, 95% CI: 1.419, 9.467). The incidence of VOD was significantly decreased with the mean AUC < 1350 µM × min (RR = 0.370, 95% CI: 0.205-0.666) and < 1500 µM × min (RR = 0.409, 95% CI: 0182-0.920). CONCLUSIONS: In children, Bu mean AUC above the cut-off value of 900 µM × min (after every 6-h dosing) was associated with decreased rates of graft failure, while the cut-off value of 1350 µM × min were associated with increased risk of VOD, particularly for the patients without VOD prophylaxis therapy. Further well-designed prospective and multi centric randomized controlled trials with larger sample size are necessary before putting our result into clinical practices.

Inhibition of miR­155­5p attenuates the valvular damage induced by rheumatic heart disease.

Autoimmunity is involved in the valvular damage caused by rheumatic heart disease (RHD). Increased evidence has linked microRNAs (miRNAs/miRs) to autoimmune disease. Signal transducer and activator of transcription 3 (STAT3) and sphingosine­1­phosphate receptor 1 (S1PR1) and suppressor of cytokine signaling 1 (SOCS1) have been widely studied for their roles in autoimmunity and inflammation. Thus, the current study aims to investigate the role played by miR­155­5p in RHD­induced valvular damage via the S1PR1, SOCS1/STAT3 and interleukin (IL)­6/STAT3 signaling pathways. An RHD rat model was induced by inactivated Group A streptococci and complete Freund's adjuvant. A recombinant adeno­associated virus (AAV­miR155­inhibitor) was used to inhibit the expression of miR­155­5p in the heart. Inflammation and fibrosis were assessed by hematoxylin and eosin staining and Sirius red staining. The expression of miR­155­5p in valvular tissues and serum exosomes was detected by reverse transcription­quantitative PCR. S1PR1, SOCS1, STAT3, phosphorylated STAT3, IL­6 and IL­17 protein expression was detected by western blotting and immunohistochemistry. The relationships between miR­155­5p and S1PR1 and SOCS1 were detected by dual luciferase assays. Cytokine concentrations were measured by ELISA. The expression of miR­155­5p in valve tissues and serum exosomes was increased along with decreased S1PR1 and activated SOCS1/STAT3 signaling in the RHD model. The expression of IL­6 and IL­17 was increased in the valves and the serum. Dual luciferase assays showed that miR­155­5p directly targeted S1PR1 and SOCS1. Inhibition of valvular miR­155­5p through AAV pretreatment increased S1PR1 expression and inhibited activation of the SOCS1/STAT3 signal pathway as a result of attenuated valvular inflammation and fibrosis as well as a decrease in IL­6 and IL­17 in the valves and serum. These results suggest that inhibition of miR­155­5p can reduce RHD­induced valvular damage via the S1PR1, SOCS1/STAT3 and IL­6/STAT3 signaling pathways.