Fecal microbiota transplantation combined with prebiotics ameliorates ulcerative colitis in mice.

Aim: To investigate the effect of treatment with fecal microbiota transplantation (FMT) and galacto- and fructo-oligosaccharides on ulcerative colitis (UC) in mice. Materials & methods: A total of 90 mice, divided into nine groups, were administered FMT or prebiotics or combined treatment. The disease activity index scores, gut microbiota and inflammation factors were evaluated. Results: The treatment using FMT combined with galacto- and fructo-oligosaccharides in a 9:1 ratio significantly reduced intestinal barrier damage and alleviated symptoms of UC. Lactobacillus and Bifidobacterium and short-chain fatty acids were significantly increased after the combined treatment. Conclusion: The results demonstrate that FMT with prebiotics is a new method for UC treatment.

Changes in the bacteria that live in the human gut can cause ulcerative colitis, a type of inflammatory disease in the bowel. Using mice, we investigated two possible treatments for ulcerative colitis: fecal microbiota transplantation, in which a sample of feces is taken from a healthy donor, processed and transferred to someone else; and prebiotics, a nondigestible food ingredient that encourages the growth of good bacteria in the gut. We found that the combination of prebiotics with fecal microbiota transplantation can improve symptoms and change the bacteria in the intestines and improves the uptake of nutrients.

Dominant negative TGFß receptor II and truncated TIM3 enhance the antitumor efficacy of CAR-T-cell therapy in prostate cancer.

BACKGROUND: The immune checkpoint molecules, Transforming growth factor beta receptor II (TGFßRII) and T cell immunoglobulin and mucin domain 3 (TIM3), have been identified as contributors to T cell immune suppression in prostate cancer. The objective of this investigation was to improve the tumor killing capability of prostate-specific membrane antigen (PSMA)-chimeric antigen receptor T (CAR-T) cells by targeting TIM3 and TGFßRII simultaneously. METHODS: To generate dnTGFßRII-trTIM3-PSMA-CAR-T (DT-PSMA-CAR-T) cells, the surface of PSMA-CAR-T cells was overexpressed with dominant negative TGFßRII (dnTGFßRII) and truncated extracellular TIM3 (trTIM3). The efficacy of DT-PSMA-CAR-T cells was assessed through in vitro killing experiments and animal experiments. RESULTS: The DT-PSMA-CAR-T cells demonstrated the ability to eradicate PSMA-positive prostate cancer cells, even in the presence of exogenous TGF-ß and/or TIM3 activating antibodies. In addition, the cells demonstrated the ability to eliminate tumor tissue in an immunodeficient mouse model transplanted with GAL9-PSMA-PC3 cells in vitro, prolonging survival without significant toxic side effects. CONCLUSIONS: This study emphasizes that upregulating dnTGFßRII and trTIM3 on the surface of T cells can potentially diminish the inhibitory effects of TGFßRII and TIM3.

Correlations of Serum 1,25-Hydroxy Vitamin D3 level with Severity and Prognosis of Neonatal Respiratory Distress Syndrome.

BACKGROUND: This study was done to explore the correlations of serum 1,25-hydroxy vitamin D3 [1,25-(OH)2-VitD3] level with severity and prognosis of neonatal respiratory distress syndrome (NRDS). METHODS: The clinical data of 145 NRDS children admitted between April 2019 and June 2020 were retrospectively analyzed. The subjects were comprised of 76 boys and 69 girls. Based on NRDS severity, they were assigned into mild group (n = 82) and severe group (n = 63), and their general data were compared. The independent factors affecting NRDS severity were evaluated by multivariate logistic regression analysis. The correlations of serum 1,25-(OH)2-VitD3 level in NRDS children with NRDS severity and other related blood test indices were analyzed using Spearman's and Pearson's methods. On the basis of multivariate analysis results, a prediction model was established using R3.6.0 software, which was validated by the receiver operating characteristic (ROC) curve and consistency index. The association between serum 1,25-(OH)2-VitD3 level and prognosis was evaluated through Kaplan-Meier curve. RESULTS: The severe group had higher groups of children with a gestational age < 39 weeks, spontaneous delivery, selective cesarean section, intrauterine distress, intrauterine infection, maternal hypertension, maternal dyslipidemia, and older maternal age than the mild group (p < 0.05). Procalcitonin, C-reactive protein, activin-A, Clara cell protein-16, interleukin-18, and IL-10 were significantly higher in the severe group than those in the mild group (p < 0.05), while serum bicarbonate, 1,25-(OH)2-VitD3, vitamin A, and IL-8 were significantly lower in the severe group than those in the mild group (p < 0.05). Multivariate logistic regression analysis results exhibited that gestational age < 39 weeks, lower 1,25-(OH)2-VitD3 and vitamin A levels, higher activin-A and CC-16 were independent risk factors for severe NRDS (p < 0.05). ROC curve analysis revealed that the area under the ROC curve of the model was 0.785, and the prediction accuracy was 88.08%. Serum 1,25-(OH)2-VitD3 level was significantly negatively correlated with NRDS severity (r = -0.287, p < 0.001), activin-A (r = -0.073, p < 0.001), and CC-16 (r = -0.098, p < 0.001), but positively correlated with vitamin A (r = 0.009, p < 0.001). Kaplan-Meier curve revealed that the survival rate of NRDS children with a high 1,25-(OH)2-VitD3 level was significantly higher than that of children with a low 1,25-(OH)2-VitD3 level (p < 0.001). CONCLUSIONS: 1,25-(OH)2-VitD3 is an independent influencing factor for the severity of NRDS and may affect the prognosis of NRDS children.

Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems.

Bone is one of the most common metastatic sites among breast cancer (BC) patients. Once bone metastasis is developed, patients' survival and quality of life will be significantly declined. At present, there are limited therapeutic options for BC patients with bone metastasis. Different nanotechnology-based delivery systems have been developed aiming to specifically deliver the therapeutic agents to the bone. The conjugation of targeting agents to nanoparticles can enhance the selective delivery of various payloads to the metastatic bone lesion. The current review highlights promising and emerging advanced nanotechnologies designed for targeted delivery of anticancer therapeutics, contrast agents, photodynamic and photothermal materials to the bone to achieve the goal of treatment, diagnosis, and prevention of BC bone metastasis. A better understanding of various properties of these new therapeutic approaches may open up new landscapes in medicine towards improving the quality of life and overall survival of BC patients who experience bone metastasis.

Potential Nanotechnology-Based Therapeutics to Prevent Cancer Progression through TME Cell-Driven Populations.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high risk of metastasis and therapeutic resistance. These issues are closely linked to the tumour microenvironment (TME) surrounding the tumour tissue. The association between residing TME components with tumour progression, survival, and metastasis has been well elucidated. Focusing on cancer cells alone is no longer considered a viable approach to therapy; thus, there is a high demand for TME targeting. The benefit of using nanoparticles is their preferential tumour accumulation and their ability to target TME components. Several nano-based platforms have been investigated to mitigate microenvironment-induced angiogenesis, therapeutic resistance, and tumour progression. These have been achieved by targeting mesenchymal originating cells (e.g., cancer-associated fibroblasts, adipocytes, and stem cells), haematological cells (e.g., tumour-associated macrophages, dendritic cells, and myeloid-derived suppressor cells), and the extracellular matrix within the TME that displays functional and architectural support. This review highlights the importance of nanotechnology-based therapeutics as a promising approach to target the TME and improve treatment outcomes for TNBC patients, which can lead to enhanced survival and quality of life. The role of different nanotherapeutics has been explored in the established TME cell-driven populations.

Modification of sweet potato (Ipomoea batatas Lam.) residues soluble dietary fiber following twin-screw extrusion.

Effect of twin-screw extrusion on soluble dietary fiber (SDF) from sweet potato residues (SPRs) were investigated using optimized conditions, at screw speed of 180 rpm, feed rate at 17 Hz, feed moisture at 40% and extrusion temperature at 150 °C. Extruded SDF, showed higher SDF levels (9.63%-29.25%), cholesterol and sodiumcholate adsorption capacity, radical scavenging capacity, and inhibition of digestive enzymes. Moreover, extrusion effectively reduced particle size and molecularweight of SDF, modulated monosaccharide ratios, and increased water retention capacity (WRC), oil retention capacity (ORC), swelling capacity (SC) and glucose absorption capacity (GAC). Additionally, scanning electron microscopy (SEM) demonstrated decomposition of macromolecules of SDF to smaller fractions and formation of a porous morphology following extrusion. Furthermore, the extruded SDF increased thermal stability as determined by differential scanning calorimetry (DSC). Overall, the SDF from SPRs with improved functional and physiochemical properties could be used as a functional additive in diverse food products.

Lipid metabolic response to polystyrene particles in nematode Caenorhabditis elegans.

Nanoplastics can be used in various fields, such as personal care products. Nevertheless, the effect of nanoplastic exposure on metabolism and its association with stress response remain largely unclear. Using Caenorhabditis elegans as an animal model, we determined the effect of nanopolystyrene exposure on lipid metabolism and its association with the response to nanopolystyrene. Exposure (from L1-larave to adult day-3) to 100 nm nanopolystyrene (≥1 µg/L) induced severe lipid accumulation and increase in expressions of mdt-15 and sbp-1 encoding two lipid metabolic sensors. Meanwhile, we found that SBP-1 acted downstream of intestinal MDT-15 during the control of response to nanopolystyrene. Intestinal transcriptional factor SBP-1 activated two downstream targets, fatty acyl CoA desaturase FAT-6 and heat-shock protein HSP-4 (a marker of endoplasmic reticulum unfolded protein response (ER UPR)) to regulate nanopolystyrene toxicity. Both MDT-15 and SBP-1 were involved in the activation of ER-UPR in nanopolystyrene exposed nematodes. Moreover, SBP-1 regulated the innate immune response by activating FAT-6 in nanopolystyrene exposed nematodes. In the intestine, function of MDT-15 and SBP-1 in regulating nanopolystyrene toxicity was under the control of upstream signaling cascade (PMK-1-SKN-1) in p38 MAPK signaling pathway. Therefore, our data raised an important molecular basis for potential protective function of lipid metabolic response in nanopolystyrene exposed nematodes.

Effect of graphene oxide exposure on intestinal Wnt signaling in nematode Caenorhabditis elegans.

Exposure to engineered nanomaterials (ENMs), such as graphene oxide (GO), can potentially induce the response of various molecular signaling pathways, which can mediate the protective function or the toxicity induction. Wnt signaling pathway is conserved evolutionarily in organisms. Using Caenorhabditis elegans as an in vivo assay model, we investigated the effect of GO exposure on intestinal Wnt signaling. In the intestine, GO exposure dysregulated Frizzled receptor MOM-5, Disheveled protein DSH-2, GSK-3 (a component of APC complex), and two ß-catenin proteins (BAR-1 and HMP-2), which mediated the induction of GO toxicity. In GO exposed nematodes, a Hox protein EGL-5 acted as a downstream target of BAR-1, and fatty acid transport ACS-22 acted as a downstream target of HMP-2. Functional analysis on HMP-2 and ACS-22 suggested that the dysregulation of these two proteins provides an important basis for the observed deficit in functional state of intestinal barrier. Our results imply the association of dysregulation in physiological and functional states of intestinal barrier with toxicity induction of GO in organisms.

Long-term and low-dose exposure to nanopolystyrene induces a protective strategy to maintain functional state of intestine barrier in nematode Caenorhabditis elegans.

Functional state of intestinal barrier plays an important role for environmental animals in being against various toxicants. We investigated GATA transcriptional factor ELT-2-mediated intestinal response to nanopolystyrere in Caenorhabditis elegans. Prolonged exposure to nanopolystyrene (≥1 µg/L) induced an increase in expression of ELT-2, and intestinal RNA interference (RNAi) knockdown of elt-2 caused enhancement in intestinal permeability. Meanwhile, mutation of elt-2 resulted in susceptibility to nanopolystyrene toxicity, and ELT-2 functioned in intestine to regulate the nanopolystyrene toxicity. ERM-1, CLEC-63, and CLEC-85 were identified as targets of ELT-2 in regulating the nanopolystyrene toxicity. ERM-1 was required for maintaining functional state in intestinal barrier, and functioned synergistically with CLEC-63 or CLEC-85 to regulate nanopolystyrene toxicity. Therefore, activation of intestinal ELT-2 by nanopolystyrere could mediate a protective strategy to maintain the functional state of intestinal barrier. During this process, intestinal ELT-2 activated two different molecular signals (ERM-1 signal and CLEC-63/85 signal) for nematodes against the nanopolystyrene toxicity.

Dysregulation of Neuronal Gαo Signaling by Graphene Oxide in Nematode Caenorhabditis elegans.

Exposure to graphene oxide (GO) induced some dysregulated microRNAs (miRNAs), such as the increase in mir-247, in nematode Caenorhabditis elegans. We here further identified goa-1 encoding a Gαo and pkc-1 encoding a serine/threonine protein kinase as the targets of neuronal mir-247 in the regulation of GO toxicity. GO exposure increased the expressions of both GOA-1 and PKC-1. Mutation of goa-1 or pkc-1 induced a susceptibility to GO toxicity, and suppressed the resistance of mir-247 mutant to GO toxicity. GOA-1 and PKC-1 could also act in the neurons to regulate the GO toxicity, and neuronal overexpression of mir-247 could not affect the resistance of nematodes overexpressing neuronal goa-1 or pkc-1 lacking 3'-UTR to GO toxicity. In the neurons, GOA-1 acted upstream of diacylglycerol kinase/DGK-1 and PKC-1 to regulate the GO toxicity. Moreover, DGK-1 and GOA-1 functioned synergistically in the regulation of GO toxicity. Our results highlight the crucial role of neuronal Gαo signaling in response to GO in nematodes.

Composition and Rheological Properties of Polysaccharide Extracted from Tamarind (Tamarindus indica L.) Seed.

A polysaccharide was extracted in high yield from tamarind (Tamarindus indica L.) seed (TSP) by acidic hot water extraction and ethanol precipitation. It was composed of 86.2% neutral polysaccharide, 5.4% uronic acid and 1.3% protein. The molecular weight of TSP was estimated to be about 1735 kDa, with glucose, xylose, and galactose in a molar ratio of 2.9:1.8:1.0 as the major monosaccharides. The steady shear and viscoelastic properties of TSP aqueous solutions were investigated by dynamic rheometry. Results revealed that TSP aqueous solution at a concentration above 0.5% (w/v) exhibited non-Newtonian shear-thinning behavior. Dynamic oscillatory analysis revealed that 10% (w/v) TSP showed as a "weak gel" structure. Apparent viscosities and viscoelastic parameters of TSP solutions decreased drastically in an alkaline solution of pH > 10, but slightly influenced by acidic solution, high temperature and the presence of salt ions and sucrose. These results indicated that TSP possessed excellent pH-resistance and thermo-stability, which might be suitable for applications in acidic beverages and high-temperature processed foodstuffs.

Identification of signaling cascade in the insulin signaling pathway in response to nanopolystyrene particles.

The molecular response of animals to nanoplastic particles is still largely unclear. In this study, we employed a modified prolonged exposure system to investigate the molecular response of Caenorhabditis elegans to nanopolystyrene particles. Exposure to nanopolystyrene particles (1 µg/L) significantly decreased expressions of daf-2 encoding an insulin receptor, age-1 encoding a PI3K, and akt-1 encoding an Akt/PKB, and increased expression of daf-16 encoding a FOXO transcriptional factor in insulin signaling pathway. Among these genes, mutation of daf-2, age-1, or akt-1 induced a resistance to toxicity of nanopolystyrene particles, whereas mutation of daf-16 induced a susceptibility to the toxicity of nanopolystyrene particles. RNAi knockdown of daf-16 could further suppress the resistance of daf-2, age-1, or akt-1 mutant to the toxicity of nanopolystyrene particles. The insulin signaling pathway acted in intestinal cells to regulate the toxicity of nanopolystyrene particles. Moreover, sod-3 encoding a manganese superoxide dismutase, mtl-1 encoding a metallothionein, and gpd-2 encoding a glyceraldehyde-3-phosphate dehydrogenase were identified as downstream targeted genes for daf-16 in the regulation of toxicity of nanopolystyrene particles. Therefore, a signaling cascade of DAF-2-AGE-1-AKT-1-DAF-16-SOD-3/MTL-1/GPD-2 was identified in response to nanopolystyrene particles in nematodes. Additionally, this signaling cascade in the insulin signaling pathway may mediate a protective response for nematodes against the adverse effects from nanopolystyrene particles.

Dysregulation of let-7 by PEG modified graphene oxide in nematodes with deficit in epidermal barrier.

In nematode Caenorhabditis elegans, epidermal RNA interference (RNAi) knockdown of bli-1 encoding a cuticular collagen caused the toxicity induction of GO-PEG (PEG surface modified graphene oxide). In this study, we further found that epidermal RNAi knockdown of bli-1 increased expression of a microRNA let-7, and let-7 mutation suppressed the susceptibility of bli-1(RNAi) nematodes to GO-PEG toxicity. let-7 regulated the toxicity induction of GO-PEG by suppressing expression and function of its direct targets (HBL-1 and LIN-41). Like the nematodes with epidermal RNAi knockdown of bli-1, epidermal RNAi knockdown of hbl-1 or lin-41 also induced functional abnormality in epidermal barrier. Therefore, a signaling cascade of BLI-1-let-7-HBL-1/LIN-41 was raised to be involved in GO-PEG toxicity induction. Our data imply the dysregulation of let-7-mediated molecular machinery for developmental timing control by GO-PEG in nematodes with deficit in epidermal barrier caused by bli-1(RNAi).

Lipid accumulation and metabolic analysis based on transcriptome sequencing of filamentous oleaginous microalgae Tribonema minus at different growth phases.

Filamentous oleaginous microalgae specie Tribonema minus is a promising feedstock for biodiesel production. However, the metabolic mechanism of lipid production in this filamentous microalgal specie remains unclear. Here, we compared the lipid accumulation of T. minus at different growth phases, and described the de novo transcriptome sequencing and assembly and identified important pathways and genes involved in TAG production. Total lipid increased by 2.5-fold and its TAG level in total lipid reached 81.1% at stationary phase. Using the genes involved in the lipid metabolism, the TAG biosynthesis pathways were generated. Moreover, results also demonstrated that, in addition to the observed overexpression of the fatty acid synthesis pathway, TAG production at stationary growth phase was bolstered by repression of the ß-oxidation pathway, up-regulation of genes that funnels acetyl-CoA to lipid biosynthesis, especially gene encoding for phospholipid:diacylglycerol acyltransferase (PDAT) which funnels DAG to TAG biosynthesis.