Reversion of pH-Induced Physiological Drug Resistance: A Novel Function of Copolymeric Nanoparticles

The extracellular pH of cancer cells is lower than the intracellular pH. Weakly basic anticancer drugs will be protonated extracellularly and display a decreased intracellular concentration. In this study, we show that copolymeric nanoparticles (NPs) are able to overcome this “pH-induced physiological drug resistance” (PIPDR) by delivering drugs to the cancer cells via endocytosis rather than passive diffussion.As a model nanoparticle, Tetradrine (Tet, Pka 7.80) was incorporated into mPEG-PCL. The effectiveness of free Tet and Tet-NPs were compared at different extracellular pHs (pH values 6.8 and 7.4, respectively) by MTT assay, morphological observation and apoptotic analysis in vitro and on a murine model by tumor volume measurement, PET-CT scanning and side effect evaluation in vivo.<0.05) when the extracellular pH decreased from 7.4 to 6.8. Meanwhile, the cytotoxicity of Tet-NPs was not significantly influenced by reduced pH. In vivo experiment also revealed that Tet-NPs reversed PIPDR more effectively than other existing methods and with much less side effects.The reversion of PIPDR is a new discovered mechanism of copolymeric NPs. This study emphasized the importance of cancer microenvironmental factors in anticancer drug resistance and revealed the superiority of nanoscale drug carrier from a different aspect

Effect of polypropylene thick/basalt composite fibers on the mechanical properties of large dose slag fly ash concrete

In this experiment, the effects of polypropylene thick fiber (PPTF) with different volume admixtures (0, 0.05%, 0.10%, 0.15%, 0.20%, 0.25%) on the compressive strength, splitting tensile strength and bending strength of large admixture of slag fly ash concrete were investigated with short-cut basalt fiber (BF) as a reference. The results show that the polypropylene thick fiber can work well with basalt fiber and improve its strengthening effect of single admixture. And 0.10% of polypropylene thick fiber and 0.10% of basalt fibers by volume have the best strengthening effect on the mechanical properties of the large amount of slag fly ash concret

Periconceptional Folic Acid Supplementation Benefit to Development of Early Sensory-Motor Function through Increase DNA Methylation in Rat Offspring

Periconceptional maternal folate levels may alter DNA methylation patterns and health outcomes in offspring. We hypothesized that maternal folic acid supplementation alters fetal neural development through DNA methylation in the fetal brain. Twenty-eight rats were randomly assigned to four groups: three groups of the female rats were fed folate-normal, folate-deficient or folate-supplemented diets from seven days before mating to delivery. In another group, folic acid supplementation diet short-period group was fed a folate-normal diet, except for 10 days (begin mating) when this group was fed a folate-supplemented diet. After delivery, the diets were changed to folate-normal diet for all four groups. The cliff avoidance and forelimb grip tests were used to assess sensory motor function of rat offspring. The results indicate that maternal folic acid supplementation improved the early development of sensory-motor function in offspring. Maternal folic acid supplementation increased the methylation potential, global DNA methylation (5-mC) and DNA methyltransferase expression and activity in the brains of the offspring. In conclusion, maternal folic acid supplementation increases DNA methylation pattern in offspring brain and improves the early development of sensory-motor function

Early Life Stage Folic Acid Deficiency Delays the Neurobehavioral Development and Cognitive Function of Rat Offspring by Hindering De Novo Telomere Synthesis

Early life stage folate status may influence neurodevelopment in offspring. The developmental origin of health and disease highlights the importance of the period of the first 1000 days (from conception to 2 years) of life. This study aimed to evaluate the effect of early life stage folic acid deficiency on de novo telomere synthesis, neurobehavioral development, and the cognitive function of offspring rats. The rats were divided into three diet treatment groups: folate-deficient, folate-normal, and folate-supplemented. They were fed the corresponding diet from 5 weeks of age to the end of the lactation period. After weaning, the offspring rats were still fed with the corresponding diet for up to 100 days. Neurobehavioral tests, folic acid and homocysteine (Hcy) levels, relative telomere length in brain tissue, and uracil incorporation in telomere in offspring were measured at different time points. The results showed that folic acid deficiency decreased the level of folic acid, increased the level of Hcy of brain tissue in offspring, increased the wrong incorporation of uracil into telomeres, and hindered de novo telomere synthesis. However, folic acid supplementation increased the level of folic acid, reduced the level of Hcy of brain tissue in offspring, reduced the wrong incorporation of uracil into telomeres, and protected de novo telomere synthesis of offspring, which was beneficial to the development of early sensory-motor function, spatial learning, and memory in adolescence and adulthood. In conclusion, early life stage folic acid deficiency had long-term inhibiting effects on neurodevelopment and cognitive function in offspring

Folic acid modulates VPO1 DNA methylation levels and alleviates oxidative stress-induced apoptosis in vivo and in vitro

Endothelial cell injury and apoptosis play a primary role in the pathogenesis of atherosclerosis. Moreover, accumulating evidence indicates that oxidative injury is an important risk factor for endothelial cell damage. In addition, low folate levels are considered a contributing factor to promotion of vascular disease because of the deregulation of DNA methylation. We aimed to investigate the effects of folic acid on injuries induced by oxidative stress that occur via an epigenetic gene silencing mechanism in ApoE knockout mice fed a high-fat diet and in human umbilical vein endothelial cells treated with oxidized low-density lipoprotein (ox-LDL). We assessed how folic acid influenced the levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG, an oxidative DNA damage marker) and cellular apoptosis in in vivo and in vitro models. Furthermore, we analyzed DNA methyltransferase (DNMT) activity, vascular peroxidase 1 (VPO1) expression, and promoter methylation in human umbilical vein endothelial cells. Our data showed that folic acid reduced 8-OHdG levels and decreased apoptosis in the aortic tissue of ApoE−/− mice. Likewise, our in vitro experiments showed that folic acid protects against endothelial dysfunction induced by ox-LDL by reducing reactive oxygen species (ROS)-derived oxidative injuries, 8-OHdG content, and the apoptosis ratio. Importantly, this effect was indirectly caused by increased DNMT activity and altered DNA methylation at VPO1 promoters, as well as changes in the abundance of VPO1 expression. Collectively, we conclude that folic acid supplementation may prevent oxidative stress-induced apoptosis and suppresses ROS levels through downregulating VPO1 as a consequence of changes in DNA methylation, which may contribute to beneficial effects on endothelial function. Keywords: Folic acid, DNA methylation, Vascular peroxidase 1, Apoptosis, Oxidative stress, Atherosclerosi

Novel CAR T-cell therapies for relapsed/refractory B-cell malignancies: latest updates from 2023 ASH annual meeting

Abstract Chimeric antigen receptors (CAR) are engineered fusion proteins that target T-cells to specific surface antigens of tumor cells to generate effective anti-tumor responses. CAR T-cell therapy is playing an increasingly important role in the treatment of relapsed/refractory B-cell malignancies (R/R BCM). Attempting to make CAR T-cells safer and more effective in treating R/R BCM, various novel engineered CAR T-cell agents are currently in the research and development or clinical trial stages. We have summarized here the latest reports on the novel CAR T-cell therapies for R/R BCM presented at the 2023 ASH Annual Meeting as well as the latest updates in related clinical trials

Medium-chain triglycerides combined with DHA improve cognitive function by inhibiting neurocyte apoptosis of the brain in SAMP8 mice

Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA, Cn-3, 22:6) are essential in improving cognitive function and protecting neurocytes. This study explored the effects of the combined intervention of MCTs and DHA on inhibiting neurocyte apoptosis of the brain and improving cognitive function in senescence-accelerated mouse-prone 8 (SAMP8). Four-month-old male SAMP8 mice were randomly divided into four treatment groups (12 mice/group): DHA, MCT, DHA + MCT, and control groups, which intervened for seven months. Twelve age-matched male senescence-accelerated mouse resistant 1 (SAMR1) was used as the natural aging group. TUNEL assay and HE staining were used to assess neurocyte apoptosis and damage in the brain of mice. Moreover, the cognitive function was analyzed using the Morris water maze (MWM) and open field (OF) tests. The results showed that the cognitive function of 11-month-old SAMP8 mice decreased with age, and further pathological examination revealed the damaged neurocyte structure, karyopyknosis, cell atrophy, and even apoptosis. MCTs combined with DHA supplementation could increase octanoic acid (C8:0), decanoic acid (C10:0), and DHA levels in the serum, inhibit neurocyte apoptosis, improve neurocyte damage, moreover delay age-related cognitive decline after seven-month treatment. Furthermore, combining MCTs and DHA was significantly more beneficial than MCTs or DHA alone. In conclusion, MCTs combined with DHA could delay cognitive decline by inhibiting neurocyte apoptosis of the brain in SAMP8 mice

Antibiotic resistance of Riemerella anatipestifer and comparative analysis of antibiotic-resistance gene detection methods

Riemerella anatipestifer is an important pathogen in waterfowl, and is generally multidrug resistant. This study assessed the current status of Riemerella anatipestifer antibiotic resistance and antibiotic-resistance genes (ARGs), compared the results of different detection methods, and evaluated a new method of studying the association between antibiotic resistance and ARGs in Riemerella anatipestifer. In this study, 51 strains of Riemerella anatipestifer were isolated from ducks on several farms, their resistance to 28 antibiotics was assessed, and the isolates were subjected to whole-genome sequencing. The number of ARGs carried by Riemerella anatipestifer was predicted, compared, and analyzed, and the consistency between ARGs and antibiotic-resistance phenotypes was assessed. The potential for loss of resistance genes during the sequencing and assembly of genome-wide framework map was assessed, and a new ARG detection method was pilot tested. The 51 strains of Riemerella anatipestifer were multidrug resistant (MDR) and had high level of resistance to aminoglycosides, trimethoprim, lincosamides, polypeptides, and macrolides. Based on the genome-wide framework map of the 51 strains, 3 local databases of ABRicate software and 1 online database of CARD website were used to detect ARGs, and a mean of 4 to 5 ARGs were identified per isolate. Although the detection results differed according to the database used, the general performance was consistent. The online website detected more types of ARGs than the ABRicate software. The association between ARGs and antibiotic-resistance phenotypes was assessed, and the ermF gene was identified as a possible key ARGs regulating macrolide resistance of Riemerella anatipestifer. The method used to investigate and detect Riemerella anatipestifer ARGs was convenient and rapid, and had strong accuracy and pertinence. The ARGs detection method reported here combined the advantages of PCR and genome detection, and could greatly reduce workload and detect ARGs more precisely