Effects of food matrix and probiotics on the bioavailability of curcumin in different nanoformulations.

BACKGROUND: Nanoparticles can improve the bioavailability of bioactive compounds. Concomitant intake of food can affect pharmacokinetic profiles by altering dissolution, absorption, metabolism, and elimination behavior. Studies on the effects of food and its supplements on the bioavailability of bioactives in nanoformulations are few. In this study, the effects of typical food (milk, sugar, high-fat diet, and regular kibble) and a widely consumed probiotic [Bifidobacterium lactis Bb-12® (Bb-12)] on the bioavailability of curcumin in four formulations [simply suspended curcumin (Cur-SS) and curcumin in nanoemulsions (Cur-NEs), in single-walled carbon nanotubes (Cur-SWNTs), and in nanostructured lipid carriers (Cur-NLCs)] were investigated. RESULTS: Fasting treatment and sugar co-ingestion can significantly enhance the bioavailability of curcumin in Cur-NEs and Cur-SWNTs, respectively. Compared with the fasting treatment, co-ingestion with regular kibble reduced the absorption of curcumin in Cur-NEs and Cur-SWNTs. Ingesting milk along with Cur-NE is also not recommended. The mechanisms behind these phenomena were briefly discussed. This study revealed for the first time that the intestinal colonization of Bb-12 reduces the bioavailability of curcumin and this reduction can be attenuated by nanoformulations SWNTs and NLCs, but not NEs. The reason for this difference was the protective effects of the former two nanoformulations against curcumin degradation by Bb-12 according to in vitro experiments. CONCLUSION: Dietary status (including supplementary probiotics) can dramatically influence the bioavailability of curcumin in nanoformulations. © 2021 Society of Chemical Industry.

Parthenolide induces autophagy via the depletion of 4E-BP1.

Parthenolide (PTL) is a sesquiterpene lactone isolated from feverfew and exhibits potent antitumor activity against various cancers. Many studies indicate that PTL treatment leads to apoptosis, however, the mechanism has not been defined. Here, we observed that cells underwent autophagy shortly after PTL treatment. Inhibition of autophagy by knocking out autophagy associated gene atg5 blocked PTL-induced apoptosis. Surprisingly, PTL decreased the level of translation initiation factor eIF4E binding protein 1 (4E-BP1) in correlation with autophagy. Ectopic expression or shRNA knockdown of 4E-BP1 further verified the effect of 4E-BP1 on PTL-induced autophagy. Meanwhile, PTL elevated the cellular reactive oxygen species (ROS) which located upstream of the depletion of 4E-BP1, and contributed to the consequent autophagy. This study revealed 4E-BP1 as a trigger for PTL-induced autophagy and may lead to therapeutic strategy to enhance the efficacy of anticancer drugs.

The N-terminal 20-amino acid region of guanine nucleotide exchange factor Vav1 plays a distinguished role in T cell receptor-mediated calcium signaling.

Vav1 is a guanine nucleotide exchange factor (GEF) specifically expressed in hematopoietic cells. It consists of multiple structural domains and plays important roles in T cell activation. The other highly conserved isoforms of Vav family, Vav2 and Vav3, are ubiquitously expressed in human tissues including lymphocytes. All three Vav proteins activate Rho family small GTPases, which are involved in a variety of biological processes during T cell activation. Intensive studies have demonstrated that Vav1 is indispensable for T cell receptor (TCR)-mediated signal transduction, whereas Vav2 and Vav3 function as GEFs that overlap with Vav1 on TCR-induced cytoskeleton reorganization. T cells lacking Vav1 exhibited severe defect in TCR-mediated calcium elevation, indicating that the co-existing Vav2 and Vav3 did not compensate Vav1 in calcium signaling. What is the functional particularity of Vav1 in lymphocytes? In this study, we identified the N-terminal 20 amino acids of Vav1 in the calponin homology (CH) domain to be essential for its interaction with calmodulin (CaM) that leads to TCR-induced calcium mobilization. Substitution of the 1-20 amino acids of Vav1 with those of Vav2 or Vav3 abolished the association with CaM, and the N-terminal mutations of Vav1 failed to potentiate normal TCR-induced calcium mobilization, that in turn, suspended nuclear factor of activated T cells (NFAT) activation and IL-2 production. This study highlights the importance of the N-terminal 20 aa of Vav1 for CaM binding, and provides new insights into the distinguished and irreplaceable role of Vav1 in T cell activation and signal transduction.

[Expression and significance of Treg/Th17 and CD4+/CD8+ T lymphocytes in experimental periodontitis in rats].

PURPOSE: To explore the expression of helper T cell 17/regulatory T cell (Th17/Treg) and CD4+/CD8+ T lymphocyte in experimental periodontitis in rats, and analyze its clinical significance. METHODS: Twenty SPF male SD rats were randomly divided into experimental group (inoculate Porphyromonas gingivalis suspension into gingival sulcus) and control group, with 10 rats in each group. The experimental group was smeared with Porphyromonas gingivalis suspension every other day within 1 week after operation, and the two groups were caged for 8 weeks. After the rats were sacrifical under anesthesia, the jaw tissue of the left maxillary second molar was stained with methylene blue to observe and measure the loss of alveolar bone (ABL). Hematoxylin-eosin (H-E) staining was used to observe the histopathological changes of the jaw. Rat peripheral blood mononuclear cells (PBMC) and T cells were isolated and cultured, Treg, Th17 cells and CD4+, CD8+ T lymphocytes in peripheral blood were detected by flow cytometry. The levels of serum interleukin-17(IL-17), IL-10 and IL-4, INF-γ were detected by enzyme-linked immunosorbent assay (ELISA). Expression changes of retinoic acid related orphan nuclear receptor (RORγt), forkhead wing like transcription factor 3 (Foxp3) and gap junction protein(Cx40) in jaw tissue were detected by Western blot. The data were statistically analyzed by SPSS 19.0 software package. RESULTS: Compared with the control group, ABL, peripheral blood Th17 ratio, Th17/Treg ratio, CD4+ ratio, CD4+/CD8+ T lymphocyte ratio, serum IL-17, IL-10 and IL-4 level, Foxp3 and Cx40 protein in jaw tissue were signifinantly increased in the experimental group(P<0.05), while Treg ratio, INF-γ, RORγt protein in jaw tissue significantly decreased(P<0.05) in the experimental group. CONCLUSIONS: Imbalance of Treg/Th17 and CD4+/CD8+ T lymphocytes leads to the abnormal high expression of inflammatory factors IL-17, IL-10 and IL-4, which may be closely related to the pathogenesis of experimental periodontitis.

Experimental investigation on the migration of leachate under flowing conditions through laboratory ERT.

With an increase of service time of landfills, a great amount of old landfills begin to leak and the leachate impairs the surrounding environment severely. Defining the flow of leachate is significant to the monitoring and restoration of the landfill. Field tests and laboratory tests are often used to investigate the leachate flow. However, many uncontrollable factors may affect the accuracy of field tests, and the application of field test results is usually limited. At the same time, it is difficult to simulate and monitor the migration process of leachate in real time in laboratory. To address this problem, a new physical simulating device is created to simulate the leachate migration under flowing conditions, and improved ERT device is designed to monitor the migration in laboratory tests. The results show that the improved ERT could delineate the migration range well in laboratory tests, providing a new method to investigate the leachate migration in laboratory test and providing a reference to the application of ERT in field tests. The relative variation rate of resistivity could reduce the influence of background, and is very suitable for time-lapse ERT. In addition, the effect of flowing rate, leakage rate, and time on the leachate migration is also investigated. The results show that the horizontal migration rate increases with an increase of flowing rate. The leakage rate has a significant influence on the vertical migration, but has limited effect on the horizontal migration. The curvature of migration front increases with an increase of flowing rate and time.

Vav1 increases Bcl-2 expression by selective activation of Rac2-Akt in leukemia T cells.

Vav proteins are guanine nucleotide exchange factors (GEFs) that activate a group of small G proteins (GTPases). Vav1 is predominantly expressed in hematopoietic cells, whereas Vav2 and Vav3 are ubiquitously distributed in almost all human tissues. All three Vav proteins contain conserved structural motifs and associate with a variety of cellular activities including proliferation, migration, and survival. Previous observation with Jurkat leukemia T cells showed that Vav1 possessed anti-apoptotic activity by enhancing Bcl-2 transcription. However the mechanism has not been unveiled. Here, we explored the effectors of Vav1 in promoting Bcl-2 expression in Jurkat cells and revealed that Rac2-Akt was specifically evoked by the expression of Vav1, but not Vav2 or Vav3. Although all three Vav isoforms existed in Jurkat cells, Rac2 was distinguishably activated by Vav1 and that led to enhanced Bcl-2 expression and cell survival. Akt was modulated downstream of Vav1-Rac2, and the activation of Akt was indispensable in the enhanced transcription of Bcl-2. Intriguingly, neither Vav2 nor Vav3 was able to activate Rac2-Akt pathway as determined by gene silencing approach. Our data illustrated a unique role of Vav1 in T leukemia survival by selectively triggering Rac2-Akt axis and elevating the expression of anti-apoptotic Bcl-2.

Effects of Ce on the short-term biocompatibility of Ti-Fe-Mo-Mn-Nb-Zr alloy for dental materials.

Effects of Ce on the short-term biocompatibility of Ti-Fe-Mo-Mn-Nb-Zr alloy designed for implant materials were studied by acute toxicity test, hemolytic test, and MTT assay. The elements and their concentration in surface films and extraction media of Ti alloys were investigated with XPS and ICP, respectively. The primary compositions of the surface films of Ti alloys with 0.3% Ce and without Ce were TiO2 and Nb2O5. There were 0.2 mg/l Fe and 0.16 mg/l Mn in the extraction medium of Ti alloy without Ce, while 0.27 mg/l Fe and 0.87 mg/l Mn in the extraction medium of Ti alloy with 0.3% Ce. The concentrations of Fe and Mn in the medium were too low to have any significant effects on human health. There was no sign of cytotoxicity in these tests. The cytotoxicity levels of Ti alloys without Ce and with 0.3% Ce were graded 0 and 1, respectively. The hemolytic degrees of Ti alloys without Ce and with 0.3% Ce were 0.558% and 0.67%, respectively. The cells being incubated in the extraction medium were normal. These phenomena indicated that Ce was innocuous within the concentration range of this study. In addition, the hemolytic ratio and toxicity level of Ti alloy with 0.3% Ce were a little higher than that of Ti alloy without Ce. This meant that Ce would slightly increase the toxicity of Ti alloy.