Possible mechanisms of auricular acupoint stimulation in the treatment of migraine by activating auricular vagus nerve. / 从耳迷走神经探讨耳穴治疗偏头痛的可能机制.

Under the guidance of traditional Chinese medicine theory, the clinical research of auricular acupoint stimulation in the treatment of migraine has gained a lot, and the curative efficacy is definite, but its mechanism remains unclear. In the present paper, we discussed the efficacy of auricular acupoint stimulation including "transcutaneous auricular vagus nerve stimulation" (taVNS) in the treatment of migraine in recent years. Through bibliometric analysis, we screened out top 10 auricular acupoints (Shenmenï¼»TF4ï¼½, Pizhixiaï¼»AT4ï¼½, Jiaoganï¼»AH6aï¼½, Ganï¼»CO12ï¼½, Yidanï¼»CO11ï¼½, Neifenmiï¼»CO18ï¼½, Shenï¼»CO10ï¼½, Nieï¼»AT2ï¼½, Zhenï¼»AT3ï¼½ and Eï¼»AT1ï¼½) which were the most frequently used for migraine. Majority of these auricular acupoints just distributed in the region innervated by auricular vagus nerve. Thus, we thought that the analgesic effect of needling these auricular acupoints for migraine was produced by triggering the auricular vagus nerve, and concluded that the central mechanism underlying induction of analgesic effect by activating auricular vagus nerve may be achieved by activating the descending pain regulation pathway of the locus coeruleus nucleus and dorsal raphe nucleus. In addition, taVNS-induced 1) regulation of the activities of brain's default network and pain matrix, 2) activation of the cortical descending pain regulation pathway, and 3) inhibition of the neuroinflammatory response may also contribute to its ameliorating effect of migraine. This paper may provide ideas for the future research on the mechanism of auricular acupoint treatment of migraine.

The induced and intrinsic resistance of Escherichia coli to sanguinarine is mediated by AcrB efflux pump.

IMPORTANCE: The use of plant extracts is increasing as an alternative to synthetic compounds, especially antibiotics. However, there is no sufficient knowledge on the mechanisms and potential risks of antibiotic resistance induced by these phytochemicals. In the present study, we found that stable drug resistant mutants of E. coli emerged after repetitive exposure to sanguinarine and demonstrated that the AcrB efflux pump contributed to the emerging of induced and intrinsic resistance of E. coli to this phytochemical. Our results offered some insights into comprehending and preventing the onset of drug-resistant strains when utilizing products containing sanguinarine.

Optimal postoperative surveillance strategies for cancer survivors with gastric neuroendocrine carcinoma based on individual risk: a multicenter real-world cohort study.

BACKGROUND: The best follow-up strategy for cancer survivors after treatment should balance the effectiveness and cost of disease detection while detecting recurrence as early as possible. Due to the low incidence of gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma [G-(MA)NEC], high-level evidence-based follow-up strategies is limited. Currently, there is a lack of consensus among clinical practice guidelines regarding the appropriate follow-up strategies for patients with resectable G-(MA)NEC. MATERIALS AND METHODS: The study included patients diagnosed with G-(MA)NEC from 21 centers in China. The random forest survival model simulated the monthly probability of recurrence to establish an optimal surveillance schedule maximizing the power of detecting recurrence at each follow-up. The power and cost-effectiveness were compared with the National Comprehensive Cancer Network, European Neuroendocrine Tumor Society, and European Society for Medical Oncology Guidelines. RESULTS: A total of 801 patients with G-(MA)NEC were included. The patients were stratified into four distinct risk groups utilizing the modified TNM staging system. The study cohort comprised 106 (13.2%), 120 (15.0%), 379 (47.3%), and 196 cases (24.5%) for modified groups IIA, IIB, IIIA, and IIIB, respectively. Based on the monthly probability of disease recurrence, the authors established four distinct follow-up strategies for each risk group. The total number of follow-ups 5 years after surgery in the four groups was 12, 12, 13, and 13 times, respectively. The risk-based follow-up strategies demonstrated improved detection efficiency compared to existing clinical guidelines. Further Markov decision-analytic models verified that the risk-based follow-up strategies were better and more cost-effective than the control strategy recommended by the guidelines. CONCLUSIONS: This study developed four different monitoring strategies based on individualized risks for patients with G-(MA)NEC, which may improve the detection power at each visit and were more economical, effective. Even though our results are limited by the biases related to the retrospective study design, we believe that, in the absence of a randomized clinical trial, our findings should be considered when recommending follow-up strategies for G-(MA)NEC.

Novel insight into the mechanism underlying synergistic cytotoxicity from two components in 5-Fluorouracil-phenylalanine co-crystal based on cell metabolomics.

Co-crystallization of active pharmaceutical ingredients (API) with co-formers can induce synergistic effects on cytotoxicity; however, the underlying mechanism is unclear. Here, cell metabolomics was used to gain insight into the mechanisms of synergistic effect from API and co-former in co-crystal. The 5-Fluorouracil-phenylalanine co-crystal system was selected as the model owing to the apparent difference of cytotoxicity occurring between co-crystal and physical mixture of two components (PM). The cytotoxicity of 5-FU, PM and co-crystal on B16 cells were evaluated by MTT assay. Based on the IC50 values from MTT assays, the cytotoxicity mechanism of 5-FU, PM and co-crystal was evaluated using a comprehensive non-targeted metabolomics strategy based on multivariate data analysis and statistics using UHPLC-Q-TOF-MS/MS platform with IDA data acquisition. Co-crystal showed higher cytotoxicity than PM against B16 cells. In the cell metabolomics study, a total of 12 differential metabolites were found. Pathway analysis indicated that differences in purine and glycerophospholipid metabolism occurred between PM and co-crystal. The downregulated deoxyguanosine diphosphate and adenosine diphosphate in the purine metabolism and downregulated L-glycerophosphocholine and upregulated C16-dihydroceramide in the glycerophospholipid metabolism were associated with cellular antiproliferation and apoptosis, which directly influenced the cytotoxicity. Cell metabolomics was used to investigate the cytotoxicity mechanism of the pharmaceutical co-crystal, providing an effective and innovative method for clarifying the synergistic mechanism of API and CCF in co-crystal.

Hyaluronic acid coated mesoporous carbon-copper peroxide for H2O2 self-supplying and near-infrared responsive multi-mode breast cancer oncotherapy.

It is challenging to develop the synergistic intelligent therapeutic nanoplatform to cure cancer. In the present study, a novel nanotherapeutic platform was constructed for H2O2 self-supplying and multimodal breast cancer therapy. In which, copper peroxide nanoparticles (CP NPs) were adsorbed on the surface of mesoporous carbon nanospheres (MCN) through electrostatic attraction, followed by loading doxorubicin (DOX) into the nanocomposite (MCN-CP) and coating hyaluronic acid (HA) on the surface, the DOX/MCN-CP-HA nanoplatform was obtained. In the system, the MCN not only possessed a high DOX loading capacity, but produced excellent photothermal therapy (PTT) effect. Importantly, the ultra-small CP NPs as the Fenton agent not only could selectively self-supplying H2O2 in acidic condition, but simultaneously release Cu2+ to catalyze the production of ·OH in the presence of H2O2. Meantime, the resulting Cu2+ possessed GSH-elimination property, which afforded enhanced chemodynamic therapy (CDT). Furthermore, the outer layer HA targeted to CD44 and achieved breast cancer cell targeting. The elevated temperature from PTT and acidic tumor microenvironment accelerated the release of DOX, which enabled DOX/MCN-CP-HA as an intelligent CDT-PTT-chemotherapy synergistic nanoplatform. In vitro and in vivo pharmacodynamic evaluations confirmed the potential of the nanoplatform for CDT-PTT-chemotherapy synergistic oncotherapy of breast cancer.

Effect of Ramie on the Production Performance of Laying Hens, and the Quality, Nutrient Composition, Antioxidation of the Eggs.

Ramie (Boehmeria nivea), which is rich in protein, fatty acid, vitamins and minerals, has become a potential alternative feed resource for poultry, and has attracted more and more attentions in nutrition research. The objective of this study is to evaluate the effect of dietary ramie at different concentrations on the production performance of the hens, and the quality, nutrient composition, and antioxidation of the eggs. A total of 432 34-week-old Lohmann commercial laying hens were divided into four groups, that were fed with corn-soybean meal-based control diet, control mixed with ramie at concentrations of 3, 6, or 9% separately for 8 weeks. Results showed that dietary ramie did not affect production performance. And egg yolk color gradually deepened as the inclusion levels of ramie increased. Ramie at tested concentration could significantly reduce the content of malondialdehyde (MDA) (p = 0.002) and 3% ramie supplementation significantly increased total antioxidative capacity (T-AOC) concentrations in egg yolk compared to the control group (p = 0.033). In addition, dietary supplementation with 6% ramie significantly reduced total cholesterol (T-CHO) content (p < 0.05) compared with controls. For egg nutrient composition, compared with the control group, the addition of 6% ramie significantly increased (p < 0.05) total omega-3 polyunsaturated fatty acids (n-3PUFA) and phenylalanine (Phe) in yolk. In conclusion, dietary inclusion of 6% ramie was most effective in improving the color, antioxidative capability, and reducing T-CHO contents of the egg yolks without any negative impacts on the production performance of the hens.

Synergistic H2O2 self-supplying and NIR-responsive drug delivery nanoplatform for chemodynamic-photothermal-chemotherapy.

Developing effectively synergistic multi-mode drug delivery nanoplatform for cancer treatment is of great significance but still challenging. Here, we construct core-shell (CaO2@Au nanoshells) nanoparticles coated with doxorubicin-loaded hyaluronic acid. The developed platform can be used as synergistic H2O2 self-supplying and near-infrared-enhanced reactive oxygen species producer for chemodynamic-photothermal-chemotherapy multi-mode drug delivery. In this platform, the CaO2 possesses a high capacity of self-supplying H2O2 in acidic conditions, while retains desired stability under physiological conditions. The in-situ deposited Au nanoshells not only provide a remarkable photothermal therapy, but function as peroxidase mimics to catalyze H2O2 to produce hydroxyl radical to afford highly efficient chemodynamic therapy. Furthermore, the outer layer hyaluronic acid can load doxorubicin and target overexpressed receptor CD44 of cancer cell, meanwhile, trigger release of DOX in photothermal condition and acidic tumor microenvironment. The results of in vitro cell viability and in vivo tumor inhibition indicate that the developed synergistic nanoplatform hold the potential as an efficient strategy for chemodynamic-photothermal-chemotherapy combination therapy of cancer.

Mechanism of Hematopoietic Reconstruction in Mice Treated with Danggui Buxue Decoction combined with Muscle-Derived Stem Cell Transplantation / 中国实验血液学杂志

OBJECTIVE@#To investigate the mechanism of hematopoietic reconstruction in mice treated with Danggui Buxue Decoction (DBD) combined with the muscle-derived stem cell transplantation (MDSCT).@*METHODS@#Female Kunming mice were randomly divided into the 6 groups: irradiation model, the bone marrow transplantation, the MDSC transplantation, the DBD 1 (4.5 g/kg), 2 (13.5 g/kg), and 3 (22.5 g/kg) + MDSC transplantation. After a week of oral administration of normal saline or different doses of DBD, The mice were exposied to 8 Gy Cs γ ray and were followed by bone marrow or MDSC transplantation. The expression levels of Notch1, Jagged1 and Hes1 in bone marrow, thymus and spleen were measured at 3 and 8 weeks after irradiation and transplantation.@*RESULTS@#In the bone marrow, 3 weeks after above-mentioned treatment, the expression of Notch1 mRNA increased obviously and the expression of Jagged1, Hes1 mRNA decreased obviously in each intervention group, compared with the irradiation model group. 8th week after treatment, the expression of Notch1 mRNA decreased obviously in each intervention group, the Jagged1 mRNA expression decreased obviously except the bone marrow group, and Hes1 mRNA expression increased (P＜0.05) in each intervention group. 3 weeks after treatment, compared with the irradiation model group, the expression of Notch1 mRNA in the thymocytes increased only in DBD1+MDSC group, Jagged1, Hes1 mRNA was increased in the MDSC transplantation group and the DBD1、2+MDSC group. 8th week after treatment, the expression of Notch1, Jagged1 mRNA expression decreased in each intervention group, the expression of Hes1 mRNA increased obviously in the MDSC transplantation group and the DBD1、2+MDSC group (P＜0.05). In the spleen, 3 weeks after treatment, the expression of Notch1, Jagged1 mRNA in the spleen of each intervention group decreased obviously, compared with the irradiation model group. The expression of Jagged1, Hes1 mRNA in each intervention group were increased obviously 8th week after treatment (P＜0.05).@*CONCLUSION@#MDSC transplantation after pretreatment of DBD can improve the hematopoietic reconstitution in mice with lethal dose radiation damage. Notch1、Jagged1 and Hes1 play different roles in this process, but the concrete mechanism needs to be further studied.

Different effects of 4ß-hydroxywithanolide E and withaferin A, two withanolides from Solanaceae plants, on the Akt signaling pathway in human breast cancer cells.

BACKGROUND: Triple-negative breast cancer (TNBC) represents a clinical challenge because it lacks sensitivity to hormone therapy or other available molecule-targeted agents. In addition, TNBC frequently exhibits over-activation of the PI3K/Akt survival pathway that can contribute to chemotherapy resistance. 4ß-Hydroxywithanolide E (4-HW) and withaferin A (WA) are two withanolides from Solanaceae plants that exhibit promising anticancer activity in vitro and in vivo. PURPOSE: The aim of this study is to investigate and compare the effects of 4-HW and WA on TNBC cells and underling mechanisms. STUDY DESIGN/METHODS: The anticancer effects of 4-HW and WA were evaluated by cell viability, cell cycle arrest, and apoptosis assays. PI3K/Akt signaling and the expression of survivin, Bcl-2 family proteins and cyclin-dependent kinase inhibitors were evaluated by Western blot. The role of PI3K/Akt signaling in the withanolides-induced anticancer effects was examined by using a PI3K inhibitor and overexpression of a constitutively active form of Akt. RESULTS: In TNBC MDA-MB-231 cells, 4-HW and WA displayed different kinetic effect on cell availability. Cell cycle analysis revealed that 4-HW induced the G1-phase arrest while WA caused the G2/M-phase block. Both withanolides induced apoptosis, but WA also caused necrosis. 4-HW inhibited the PI3K/Akt pathway and survivin expression as well as up-regulated the cyclin-dependent kinase inhibitors p21 and p27. In contrast, WA is a more potent inhibitor of Hsp90 and elicited Akt activation at low doses but inhibited Akt signaling at higher doses by depleting the Akt protein. The PI3K inhibitor LY294002 mimicked the effects of 4-HW and potentiated the cytotoxic activity of WA. In contrast, overexpressing a constitutively active form of myristoylated Akt rescue cancer cells from 4-HW-induced cell death. CONCLUSION: The withanolides 4-HW and WA potently inhibit the viability of TNBC cells through induction of cell cycle arrest and apoptosis/necrosis. The PI3K/Akt pathway plays distinct roles in cancer cells respond to 4-HW and WA. These results suggest the potential applications of the withanolides for the treatment of TNBC.

Salt Adaptation and Evolutionary Implication of a Nah-related PAHs Dioxygenase cloned from a Halophilic Phenanthrene Degrading Consortium.

Polycyclic aromatic hydrocarbons (PAHs) pollutions often occur in marine and other saline environment, largely due to anthropogenic activities. However, study of the PAHs-degradation genotypes in halophiles is limited, compared with the mesophilic terrestrial PAHs degraders. In this study, a bacterial consortium (CY-1) was enriched from saline soil contaminated with crude oil using phenanthrene as the sole carbon source at 10% salinity. CY-1 was dominated by the moderate halophilic Marinobacter species, and its dominant PAHs ring-hydroxylating dioxygenase (RHD) genotypes shared high identity to the classic nah-related RHDs found in the mesophilic species. Further cloning of a 5.6-kb gene cluster from CY-1 unveiled the existence of a new type of PAHs degradation gene cluster (hpah), which most probably evolves from the nah-related gene clusters. Expression of the RHD in this gene cluster in E. coli lead to the discovery of its prominent salt-tolerant properties compared with two RHDs from mesophiles. As a common structural feature shared by all halophilic and halotolerant enzymes, higher abundance of acidic amino acids was also found on the surface of this RHD than its closest nah-related alleles. These results suggest evolution towards saline adaptation occurred after horizontal transfer of this hpah gene cluster into the halophiles.

The Eag domain regulates the voltage-dependent inactivation of rat Eag1 K+ channels.

Eag (Kv10) and Erg (Kv11) belong to two distinct subfamilies of the ether-à-go-go K+ channel family (KCNH). While Erg channels are characterized by an inward-rectifying current-voltage relationship that results from a C-type inactivation, mammalian Eag channels display little or no voltage-dependent inactivation. Although the amino (N)-terminal region such as the eag domain is not required for the C-type inactivation of Erg channels, an N-terminal deletion in mouse Eag1 has been shown to produce a voltage-dependent inactivation. To further discern the role of the eag domain in the inactivation of Eag1 channels, we generated N-terminal chimeras between rat Eag (rEag1) and human Erg (hERG1) channels that involved swapping the eag domain alone or the complete cytoplasmic N-terminal region. Functional analyses indicated that introduction of the homologous hERG1 eag domain led to both a fast phase and a slow phase of channel inactivation in the rEag1 chimeras. By contrast, the inactivation features were retained in the reverse hERG1 chimeras. Furthermore, an eag domain-lacking rEag1 deletion mutant also showed the fast phase of inactivation that was notably attenuated upon co-expression with the rEag1 eag domain fragment, but not with the hERG1 eag domain fragment. Additionally, we have identified a point mutation in the S4-S5 linker region of rEag1 that resulted in a similar inactivation phenotype. Biophysical analyses of these mutant constructs suggested that the inactivation gating of rEag1 was distinctly different from that of hERG1. Overall, our findings are consistent with the notion that the eag domain plays a critical role in regulating the inactivation gating of rEag1. We propose that the eag domain may destabilize or mask an inherent voltage-dependent inactivation of rEag1 K+ channels.

Mechanisms of cardiovascular protection by resveratrol.

The phytoantitoxin resveratrol is a plant-derived polyphenol with phytoestrogenic properties. Resveratrol protects the cardiovascular system by mechanisms that include defense against ischemic-reperfusion injury, promotion of vasorelaxation, protection and maintenance of intact endothelium, anti-atherosclerotic properties, inhibition of low-density lipoprotein oxidation, suppression of platelet aggregation, and estrogen-like actions. The purpose of this article is to review the mechanisms of these effects.