[Bmal1 mediates the neuroprotective effect of sodium butyrate in a mouse model of Parkinson's disease].

OBJECTIVE: To investigate the mechanisms that mediate the neuroprotective effect of the intestinal microbial metabolite sodium butyrate (NaB) in a mouse model of Parkinson's disease (PD) via the gut-brain axis. METHODS: Thirty-nine 7-week-old male C57BL/6J mice were randomized equally into control group, PD model group, and NaB treatment group. In the latter two groups, PD models were established by intraperitoneal injection of 30 mg/kg 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) once daily for 5 consecutive days, and normal saline was injected in the control group. After modeling, the mice received daily gavage of NaB (300 mg/kg) or an equal volume of saline for 14 days. Behavioral tests were carried out to assess the changes in motor function of the mice, and Western blotting was performed to detect the expressions of tyrosine hydroxylase (TH) and α-synuclein (α-syn) in the striatum and nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), and the tight junction proteins ZO-1, Occludin, and Claudinin the colon. HE staining was used to observe inflammatory cell infiltration in the colon of the mice. RNA sequencing analysis was performed to identify the differentially expressed genes in mouse colon tissues, and their expressions were verified using qRT-PCR and Western blotting. RESULTS: The mouse models of PD with NaB treatment showed significantly increased movement speed and pulling strength of the limbs with obviously upregulated expressions of TH, Occludin, and Claudin and downregulated expressions of α-syn, NF-κB, TNF-α, and IL-6 (all P < 0.05). HE staining showed that NaB treatment significantly ameliorated inflammatory cell infiltration in the colon of the PD mice. RNA sequencing suggested that Bmal1 gene probably mediated the neuroprotective effect of NaB in PD mice (P < 0.05). CONCLUSION: NaB can improve motor dysfunction, reduce dopaminergic neuron loss in the striatum, and ameliorate colonic inflammation in PD mice possibly through a mechanism involving Bmal1.

Experimental Limits on Solar Reflected Dark Matter with a New Approach on Accelerated-Dark-Matter-Electron Analysis in Semiconductors.

Recently a dark matter-electron (DM-electron) paradigm has drawn much attention. Models beyond the standard halo model describing DM accelerated by high energy celestial bodies are under intense examination as well. In this Letter, a velocity components analysis (VCA) method dedicated to swift analysis of accelerated DM-electron interactions via semiconductor detectors is proposed and the first HPGe detector-based accelerated DM-electron analysis is realized. Utilizing the method, the first germanium based constraint on sub-GeV solar reflected DM-electron interaction is presented with the 205.4 kg·day dataset from the CDEX-10 experiment. In the heavy mediator scenario, our result excels in the mass range of 5-15 keV/c^{2}, achieving a 3 orders of magnitude improvement comparing with previous semiconductor experiments. In the light mediator scenario, the strongest laboratory constraint for DM lighter than 0.1 MeV/c^{2} is presented. The result proves the feasibility and demonstrates the vast potential of the VCA technique in future accelerated DM-electron analyses with semiconductor detectors.

Dual second harmonic generation and up-conversion photoluminescence emission in highly-optimized LiNbO3 nanocrystals doped and co-doped with Er3+ and Yb3.

Preparation from the aqueous alkoxide route of doped and co-doped lithium niobate nanocrystals with Er3+ and Yb3+ ions, and detailed investigations of their optical properties are presented in this comprehensive work. Simultaneous emission under femtosecond laser excitation of second harmonic generation (SHG) and up-conversion photoluminescence (UC-PL) is studied from colloidal suspensions according to the lanthanide ion contents. Special attention has been paid to produce phase pure nanocrystals of constant size (∼20 nm) thus allowing a straightforward comparison and optimization of the Er content for increasing the green UC-PL signals under 800 nm excitation. An optimal molar concentration at about 4 molar% in erbium ions is demonstrated, that is well above the concentration usually achieved in bulk crystals. Similarly, for co-doped LiNbO3 nanocrystals, different lanthanide concentrations and Yb/Er content ratios are tested allowing optimization of the green and red up-conversion excited at 980 nm, and analysis of the underlying mechanisms from excitation spectra. All together, these findings provide valuable insights into the wet-chemical synthesis and potential of doped and co-doped LiNbO3 nanocrystals for advanced applications, combining both SHG and UC-PL emissions from the particle core.

CXCL12 gene silencing down-regulates metastatic potential via blockage of MAPK/PI3K/AP-1 signaling pathway in colon cancer

Background: To investigate the effect of CXCL12 gene silencing on proliferation,invasion, angiogenesis and the relationship of MAPK/PI3K/AP-1 signaling pathway in colon cancer cells. Methods: RT-PCR and Western-blot were used to detect the expression of CXCL12 mRNA and protein in four colon cancer cell lines. Human colon cancer cells were transfected with CXCL12 siRNA carrying by Lipofectamine 2000. The expression of CXCL12 protein was confirmed by immunoblotting. WST-1, invasion and angiogenesis assay were used to examine the effect on proliferation, invasion and angiogenesis in colon cancer cells after CXCL12 siRNA silence, respectively. The phosphorylation of MAPK/PI3K/AP-1 protein levels was detected by Western blotting in CXCL12 siRNA suppression DLD-1 cell. Results: CXCL12 mRNA and proteins were only expressed in DLD-1 colon cancer cell lines. CXCL12 siRNA were transfected into DLD-1 cells, the expression CXCL12 proteins was significantly inhibited (P < 0.01), and the proliferation, invasion and angiogenesis of DLD-1 cells were inhibited significantly (P < 0.01). CXCL12 gene silencing resulted in blockage of MAPK, PI3K and AP-1 phosphorylation by CXCL12-induced in DLD-1 colon cancer cell. Conclusion: The silencing CXCL12 gene significantly inhibits the proliferation, invasion and angiogenesis ability of some types colon carcinoma cells through down-regulation of MAPK/PI3K/AP-1 signaling pathway

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Exosomes promote cetuximab resistance via the PTEN/Akt pathway in colon cancer cells

Cetuximab is widely used in patients with metastatic colon cancer expressing wildtype KRAS. However, acquired drug resistance limits its clinical efficacy. Exosomes are nanosized vesicles secreted by various cell types. Tumor cell-derived exosomes participate in many biological processes, including tumor invasion, metastasis, and drug resistance. In this study, exosomes derived from cetuximab-resistant RKO colon cancer cells induced cetuximab resistance in cetuximab-sensitive Caco-2 cells. Meanwhile, exosomes from RKO and Caco-2 cells showed different levels of phosphatase and tensin homolog (PTEN) and phosphor-Akt. Furthermore, reduced PTEN and increased phosphorylated Akt levels were found in Caco-2 cells after exposure to RKO cell-derived exosomes. Moreover, an Akt inhibitor prevented RKO cell-derived exosome-induced drug resistance in Caco-2 cells. These findings provide novel evidence that exosomes derived from cetuximab-resistant cells could induce cetuximab resistance in cetuximab-sensitive cells, by downregulating PTEN and increasing phosphorylated Akt levels.

Inflammation-based indexes and clinicopathologic features are strong predictive values of preoperative circulating tumor cell detection in gastric cancer patients

Circulating tumor cell (CTC) count and the host inflammatory response are two independent predictors for patients with various malignant disease. Several inflammation-based indicators have been demonstrated to have prognostic value in many malignant solid tumors, including systemic immune-inflammation index (SII), neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and prognostic nutrition index (PNI). The aim of this study was to evaluate the predictive value of the inflammation-based indexes including SII, NLR PLR, and PNI for CTC detection of gastric cancer patients before surgery. Methods. CTCs were measured using the isolation method by size of epithelial tumor cells and Wright staining for 60 patients with gastric cancer who underwent surgery. The indicators of SII, NLR, PLR, and PNI were calculated based on clinical laboratory testing. Results. The detected CTC number was correlated with extension of tumor invasion (p = 0.037), lymph node metastasis (p < 0.001), and TNM stage (p < 0.001). The CTC detection ratio was significantly correlated with T stage (p = 0.041), lymph node metastasis (p = 0.001), nerve fiber invasion of tumor outside the lymph nodes (p = 0.017), and TNM stage (p < 0.001). Statistical analysis showed that SII (p < 0.001), NLR (p < 0.001), PLR (p < 0.001), and PNI (p < 0.001) were significantly associated with positive CTC count and CTC detection rate. Conclusions. This study provides evidence that preoperative indicators consisting of SII, NLR, PLR, and PNI are robust predictors for CTC detection in gastric cancer patients undergoing tumor resection (AU)

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miR-26a-5p suppresses tumor metastasis by regulating EMT and is associated with prognosis in HCC

Objective. To determine the role of miR-26a-5p in tumor invasion and metastasis in hepatocellular carcinoma (HCC). Methods. We evaluated miR-26a-5p expression in HCC tissues by quantitative PCR and then analyzed its clinical significance using a Cox regression model. Transwell and nude mouse models were used to examine tumor metastasis in vitro and in vivo, respectively. The relationship between miR-26a-5p and epithelial-mesenchymal transition was also investigated by q-PCR and western blot. Results. Strong downregulation of miR-26a-5p was observed in tumor tissues compared to paired adjacent normal tissues. Moreover, patients with low miR-26a-5p expression had a significantly poorer prognosis than those with high expression. The multivariate analysis indicated that miR-26a-5p expression was an independent prognostic indicator. The experimental transwell model and athymic mouse model revealed that miR-26a-5p depressed tumor metastasis in vitro and in vivo, respectively. In addition, the decreased miR-26a-5p level observed in HCC was associated with reduced E-cadherin expression and upregulation of vimentin, which affects the molecular mechanism of EMT. Conclusion. Downregulation of miR-26a-5p promotes tumor metastasis by targeting EMT and influences the prognosis of HCC patients. Therefore, miR-26a-5p has potential as a new biomarker and therapeutic target (AU)

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Effect of salt intake and potassium supplementation on brachial-ankle pulse wave velocity in Chinese subjects: an interventional study

Accumulating evidence has suggested that high salt and potassium might be associated with vascular function. The aim of this study was to investigate the effect of salt intake and potassium supplementation on brachial-ankle pulse wave velocity (PWV) in Chinese subjects. Forty-nine subjects (28-65 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a low-salt diet for 7 days (3.0 g/day NaCl), a high-salt diet for an additional 7 days (18.0 g/day NaCl), and a high-salt diet with potassium supplementation for a final 7 days (18.0 g/day NaCl+4.5 g/day KCl). Brachial-ankle PWV was measured at baseline and on the last day of each intervention. Blood pressure levels were significantly increased from the low-salt to high-salt diet, and decreased from the high-salt diet to high-salt plus potassium supplementation. Baseline brachial-ankle PWV in salt-sensitive subjects was significantly higher than in salt-resistant subjects. There was no significant change in brachial-ankle PWV among the 3 intervention periods in salt-sensitive, salt-resistant, or total subjects. No significant correlations were found between brachial-ankle PWV and 24-h sodium and potassium excretions. Our study indicates that dietary salt intake and potassium supplementation, at least in the short term, had no significant effect on brachial-ankle PWV in Chinese subjects.

ERKs and mitochondria-related pathways are essential for glycyrrhizic acid-mediated neuroprotection against glutamate-induced toxicity in differentiated PC12 cells

The present study focuses on the neuroprotective effect of glycyrrhizic acid (GA, a major compound separated from Glycyrrhiza Radix, which is a crude Chinese traditional drug) against glutamate-induced cytotoxicity in differentiated PC12 (DPC12) cells. The results showed that GA treatment improved cell viability and ameliorated abnormal glutamate-induced alterations in mitochondria in DPC12 cells. GA reversed glutamate-suppressed B-cell lymphoma 2 levels, inhibited glutamate-enhanced expressions of Bax and cleaved caspase 3, and reduced cytochrome C (Cyto C) release. Exposure to glutamate strongly inhibited phosphorylation of AKT (protein kinase B) and extracellular signal-regulated kinases (ERKs); however, GA pretreatment enhanced activation of ERKs but not AKT. The presence of PD98059 (a mitogen-activated protein/extracellular signal-regulated kinase kinase [MEK] inhibitor) but not LY294002 (a phosphoinositide 3-kinase [PI3K] inhibitor) diminished the potency of GA for improving viability of glutamate-exposed DPC12 cells. These results indicated that ERKs and mitochondria-related pathways are essential for the neuroprotective effect of GA against glutamate-induced toxicity in DPC12 cells. The present study provides experimental evidence supporting GA as a potential therapeutic agent for use in the treatment of neurodegenerative diseases.