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Tanshinone IIA (Tan IIA) possesses potent anti-atherogenic function, however, the underlying pharmacological mechanism remains incompletely understood. Previous studies suggest that oxidized LDL (oxLDL)-induced NLRP3 (NOD-like receptor (NLR) family, pyrin domain-containing protein 3) inflammasome activation in macrophages plays a vital role in atherogenesis. Whether the anti-atherogenic effect of Tan IIA relies on the inhibition of the NLRP3 inflammasome has not been investigated before. In this study, we found that Tan IIA treatment of high-fat diet fed ApoE-/- mice significantly attenuated NLRP3 inflammasome activation in vivo. Consistently, Tan IIA also potently inhibited oxLDL-induced NLRP3 inflammasome activation in mouse macrophages. Mechanically, Tan IIA inhibited NF-κB activation to downregulate pro-interleukin (IL) -1β and NLRP3 expression, and decreased oxLDL-induced expression of lectin-like oxidized LDL receptor-1 (LOX-1) and cluster of differentiation 36 (CD36), thereby attenuating oxLDL cellular uptake and subsequent induction of mitochondrial and lysosomal damage - events that promote the NLRP3 inflammasome assembly. Through regulating both the inflammasome 'priming' and 'activation' steps, Tan IIA potently inhibited oxLDL-induced NLRP3 inflammasome activation, thereby ameliorating atherogenesis.Tumor microenvironment is hypoxic, which can cause resistance to chemotherapy, but the detailed mechanisms remain elusive. Here we find that mild hypoxia (5% O2) further increases cisplatin resistance in the already resistant HepG2/DDP but not the sensitive HepG2 cells. We find that Nrf2 is responsible for cisplatin resistance under hypoxia, as Nrf2 knockdown sensitizes HepG2/DDP cells while Nrf2 hyper-activation (though KEAP1 knockdown) increases resistance of HepG2 cells to cisplatin. Nrf2 binds to an enhancer element in the upstream of HIF-1α gene independently of hypoxia, promoting HIF-1α mRNA synthesis under hypoxic condition. As a result, Nrf2-dependent transcription counteracts HIF-1α degradation under mild hypoxia condition, leading to preferential cisplatin-resistance in HepG2/DDP cells. Our data suggest that Nrf2 regulation of HIF-1α could be an important mechanism for chemotherapy resistance in vivo.As the first clinical proteasome inhibitor, Bortezomib (BTZ) has been reported to improve the outcome of lymphoma. However, due to the unstable property, low bioavailability, and hydrophobic properties of BTZ, it is needed to develop effective drug delivery systems to deliver BTZ into targeted cells or organs. Here we developed a bortezomib (BTZ)-loaded HMSNs (BTZ@HMSNs) system, which can sustain the release of BTZ in targeted tissues. In vitro assays showed that BTZ@HMSNs limited cell proliferation and augmented apoptosis of lymphoma SNK-1 cells. Moreover, BTZ@HMSNs significantly diminished migration and invasion of SNK-1 cells as compared with BTZ. In contrast to the upregulation of SHP-1, BTZ@HMSNs decreased the mRNA levels of c-Kit, NF-κB, and JAK1, which elicit oncogenic role in lymphoma development. Importantly, lymphoma mice model showed that BTZ@HMSNs significantly activated p53 signaling and reduced tumor volume and weight compared with free BTZ. Our data thus demonstrate that BTZ@HMSNs manifests improved tumor-suppressing effect in vitro and in vivo compared to free BTZ. We believe that HMSNs is a promising strategy for delivering therapeutic agents for cancer treatment.Primary Sjögren syndrome (pSS) is a common autoimmune disease. Here, we performed the first proteome and phosphoproteome analyses of peripheral blood mononuclear cells in pSS patients to obtain a comprehensive profile and identify the potential crucial proteins and pathways for the screening and evaluation of pSS patients. Peripheral blood mononuclear cells from 8 pSS-confirmed patients (American-European Consensus Group Criteria, 2002) and 10 normal controls were selected. Label-free quantitative proteomics was utilized to obtain quantitative information. In total, 787 proteins were identified as differentially expressed proteins, and 175 phosphosites on 123 proteins were identified as differentially phosphorylated proteins. We performed functional enrichment analyses with these proteins and phosphoproteins based on public database. SEL120 mouse Furthermore, protein-protein interaction network analyses were performed by using multiple algorithms. Using module and hub protein analyses, we identified 16 modules for the proteins, 2 clusters for the phosphoproteins and selected the top 10 hub proteins. Finally, we identified 22 motifs using motif analysis of the phosphosites and found 17 newly identified motifs, while 6 motifs were experimentally verified for known protein kinases. The findings distinguished pSS patients from normal controls at the peripheral blood mononuclear cells level and revealed potential candidates for use in pSS diagnosis.

To assess the value of real-time three-dimensional echocardiography (RT-3DE) in evaluating changes in left atrial volume and function in type 2 diabetes mellitus (DM) and type 2 diabetic nephropathy (DN) patients.

104 control subjects, 109 DN patients, and 111 DM patients were recruited and underwent RT-3DE. Data pertaining to the left atrium were analyzed using the 3DQA software in order to determine left atrial maximum volume index (LAVImax), left atrial pre-systolic volume index (LAVIp), left atrial minimum volume index (LAVImin), total left atrial ejection fraction (LAEFt), passive left atrial ejection fraction (LAEFp), and active left atrial ejection fraction (LAEFa). Differences between these three groups and correlations between individual index values and E/e' ratios were additionally assessed.

LAVImax, LAVIp, and LAVImin were higher in the DN and DM groups relative to controls, whereas LAEFt and LAEFp were higher in controls relative to DM and DN patients (P < 0.05). LAVImax, LAVIp, and LAVImin in the DN group were significantly higher than those in the DM group, while LAEFt, LAEFp were higher in DM patients relative to DN patients (P < 0.05). The E/e' ratio was also found to be significantly correlated with LAVImax, LAVIp, and LAVImin.

Our results indicate that RT-3DE can be used to assess changes in left atrial volume and function in patients with diabetes and can be used to monitor disease progression-related damage to such left atrial functionality.

Our results indicate that RT-3DE can be used to assess changes in left atrial volume and function in patients with diabetes and can be used to monitor disease progression-related damage to such left atrial functionality.Chronic hepatitis B (CHB) has been reported to be associated with impaired prognosis for patients with nasopharyngeal carcinoma (NPC). However, the latent mechanism is unclear. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) induce immune suppression in CHB and promote the development of hepatocellular carcinoma. Lectin-type oxidized LDL receptor-1 (LOX-1) was recently identified as a specific marker for PMN-MSDC. We found NPC survivors with CHB had high levels of LOX-1+ PMN-MDSCs. LOX-1+ PMN-MDSCs significantly reduced T cell proliferation and activation. Endoplasmic reticulum stress was induced in LOX-1+ PMN-MDSCs. In addition, LOX-1+ PMN-MDSCs increased their expression of NOX2, a key reactive oxygen species (ROS)-related genes, and levels of ROS illustrated by the DCFDA test. The ROS inhibitor N-acetylcysteine abrogated the suppression of LOX-1+ PMN-MDSCs on T cell activation. The EBV DNA-positivity rate was higher in NPC survivors with CHB than in NPC patients without CHB. Those presenting with positive EBV DNA displayed higher LOX-1+ PMN-MDSC levels. LOX-1+ PMN-MDSCs suppressed the CD8+ T cell response against EBV. This study revealed LOX-1+ PMN-MDSC accumulation and activation in NPC survivors with CHB. LOX-1+ PMN-MDSCs might suppress the host immune response to EBV through ER stress/ROS pathway. These results explained the association of CHB with unfavorable NPC prognosis.Bnip3, which is regulated by Hif-1 in cells under oxygen deprivation, is a death related protein associated with autophagy and apoptosis. Hif-1 was reported to regulate autophagy to activate hepatic stellate cells (HSCs), while the specific molecular mechanism is vague. The possible mechanism of Hif-1 regulating autophagy of HSCs via Bnip3 was explored in this study. Bnip3 was detected in fibrotic liver tissues from humans and mice. Hif-1 was inhibited by chemical inhibitor and Bnip3 was detected in activated HSCs. The co-localization of Bnip3 and LC3B was captured by confocal microscopy and autophagic flow was assessed in Bnip3 siRNA transfected cells. Bnip3 interacted proteins were screened with mass spectrometry. The interaction of Bnip3 and vimentin was detected with co-immunoprecipitation and confocal microscopy. The results showed that Bnip3 was increased in fibrotic liver tissues and activated HSCs. link2 Hif-1 inhibition suppressed Bnip3 expression in activated HSCs. Bnip3 was partially co-localized with autophagosomes and Bnip3 inhibition suppessed autophagy in activated HSCs. Bnip3 interacted with vimentin and Bnip3 expression was inhibited as vimentin was inhibited in activated HSCs. link3 Conclusively, this study indicated that Bnip3 promoted autophagy and activation of HSCs, via interacting with vimentin, an intermediate filament protein with highly abundant expression in HSCs.5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare hereditary disease characterized by defects in folate and homocysteine metabolism. Individuals with inherited MTHFR gene mutations have a higher tendency to develop neurodegeneration disease as Alzheimer' disease and atherosclerosis. MTHFR is a rate-limiting enzyme catalyzing folate production, various SNPs/mutations in the MTHFR gene have been correlated to MTHFR deficiency. However, the molecular mechanisms underpinning the pathogenic effects of these SNPs/mutations have not been clearly understood. In the present study, we reported a severe MTHFR deficiency patient with late-onset motor dysfunction and sequenced MTHFR gene exons of the family. The patient carries an MD-associating SNP (rs748289202) in one MTHFR allele and the rs545086633 SNP with unknown disease relevance in the other. The rs545086633 SNP (p.Leu439Pro) results in an L439P substitution in MTHFR protein, and drastically decreases mutant protein expression by promoting proteasomal degradation. L439 in MTHFR is highly conserved in vertebrates. Our study demonstrated that p.Leu439Pro in MTHFR is the first mutation causing significant intracellular defects of MTHFR, and rs545086633 should be examined for the in-depth diagnosis and treatment of MD.

Triple-negative breast cancer (TNBC) is a special type of breast cancer, its tumor cell metastasis rate is much higher than other types, and at the same time has a high rate of postoperative recurrence, which significantly threatens the health of women. Thus, it is urgent to explore a new treatment for TNBC.

MiR-106a-5p was up-regulated in TNBC tissues and cells, and was positively correlated with the tumor grade, which indicated poor prognosis in TNBC patients. Mesenchymal stem cells (MSCs) can transport miR-106a-5p into TNBC cells via exosomes. Functional analysis showed exo-miR-106a-5p secreted by MSCs promoted tumor progression in TNBC cells. Furthermore, lncRNA HAND2-AS1 inhibited miR-106a-5p levels, and HAND2-AS1 was decreased in TNBC tissues and cells. Besides, overexpression of HAND2-AS1 reduced the secretion of exo-miR-106a-5p secretion from MSCs, thus suppressed TNBC development.

Our study revealed that HAND2-AS1 inhibited the growth of TNBC, which were mediated by the inhibitory effects of MSC-derived exosomal miR-106a-5p.