Arsenic trioxide alleviates atherosclerosis by inhibiting CD36-induced endocytosis and TLR4/NF-κB-induced inflammation in macrophage and ApoE-/- mice.

BACKGROUND: Inflammation and lipid accumulation are key events in atherosclerosis progression. Despite arsenic trioxide's (ATO) toxicity, at appropriate doses, it is a useful treatment for various diseases treatment. ATO prevents vascular restenosis; however, its effects on atherosclerotic plaque development and instability remain unclear. METHODS: ApoE-/- mice were fed high-fat diet for 4 months, and starting at the third month, ATO was intravenously administered every other day. Atherosclerotic lesion size, histological characteristics, and related protein and lipid profiles were assessed using samples from the aorta, carotid artery, and serum. The anti-inflammatory and anti-pyroptosis effects of ATO were investigated by stimulating RAW264.7 and THP-1 cell lines with oxidized low-density lipoprotein (ox-LDL) or lipopolysaccharide (LPS). RESULTS: ATO reduced atherosclerotic lesion formation and plasma lipid levels in ApoE-/- mice. In the serum and aortic plaques, ATO reduced the levels of pro-inflammatory factors, including interleukin (IL) 6 and tumor necrosis factor α, but increased IL-10 levels. Mechanistically, ATO promoted the CD36-mediated internalization of ox-LDL in a peroxisome proliferator-activated receptor γ-dependent manner. Furthermore, ATO downregulated Toll-like receptor 4 (TLR4) expression in plaques and macrophages and inhibited p65 nuclear translocation and IκBα degradation. ATO reduced macrophage pyroptosis by downregulating NLR family pyrin domain-containing 3 (NLRP3) expression and caspase 1 activation. CONCLUSION: ATO has potential atheroprotective effects, especially in macrophages. The mechanisms were inhibition of CD36-mediated foam cell formation and suppression of inflammatory responses and pyroptosis mediated by TLR4/nuclear factor κB and NLRP3 activation. Our findings provide evidence supporting the potential atheroprotective value of ATO.

Sepsis induced cardiotoxicity by promoting cardiomyocyte cuproptosis.

BACKGROUND: Currently, sepsis induced cardiotoxicity is among the major causes of sepsis-related death. The specific molecular mechanisms of sepsis induced cardiotoxicity are currently unknown. Therefore, the purpose of this paper is to identify the key molecule mechanisms for sepsis induced cardiotoxicity. METHODS: Original data of sepsis induced cardiotoxicity was derived from Gene Expression Omnibus (GEO; GSE63920; GSE44363; GSE159309) dataset. Functional enrichment analysis was used to analysis sepsis induced cardiotoxicity related signaling pathways. Our findings also have explored the relationship of cuproptosis and N6-Methyladenosine (m6A) in sepsis induced cardiotoxicity. Mice are randomly assigned to 3 groups: saline treatment control group, LPS group administered a single 5 mg/kg dose of LPS for 24 h, LPS + CD274 inhibitor group administered 10 mg/kg CD274 inhibitor for 24 h. RESULTS: Overall, expression of cuproptosis-related genes (CRGs) CD274, Ceruloplasmin (CP), Vascular endothelial growth factor A (VEGFA), Copper chaperone for cytochrome c oxidase 11 (COX11), chemokine C-C motif ligand 8 (CCL8), Mitogen-activated protein kinase kinase 1(MAP2K1), Amine oxidase 3 (AOC3) were significantly altered in sepsis induced cardiotoxicity. The results of spearman correlation analysis was significant relationship between differentially regulated genes (DEGs) of CRGs and the expression level of m6A methylation genes. GO and KEGG showed that these genes were enriched in response to interferon-beta, MHC class I peptide loading complex, proteasome core complex, chemokine receptor binding, TAP binding, chemokine activity, cytokine activity and many more. These findings suggest that cuproptosis is strongly associated with sepsis induced cardiotoxicity. CONCLUSION: In the present study, we found that cuproptosis were associated with sepsis induced cardiotoxicity. The CD274, CP, VEGFA, COX11, CCL8, MAP2K1, AOC3 genes are showing a significant difference expression in sepsis induced cardiotoxicity. Our studies have found significant correlations between CRGs and m6A methylation related genes in sepsis induced cardiotoxicity. These results provide insight into mechanism for sepsis induced cardiotoxicity.

L-serine combined with carboxymethyl chitosan guides amorphous calcium phosphate to remineralize enamel.

The aim of this study is to investigate a robust and stable calcium-phosphorus system to remineralize human early enamel caries lesions with nanocomplexes of carboxymethyl chitosan/L-serine/amorphous calcium phosphate (CMC-Ser-ACP) to develop an effective method for mimicking the amelogenin (AMEL) mineralization pattern through ACP assembly. A CMC-Ser-ACP nanocomplex solution was first synthesized by a chemical precipitation method, and then 1% sodium hypochlorite (NaClO) was added to induce ACP phase formation. The morphologies of the nanocomplexes were characterized by transmission electron microscopy (TEM), and zeta potential analysis and Fourier transform infrared spectroscopy (FTIR) were performed to detect surface charge and functional group changes. The subtle changes of the demineralized enamel models induced by the remineralization effect were observed by scanning electron microscopy (SEM) and X-ray diffraction (XRD). The CMC-Ser-ACP nanocomplex solution could be preserved without any precipitation for 45 days. After the application of NaClO and through the guidance of Ser, ACP nanoparticles transformed into relatively orderly arranged hydroxyapatite (HAP) crystals, generating an aprismatic enamel-like layer closely integrated with the demineralized enamel, which resulted in enhanced mechanical properties for the treatment of early enamel caries lesions. The CMC-Ser-ACP nanocomplex solution is a remineralization system with great solution stability, and when NaClO is added, it can rapidly regenerate an aprismatic enamel-like layer in situ on the demineralized enamel surface. This novel remineralization system has stable chemical properties and can greatly increase the therapeutic effects against early enamel caries.

Lyophilized mRNA-lipid nanoparticle vaccines with long-term stability and high antigenicity against SARS-CoV-2.

Advanced mRNA vaccines play vital roles against SARS-CoV-2. However, most current mRNA delivery platforms need to be stored at -20 °C or -70 °C due to their poor stability, which severely restricts their availability. Herein, we develop a lyophilization technique to prepare SARS-CoV-2 mRNA-lipid nanoparticle vaccines with long-term thermostability. The physiochemical properties and bioactivities of lyophilized vaccines showed no change at 25 °C over 6 months, and the lyophilized SARS-CoV-2 mRNA vaccines could elicit potent humoral and cellular immunity whether in mice, rabbits, or rhesus macaques. Furthermore, in the human trial, administration of lyophilized Omicron mRNA vaccine as a booster shot also engendered strong immunity without severe adverse events, where the titers of neutralizing antibodies against Omicron BA.1/BA.2/BA.4 were increased by at least 253-fold after a booster shot following two doses of the commercial inactivated vaccine, CoronaVac. This lyophilization platform overcomes the instability of mRNA vaccines without affecting their bioactivity and significantly improves their accessibility, particularly in remote regions.

Overexpression of lncRNA HOXA-AS2 promotes the progression of oral squamous cell carcinoma by mediating SNX5 expression.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common head and neck cancers. Long non-coding RNA HOXA-AS2 (lncRNA HOXA-AS2) have been extensively studied in various cancers. However, the expression and function of HOXA-AS2 in OSCC still remain unknown. The aim of this study is to investigate the roles of HOXA-AS2 in OSCC. METHODS: OSCC tissues and adjacent normal tissues were obtained from OSCC patients. RT-qPCR and Western blot assays were used to detect the expression of target genes in OSCC tissues or cells. Cells proliferation, migration and invasion were detected by CCK-8 and transwell assays, respectively. The target gene of HOXA-AS2 was confirmed by dual-luciferase reporter gene assay. RESULTS: We found that HOXA-AS2 expression was remarkably upregulated in OSCC tissues and cell lines. The downregulation of HOXA-AS2 inhibited cells proliferation, migration and invasion. Our bioinformatics analysis found that HOXA-AS2 can target miR-520c-3p, which was confirmed by dual-luciferase reporter gene assay. The expression of HOXA-AS2 was found to be negatively associated with miR-520c-3p in OSCC tissues. Moreover, sorting nexin 5 (SNX5), a downstream target of miR-520c-3p, was inhibited by miR-520c-3p overexpression. SNX5 was also increased in OSCC tissues and cell lines. Additionally, we found that the higher expression of SNX5 was strongly associated with the tumor grade of OSCC patients in Oncomine database. Most importantly, the knockdown of HOXA-AS2 induced cells apoptosis by promoting autophagy by regulating SNX5. CONCLUSION: HOXA-AS2 served an oncogene and promoted OSCC progression via the miR-520c-3p/SNX5 axis. Thus, HOXA-AS2 may be a new biomarker for diagnosis and treatment of OSCC.

Analysis and Validation of Differentially Expressed Ferroptosis-Related Genes in Regorafenib-Induced Cardiotoxicity.

Background: Although tyrosine kinase inhibitors (TKIs) constitute a type of anticancer drugs, the underlying mechanisms of TKI-associated cardiotoxicity remain largely unknown. Ferroptosis is a regulated cell death form that implicated in several tumors' biological processes. Our objective was to probe into the differential expression of ferroptosis-related genes in regorafenib-induced cardiotoxicity through multiple bioinformatics analysis and validation. Methods and Materials: Four adult human cardiomyocyte cell lines treated with regorafenib were profiled using Gene Expression Omnibus (GEO) (GSE146096). Differentially expressed genes (DEGs) were identified using DESeq2 in R (V.3.6.3). Then, Gene Ontology (GO) Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment Analysis, and Gene Set Enrichment Analysis (GSEA) were used to explore DEGs' bioinformatics functions and enriched pathways. We intersected DEGs with 259 ferroptosis-related genes from the FerrDb database. Finally, the mRNA levels of differentially expressed ferroptosis-related genes (DEFRGs) were validated in regorafenib-cultured cardiomyocytes to anticipate the link between DEFRGs and cardiotoxicity. Results: 747,1127,773 and 969 DEGs were screened out in adult human cardiomyocyte lines A, B, D, and E, respectively. The mechanism by which REG promotes cardiotoxicity associated with ferroptosis may be regulated by PI3K-Akt, TGF-beta, and MAPK. GSEA demonstrated that REG can promote cardiotoxicity by suppressing genes and pathways encoding extracellular matrix and related proteins, oxidative phosphorylation, or ATF-2 transcription factor network. After overlapping DEGs with ferroptosis-related genes, we got seven DEFRGs and found that ATF3, MT1G, and PLIN2 were upregulated and DDIT4 was downregulated. The ROC curve demonstrated that these genes predict regorafenib-induced cardiotoxicity well. Conclusion: We identified four DEFRGs which may become potential predictors and participate in the regorafenib-induced cardiotoxicity. Our findings provide possibility that targeting these ferroptosis-related genes may be an alternative for clinical prevention and therapy of regorafenib-related cardiotoxicity.

Efficacy of Fenestration Decompression for the Treatment of Oral and Maxillofacial Cysts.

Background: Surgery is the mainstay of treatment for oral and maxillofacial cysts. Compared with open surgery that will bring more harm to patients, fenestration decompression, as a surgical method with good curative effects and little damage, has received increasing attention in the treatment of oral and maxillofacial cysts. Methods: The clinical data of 135 patients with oral and maxillofacial cysts visited the Fifth Central Hospital of Tianjin between June 2019 and September 2021 were collected for retrospective analysis. Patients were assigned to two groups based on the treatment plan implemented: the control group (n = 64) treated with curettage of cysts and the observation group (n = 71) with fenestration decompression. Therapeutic efficacy parameters and surgical indicators were detected. Additionally, postoperative cyst, pain, complication rate, and recurrence, as well as life quality six months after treatment, were evaluated and compared. Results: In comparison with the control group, the observation group was observed to have a higher total effective rate, less operation time, shorter hospital stays, and less intraoperative bleeding (P < 0.05). In addition, the shrinkage rate, shrinkage volume, and postoperative density of the cyst cavity were higher in the observation group than in the control group (P < 0.05). The observation group also outperformed the control group with lower postoperative VAS score, complication rate, and half-year recurrence rate (P < 0.05). Furthermore, significantly better life quality was determined in the observation group after half a year of treatment (P < 0.05). Conclusion: Fenestration decompression is highly effective in treating oral and maxillofacial cysts, contributing to fewer complications, markedly relieved symptoms, shorter hospitalization time, well-preserved facial nerves, and low recurrence rate in the later period, which is worthy of clinical promotion.

A spectroscopic probe with FRET-ICT feature for thiophenol monitoring in real water samples.

Thiophenol (PhSH) is widely used in industry, however, it is extremely harmful to the environment and human health due to its high toxicity. In this work, we developed a new FRET-ICT-based ratiometric fluorescent and colorimetric probe (DMNP) for detecting PhSH. DMNP had an ultrahigh energy transfer efficiency (99.7%) and clear spacing of two emission peaks (133 nm). DMNP achieved a fast response to PhSH and exhibited drastic enhancement (over 2100 folds) of the fluorescence intensity ratio upon addition of PhSH. DMNP showed good linear response in the PhSH concentration ranges of 0.5-13 µM and 17.0-22.0 µM. Meanwhile, DMNP could also be applied to monitor PhSH in a variety of real water samples.

Dihydromyricetin protects against Doxorubicin-induced cardiotoxicity through activation of AMPK/mTOR pathway.

BACKGROUND: Doxorubicin (DOX) is a highly effective broad-spectrum antitumor agent, but its clinical administration is limited by self-induced cardiotoxicity. Dihydromyricetin (DHM) is a flavonoid compound extracted from the Japanese raisin tree. Evidence that DHM has neovascular protective properties makes it a candidate for studying cardiotoxicity prevention strategy. However, it remains unknown if DHM can protect against cardiotoxicity caused by DOX. PURPOSE: The present study was performed to evaluate the protective effect of DHM on DOX-induced cardiotoxicity in vivo and in vitro. METHODS: C57BL/6 mice were intraperitoneally injected with DOX to construct cardiac injury model in vivo, and AC16 cells were exposed to DOX to induce cell injury in vitro. Left ventricular function of mice were detected by echocardiography, the apoptosis of mice cardiac tissue and AC16 cells were detected by TUNEL and Hoechst33342/PI double staining. The expression of apoptosis and autophagy related proteins were detected by western blotting, immunohistochemical staining and immunofluorescence staining. RESULTS: Echocardiographic results showed that DOX-induced cardiotoxicity were significantly alleviated by DHM pretreatment. DOX induced cardiotoxicity of mice by inhibiting AMPK activation, increasing apoptosis and decreasing autophagy. However, under the same conditions, the heart tissue of DHM-pretreated mice showed increased autophagy and decreased apoptosis via activation AMPK/mTOR pathway. The same results were observed in vitro, and it was also found that DHM can inhibit the production of intracellular ROS in vitro. CONCLUSION: DHM protects against cardiotoxicity by inhibiting apoptosis and oxidative stress and it can allevate theautophagy inhibition caused by DOX through AMPK/mTOR pathway. DHM preconditioning may be a breakthrough in protecting DOX-induced cardiotoxicity in the future clinical applications.

A synergetic FRET/ICT platform-based fluorescence probe for ratiometric imaging of bisulfite in lipid droplets.

A deep-red emission and lipid droplets-targeted fluorescence probe (named ZFPy) for effective bioimaging of bisulfite was developed from flavone moiety and benzoindole derivative based on intramolecular charge transfer (ICT) and Förster resonance energy transfer (FRET) platform. ZFPy displayed promising fluorescence parameters including bright deep red fluorescence (615 nm), large Stokes shift (205 nm), extended emission window gap (140 nm), high absolute fluorescence quantum yield (4.1%) and stable emission signal output. In addition, ZFPy realized ratiometric fluorescence monitoring for SO2 derivatives with low detection limit (30 nM), preferable linearity, high sensitivity and selectivity. Interestingly, dual fluorophores (i.e. the donor moiety and 1,1,2,3-tetra-substituent-1H-benzo[e]indol-3-ium iodide moiety) released the same emission band about 475 nm to enhance the emission signal when ZFPy reacted with SO2 derivatives, to the best of our knowledge, this is the first synergetic FRET/ICT platform for fluorescence probe, which might effectively offer ZFPy a high sensitivity and low detection limit in the detection of SO2 derivatives. More importantly, ZFPy could image exogenous and endogenous SO2 derivatives in living HeLa, HepG2 and L-O2 cells with good biocompatibility and photostability. ZFPy also preferred to load on lipid droplets with high Pearson's coefficient (0.95).

Kinesin family member 20B regulates tongue cancer progression by promoting cell proliferation.

Oral cancer refers to the malignant tumors that occur in the oral cavity, of which 80% are squamous cell carcinomas. The incidence of oral cancer accounts for ~5% of the incidence of systemic malignancies, with rapid progression, extensive infiltration and poor prognosis. In the present study, Kinesin family member (KIF)20B, a member of Kinesin­6 family, was identified as a potential biomarker which could promote cancer progression. A total of 82 patients were recruited and KIF20B expression levels were investigated by immunohistochemistry, and were divided into high and low groups based on the median of KIF20B expression levels. The clinicopathological features and survival­associated data of the two groups were analyzed and the results were provided as a table and by a Kaplan­Meier plot, respectively. Additionally, KIF20B was successfully silenced in two tongue cancer cell lines, CAL­27 and TCA­8113. MTT and colony formation assay were performed to determine the changes of cell proliferation in knocked down­KIF20B cell lines. In addition, proliferation­associated proteins Ki67 and PCNA were investigated, by western blotting. In animal experiments, subcutaneous tumor formation was performed with control cells and cells with knocked down KIF20B, to determine the inhibitory effect of KIF20B in vivo. Firstly, it was found that there was significantly high expression levels of KIF20B in tongue cancer patients (P<0.05). Patients with high expression of KIF20B had poorer clinicopathological results including tumor differentiation level, lymph node metastasis and clinical stages. The overall survival and relapse­free survival of high­expression group were also poor. Secondly, after successful establishment of cells with knocked down KIF20B, this resulted in a notable reduction in cell proliferation in vitro. Subsequent western blotting further confirmed that Ki67 and PCNA expression levels had a significant decline. Finally, it was demonstrated that knocking down KIF20B could inhibit tumor volume growth in vivo. In conclusion, the high level of KIF20B in oral squamous cell carcinoma was significantly associated with poor clinicopathological features and survival. KIF20B might promote cancer development through enhancing cell proliferation in vitro, and might be a potential biomarker of oral squamous cell carcinoma.