Lipopolysaccharide binding protein resists hepatic oxidative stress by regulating lipid droplet homeostasis.

Oxidative stress-induced lipid accumulation is mediated by lipid droplets (LDs) homeostasis, which sequester vulnerable unsaturated triglycerides into LDs to prevent further peroxidation. Here we identify the upregulation of lipopolysaccharide-binding protein (LBP) and its trafficking through LDs as a mechanism for modulating LD homeostasis in response to oxidative stress. Our results suggest that LBP induces lipid accumulation by controlling lipid-redox homeostasis through its lipid-capture activity, sorting unsaturated triglycerides into LDs. N-acetyl-L-cysteine treatment reduces LBP-mediated triglycerides accumulation by phospholipid/triglycerides competition and Peroxiredoxin 4, a redox state sensor of LBP that regulates the shuttle of LBP from LDs. Furthermore, chronic stress upregulates LBP expression, leading to insulin resistance and obesity. Our findings contribute to the understanding of the role of LBP in regulating LD homeostasis and against cellular peroxidative injury. These insights could inform the development of redox-based therapies for alleviating oxidative stress-induced metabolic dysfunction.

Multiwalled Carbon Nanotubes-Reprogrammed Macrophages Facilitate Breast Cancer Metastasis via NBR2/TBX1 Axis.

In recent years, carbon nanotubes have emerged as a widely used nanomaterial, but their human exposure has become a significant concern. In our former study, we reported that pulmonary exposure of multiwalled carbon nanotubes (MWCNTs) promoted tumor metastasis of breast cancer; macrophages were key effectors of MWCNTs and contributed to the metastasis-promoting procedure in breast cancer, but the underlying molecular mechanisms remain to be explored. As a follow-up study, we herein demonstrated that MWCNT exposure in breast cancer cells and macrophage coculture systems promoted metastasis of breast cancer cells both in vitro and in vivo; macrophages were skewed into M2 polarization by MWCNT exposure. LncRNA NBR2 was screened out to be significantly decreased in MWCNTs-stimulated macrophages through RNA-seq; depletion of NBR2 led to the acquisition of M2 phenotypes in macrophages by activating multiple M2-related pathways. Specifically, NBR2 was found to positively regulate the downstream gene TBX1 through H3k27ac activation. TBX1 silence rescued NBR2-induced impairment of M2 polarization in IL-4 & IL-13-stimulated macrophages. Moreover, NBR2 overexpression mitigated the enhancing effects of MWCNT-exposed macrophages on breast cancer metastasis. This study uncovered the molecular mechanisms underlying breast cancer metastasis induced by MWCNT exposure.

Ropivacaine as a novel AKT1 specific inhibitor regulates the stemness of breast cancer.

BACKGROUND: Ropivacaine, a local anesthetic, exhibits anti-tumor effects in various cancer types. However, its specific functions and the molecular mechanisms involved in breast cancer cell stemness remain elusive. METHODS: The effects of ropivacaine on breast cancer stemness were investigated by in vitro and in vivo assays (i.e., FACs, MTT assay, mammosphere formation assay, transwell assays, western blot, and xenograft model). RNA-seq, bioinformatics analysis, Western blot, Luciferase reporter assay, and CHIP assay were used to explore the mechanistic roles of ropivacaine subsequently. RESULTS: Our study showed that ropivacaine remarkably suppressed stem cells-like properties of breast cancer cells both in vitro and in vivo. RNA-seq analysis identified GGT1 as the downstream target gene responding to ropivacaine. High GGT1 levels are positively associated with a poor prognosis in breast cancer. Ropivacaine inhibited GGT1 expression by interacting with the catalytic domain of AKT1 directly to impair its kinase activity with resultant inactivation of NF-κB. Interestingly, NF-κB can bind to the promoter region of GGT1. KEGG and GSEA analysis indicated silence of GGT1 inhibited activation of NF-κB signaling pathway. Depletion of GGT1 diminished stem phenotypes of breast cancer cells, indicating the formation of NF-κB /AKT1/GGT1/NF-κB positive feedback loop in the regulation of ropivacaine-repressed stemness in breast cancer cells. CONCLUSION: Our finding revealed that local anesthetic ropivacaine attenuated breast cancer stemness through AKT1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast cancer treatment.

TMEM16A enhances the activity of the Cdc42-NWASP signaling pathway to promote invasion and metastasis in oral squamous cell carcinoma.

OBJECTIVE: We explored the relationship between TMEM16A and metastasis and development in oral squamous cell carcinoma (OSCC). STUDY DESIGN: The University of Alabama at Birmingham and Gene Expression Profiling Interactive Analysis Databases were employed to analyze the relationship between the expression of TMEM16A and the survival of patients with OSCC. TMEM16A was knocked down and overexpressed in CAL27 and SCC-4 cells, respectively, and the malignant behavior and expression of key proteins were detected. The Cdc42-NWASP pathway was inhibited, and the effects of TMEM16A and the Cdc42-NWASP pathway on promoting the malignant behavior of cancer cells were verified. A xenograft tumor model was constructed, and tumor growth, cell proliferation index, apoptosis, and Cdc42-NWASP signal pathway activity were detected. RESULTS: The expression of TMEM16A in oral cancer tissues was significantly higher than in adjacent tissues, and mice with high expression of TMEM16A had shorter survival. Overexpression of TMTM16A could significantly promote the occurrence of cancer and reduce the apoptosis of cancer cells, whereas the activity of the Cdc42 pathway was higher. Knocking down TMEM16A or inhibiting the Cdc42-NWASP pathway could reverse these results. CONCLUSION: The activation of the Cdc42-NWASP pathway by high TMEM16A expression is closely related to OSCC and may become a new therapeutic target to prevent OSCC metastasis.

Advances in Medicinal Chemistry of Estrogen-related Receptor Alpha (ERRα) Inverse Agonists.

Estrogen-related receptor alpha (ERRα), a member of the nuclear receptor superfamily, is strongly expressed in breast cancer cells. Its overexpression is associated with poor prognosis in triple- negative Breast Cancer (TNBC). ERRα expression could be inhibited by the downregulation of upstream oncogenic growth factors mTOR, HER2, and PI3K. Low expression of ERRα could suppress the migration and angiogenesis of tumor cells by inhibiting the activity of its downstream signals VEGF and WNT11. Studies have confirmed that ERRα inverse agonists can inhibit ERRα expression to treat breast cancer. Inverse agonists of ERRα could disrupt the interactions of ERRα with its coactivators and inhibit tumor development. Existing ERRα inverse agonists have shown moderate efficacy in inhibiting the growth of breast cancer cells. Clinical inverse agonists of ERRα have not been found in the literature. This review focuses on the research progress and the structureactivity relationship of ERRα inverse agonists, providing guidance for the research and discovery of new anti-tumor compounds for TNBC.

Bioprospecting the American Alligator Peptidome for antiviral peptides against Venezuelan equine encephalitis virus.

The innate immune protection provided by cationic antimicrobial peptides (CAMPs) has been shown to extend to antiviral activity, with putative mechanisms of action including direct interaction with host cells or pathogen membranes. The lack of therapeutics available for the treatment of viruses such as Venezuelan equine encephalitis virus (VEEV) underscores the urgency of novel strategies for antiviral discovery. American alligator plasma has been shown to exhibit strong in vitro antibacterial activity, and functionalized hydrogel particles have been successfully employed for the identification of specific CAMPs from alligator plasma. Here, a novel bait strategy in which particles were encapsulated in membranes from either healthy or VEEV-infected cells was implemented to identify peptides preferentially targeting infected cells for subsequent evaluation of antiviral activity. Statistical analysis of peptide identification results was used to select five candidate peptides for testing, of which one exhibited a dose-dependent inhibition of VEEV and also significantly inhibited infectious titers. Results suggest our bioprospecting strategy provides a versatile platform that may be adapted for antiviral peptide identification from complex biological samples.

Changes in and effects of Kupffer cells on residual tumor after cryoablation in rabbit hepatic VX2 tumor.

OBJECTIVE: Cryoablation can directly kill tumor cells through sudden changes in temperature. It can also enhance lymphocyte function and cause distant tumor regression far from the ablation treatment area. In order to further explore the changes of immune function after cryoablation, the changes of Kupffer cells (KCs), the main immune cells in the liver, and their effects on untreated tumors in vivo were studied. METHODS: Rabbit VX2 liver cancer models were constructed. The growth of liver tumors was confirmed by ultrasound after transplantation for 3 weeks. Fifteen Japanese white rabbits were divided into a tumor control group and cryoablation group. Cryoablation group was treated with cryoablation of a single or partial tumor. Histologic and immunohistochemical changes of the treatment area and untreated tumor area before and after cryoablation were observed, and the phagocytic function changes of KCs around the untreated area and treatment area were observed by electron microscopy. RESULTS: Cryoablation areas showed necrosis, infiltration of inflammatory cells (including KCs), and fibrosis of tissue. The number of inflammatory cells in the unfrozen tumor area was increased in the same treated rabbit. There was a significant difference in the maximum diameter of unfrozen tumors between the frozen group and control group at 15th days after cryoablation (P<0.05), while the difference was not obvious at the 3rd and 7th day (P>0.05). Electron microscopy showed that the number of debris fragments engulfed by KCs around the tumor after cryoablation was significantly higher than that of the control group. In the same rabbit, we compared the amount of debris between tissue surrounding the unfrozen area and around the cryoablation area. There was a significant difference on the 3rd day after cryoablation, P=0.043, while there was no significant difference on the 7th day, P=0.348. CONCLUSION: After cryoablation, inflammatory cells aggregated around the cryoablated area. The activity of KCs had been increased and the function of phagocytosis enhanced. KCs had a certain inhibitory effect on the untreated tumor in the same animal at the early stage (within 15 days), but it was not enough to restrain the growth of the untreated tumors.

Peptide-TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens.

Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.

A 7-Hydroxybenzoxazinone-Containing Fluorescence Turn-On Probe for Biothiols and Its Bioimaging Applications.

In this work, a novel 7-hydroxybenzoxazinone-based fluorescent probe (PBD) for the selective sensing of biothiols is reported. Upon treatment with biothiols, PBD shows a strong fluorescence enhancement (up to 70-fold) and a large Stokes shift (155 nm). Meanwhile, this probe exhibits high resistance to interference from other amino acids and competing species. PBD features good linearity ranges with a low detection limit of 14.5 nM for glutathione (GSH), 17.5 nM for cysteine (Cys), and 80.0 nM for homocysteine (Hcy), respectively. Finally, the potential utility of this probe for biothiol sensing in living HeLa cells is demonstrated.

[Bronchial glomus tumor: report of 2 cases and review of the literature].

OBJECTIVE: Glomus tumor is a small, predominantly benign tumor, and typically occurs in the soft tissues, rarely in bronchus. The aim of this study was to discuss the clinical manifestation, histology, diagnosis and differential diagnosis of bronchial glomus tumor. METHODS: We studied the histopathological and immunohistochemical results of 2 cases with bronchial glomus tumor. One case was diagnosed by bronchoscopic biopsy, and another by surgery. We searched Wanfang, VIP, CNKI and PubMed database for related articles with key word "bronchial glomus tumor" both in English and in Chinese for literature review. RESULTS: Fiberoptic bronchoscopy demonstrated a bronchial neoplasm in both 2 cases. For Case one, the tumor was pink under fluorescence bronchoscopy, and was histologically composed of groups of nuclear-irregular round cells in interstices, with pale staining plasma and unclear boundary. Immunohistochemically, cytokeratin (CK) was negative, while vimentin and CD34 vascular endothelial cell were positive, smooth muscle actin (SMA) weakly positive, and Synaptophysin partially positive in tumor cells. These results led to the diagnosis of bronchial glomus tumor of right upper lobe bronchus. The tumor of Case two was histologically from the right main bronchus mesechyma, and it invaded into submucosa, but not involving the tracheal cartilage. Histological examination showed groups of medium sized tumor cells with round nuclei, and abundance of interstitial vasculature. No cellular atypia or mitoses were observed. Immunohistochemical staining demonstrated positive reactivity for vimentin, SMA and CD99. Pathological diagnosis was right main bronchus glomus tumor (malignant potential indeterminacy). We identified 16 studies from databases, of which 15 studies including 15 cases (12 males, 3 females) were applicable. Age of onset ranged from 20 to 79 years. The lesion was in the left main bronchus in 8 cases, the right main broncus in 2, the right middle lobe bronchus in 3, and the right upper lobe bronchus in 2 cases. The tumor size ranged from 0.7 to 6.5 cm. Cough, dyspnea with or without fever were observed in 7 patients. Seven cases had blood in phlegm, and 4 patients showed pulmonary atelectasis. All cases showed negative CK staining and positive SMA staining. CONCLUSION: Bronchial glomus tumor usually lacks clinical manifestations, and is often misdiagnosed as bronchial asthma. It can be classified as solid glomus tumor, ball hemangioma, ball vascular leiomyoma by histopathology. Glomus tumors show positive immunohistochemical stainings for vimentin and smooth muscle actin (SMA), and are usually negative for cytokeratin (CK) and epithelial markers. Clinical differential diagnoses such as sclerosing hemangioma, hemangiopericytoma, carcinoid tumor and epithelial tumor should be considered.

[Comparison of chemical components between Baishao and Chishao water extracts and their effects on proliferation of rat thoracic aorta smooth muscle cells].

OBJECTIVE: To compare the chemical components in Baishao and Chishao water extracts and investigate their effects on the proliferation of rat thoracic aorta smooth muscle cells in vitro. METHODS: The contents and chemical structures of monomers separated from the water extracts of Baishao and Chishao were analyzed using high-performance liquid chromatography and mass spectroscopy. Rat thoracic aorta smooth muscle cell line A7r5 and its platelet-derived growth factor-BB (PDGF-BB)-induced proliferation model were exposed to different concentrations of Baishao and Chishao water extracts, and the cell viability was analyzed by mitochondrial-dependent reduction of MTT and real-time cell analyzer. RESULTS: The growth of A7r5 cells was significantly stimulated by 300 µg/ml Baishao water extract (P<0.01), but Chishao water extract produced no such effect (P>0.05). In PDGF-BB-induced cell proliferation model, the cell growth was significantly suppressed by 100-500 µg/ml Chishao water extract (P<0.01), while Baishao water extract showed no obvious effect on the cell proliferation (P>0.05). CONCLUSION: Baishao and Chishao water extracts have different chemical components and produce different biological effects.

[Lung cancer with marked blood eosinophilia: case report and literature review].

OBJECTIVE: To study the clinical characteristics and significance of blood eosinophilia in lung cancer. METHODS: A case of lung cancer with eosinophilia in the peripheral blood was analyzed, and the related literature was reviewed. RESULTS: A 80-year-old male patient presented with chest pain was admitted to this hospital. Chest CT scan showed a cavity in the right upper lung. Peripheral blood leukocyte count was 2.15 x 10(9)/L, of which 16.9% was mature eosinophils. Histological examination of the biopsy specimens obtained under CT guidance confirmed the diagnosis of lung squamous cell carcinoma. There was also evidence of metastasis to the bones. CONCLUSIONS: Paraneoplastic eosinophilia is uncommon in solid malignancies and indicative of tumor dissemination with generally poor prognosis.