Nonreciprocal magnon blockade based on nonlinear effects.

We present an alternative scheme to achieve nonreciprocal unconventional magnon blockade (NUMB) in a hybrid system formed by two microwave cavities and one yttrium iron garnet (YIG) sphere, where the pump and signal cavities interact nonlinearly with each other and the signal cavity is coupled to the YIG sphere. It is found that the nonlinear coupling occurs between the pump cavity and magnon modes due to the dispersive interactions among three bosonic modes. Meanwhile, the Kerr nonlinearity is present in the pump cavity. Based on these nonlinear effects, a nonreciprocal magnon blockade could be achieved with the help of the weak parametric driving of the pump cavity. The present work provides an alternative method to prepare single magnon resource, which may be helpful for quantum information processing.

Identification of a cuproptosis and copper metabolism gene-related lncRNAs prognostic signature associated with clinical and immunological characteristics of hepatocellular carcinoma.

Background: The relationship between cuproptosis and HCC is still in the exploratory stage. Long noncoding RNAs (lncRNAs) have recently been linked to the progression of hepatocellular carcinoma (HCC). However, the clinical significance of lncRNAs associated with cuproptosis remains unclear. Methods: Based on The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) dataset, we identified characteristic prognostic lncRNAs by univariate, LASSO, and multifactorial regression analysis, and constructed a prognostic signature of cuproptosis-related lncRNAs in HCC. The role of lncRNAs were identified through CCK-8, clone formation in Huh-7 cells with high expression of FDX1. Prognostic potential of the characteristic lncRNAs was evaluated in each of the two cohorts created by randomly dividing the TCGA cohort into a training cohort and a test cohort in a 1:1 ratio. Immune profiles in defined subgroups of cuproptosis-related lncRNA features as well as drug sensitivity were analyzed. Results: We constructed a multigene signature based on four characteristic prognostic lncRNAs (AL590705.3, LINC02870, KDM4A-AS1, MKLN1-AS). These four lncRNAs participated in the development of cuproptosis. HCC patients were classified into high-risk and low-risk groups based on the median value of the risk score. The receiver operating characteristic curve area under the curve values for 1-, 3-, and 5-year survival were 0.773, 0.728, and 0.647, respectively, for the training cohort, and 0.764, 0.671, and 0.662, respectively, for the test cohort. Univariate and multifactorial regression analyses indicated that this prognostic feature was an independent prognostic factor for HCC. Principal component analysis plots clearly distinguished between low- and high-risk patients in terms of their probability of survival. Furthermore, gene set enrichment analysis showed that a variety of processes associated with tumor proliferation and progression were enriched in the high-risk group compared with the low-risk group. Moreover, there were significant differences in the expression of immune cell subpopulations, immune checkpoint genes, and potential drug screening, which provided distinct therapeutic recommendations for individuals with various risks. Conclusions: We constructed a novel cuproptosis-associated lncRNA signature with a significant predictive value for the prognosis of patients with HCC. Cuproptosis-associated lncRNAs are associated with the tumor immune microenvironment of HCC and even the efficacy of tumor immunotherapy.

Hypothermia Protects against Ischemic Stroke through Peroxisome-Proliferator-Activated-Receptor Gamma.

Ischemic stroke (IS) remains a global public health burden and requires novel strategies. Hypothermia plays a beneficial role in central nervous system diseases. However, the role of hypothermia in IS has not yet been elucidated. In this study, we determined the role of hypothermia in IS and explored its underlying mechanisms. The IS phenotype was detected based on infarct size, infarct volume, and brain edema in mice. Neuroinflammation was evaluated by the activation of microglial cells and the expression of inflammatory genes after ischemia/reperfusion (I/R) and oxygen-glucose deprivation/reperfusion (OGD/R). Neuronal cell apoptosis, cleaved caspase-3 and Bax/Bcl-2 expressions, cell viability, and lactate dehydrogenase (LDH) release were detected after I/R and OGD/R. Blood-brain barrier (BBB) permeability was calculated based on Evans blue extravasation, tight junction protein expression, cell viability, and LDH release after I/R and OGD/R. The expression of peroxisome proliferator-activated receptor gamma (PPARγ) was assessed after OGD/R. Our results suggested that hypothermia significantly reduced infarct size, brain edema, and neuroinflammation after I/R. Hypothermia increased PPARγ expression in microglial cells after OGD/R. Mechanistic studies revealed that hypothermia was a protectant against IS, including attenuated apoptosis of neuronal cells and BBB disruption after I/R and OGD/R, by upregulating PPARγ expression. The hypothermic effect was reversed by GW9662, a PPARγ inhibitor. Our data showed that hypothermia may reduce microglial cell-mediated neuroinflammation by upregulating PPARγ expression in microglial cells. Targeting hypothermia may be a feasible approach for IS treatment.

microRNA-455-5p alleviates neuroinflammation in cerebral ischemia/reperfusion injury.

Neuroinflammation is a major pathophysiological factor that results in the development of brain injury after cerebral ischemia/reperfusion. Downregulation of microRNA (miR)-455-5p after ischemic stroke has been considered a potential biomarker and therapeutic target for neuronal injury after ischemia. However, the role of miR-455-5p in the post-ischemia/reperfusion inflammatory response and the underlying mechanism have not been evaluated. In this study, mouse models of cerebral ischemia/reperfusion injury were established by transient occlusion of the middle cerebral artery for 1 hour followed by reperfusion. Agomir-455-5p, antagomir-455-5p, and their negative controls were injected intracerebroventricularly 2 hours before or 0 and 1 hour after middle cerebral artery occlusion (MCAO). The results showed that cerebral ischemia/reperfusion decreased miR-455-5p expression in the brain tissue and the peripheral blood. Agomir-455-5p pretreatment increased miR-455-5p expression in the brain tissue, reduced the cerebral infarct volume, and improved neurological function. Furthermore, primary cultured microglia were exposed to oxygen-glucose deprivation for 3 hours followed by 21 hours of reoxygenation to mimic cerebral ischemia/reperfusion. miR-455-5p reduced C-C chemokine receptor type 5 mRNA and protein levels, inhibited microglia activation, and reduced the production of the inflammatory factors tumor necrosis factor-α and interleukin-1ß. These results suggest that miR-455-5p is a potential biomarker and therapeutic target for the treatment of cerebral ischemia/reperfusion injury and that it alleviates cerebral ischemia/reperfusion injury by inhibiting C-C chemokine receptor type 5 expression and reducing the neuroinflammatory response.

Retraction: 8-bromo-7-methoxychrysin targets NF-κB and FoxM1 to inhibit lung cancer stem cells induced by pro-inflammatory factors.

[This retracts the article DOI: 10.7150/jca.30143.].

Large and robust mechanical squeezing of optomechanical systems in a highly unresolved sideband regime via Duffing nonlinearity and intracavity squeezed light.

We propose a scheme to generate strong and robust mechanical squeezing in an optomechanical system in the highly unresolved sideband (HURSB) regime with the help of the Duffing nonlinearity and intracavity squeezed light. The system is formed by a standard optomechanical system with the Duffing nonlinearity (mechanical nonlinearity) and a second-order nonlinear medium (optical nonlinearity). In the resolved sideband regime, the second-order nonlinear medium may play a destructive role in the generation of mechanical squeezing. However, it can significantly increase the mechanical squeezing (larger than 3dB) in the HURSB regime when the parameters are chosen appropriately. Finally, we show the mechanical squeezing is robust against the thermal fluctuations of the mechanical resonator. The generation of large and robust mechanical squeezing in the HURSB regime is a combined effect of the mechanical and optical nonlinearities.

Large mechanical squeezing beyond 3dB of hybrid atom-optomechanical systems in a highly unresolved sideband regime.

We propose a scheme for the generation of strong mechanical squeezing beyond 3dB in hybrid atom-optomechanical systems in the highly unresolved sideband (HURSB) regime where the decay rate of cavity is much larger than the frequency of the mechanical oscillator. The system is formed by two two-level atomic ensembles and an optomechanical system with cavity driven by two lasers with different amplitudes. In the HURSB regime, the squeezing of the movable mirror can not be larger than 3dB if no atomic ensemble or only one atomic ensemble is put into the optomechanical system. However, if two atomic ensembles are put into the optomechanical system, the strong mechanical squeezing beyond 3dB is achieved even in the HURSB regime. Our scheme paves the way toward the implementation of strong mechanical squeezing beyond 3dB in hybrid atom-optomechanical systems in experiments.

8-bromo-7-methoxychrysin targets NF-κB and FoxM1 to inhibit lung cancer stem cells induced by pro-inflammatory factors.

We have previously reported that 8-bromo-7-methoxychrysin (BrMC), a novel synthetic derivative of chrysin, was demonstrated anti-tumor activities against several human cancers, including lung cancer. Interaction between inflammation and cancer stem cell are recently increasingly recognized in tumorigenesis and progression. The purpose of this study was to investigate whether BrMC inhibits lung cancer stemness of H460 cells induced by inflammatory factors (TGF-ß combined with TNF-α) and its potential mechanism. Our results showed that BrMC inhibited lung cancer stemness, as validated by enhanced self-renewal ability, higher in vitro tumorigenicity, and increased expression of CD133, CD44, Bmi1 and Oct4 in H460 cells administered TNF-α after prolonged induction by TGF-ß, in a concentration-dependent manner. Both NF-κB inhibition by SN50 and FoxM1 suppression by thiostrepton (THI) prompted the inhibition of BrMC on lung CSCs. Conversely, overexpression of NF-κBp65 significantly antagonized the above effects of BrMC. Meanwhile, overexpression of FoxM1 also significantly compromised BrMC function on suppression of FoxM1 and NF-κBp65 as well as stemness of lung CSCs. Our results suggest that activation of NF-κB and FoxM1 by cytokines facilitate the acquisition CSCs phenotype, and compromise the chemical inhibition, which may represent an effective therapeutic target for treatment of human lung cancer. Moreover, BrMC may be a potential promising candidate for targeting NF-κB/ FoxM1 to prevent the tumorigenesis under inflammatory microenvironment.

DHA inhibits protein degradation more efficiently than EPA by regulating the PPARγ/NFκB pathway in C2C12 myotubes.

This study was conducted to evaluate the mechanism by which n-3 PUFA regulated the protein degradation in C2C12 myotubes. Compared with the BSA control, EPA at concentrations from 400 to 600 µM decreased total protein degradation (P < 0.01). However, the total protein degradation was decreased when the concentrations of DHA ranged from 300 µM to 700 µM (P < 0.01). DHA (400 µM, 24 h) more efficiently decreased the I κ B α phosphorylation and increased in the I κ B α protein level than 400 µM EPA (P < 0.01). Compared with BSA, 400 µM EPA and DHA resulted in a 47% or 68% induction of the NF κ B DNA binding activity, respectively (P < 0.01). Meanwhile, 400 µM EPA and DHA resulted in a 1.3-fold and 2.0-fold induction of the PPAR γ expression, respectively (P < 0.01). In C2C12 myotubes for PPAR γ knockdown, neither 400 µM EPA nor DHA affected the levels of p-I κ B α , total I κ B α or NF κ B DNA binding activity compared with BSA (P > 0.05). Interestingly, EPA and DHA both still decreased the total protein degradation, although PPAR γ knockdown attenuated the suppressive effects of EPA and DHA on the total protein degradation (P < 0.01). These results revealed that DHA inhibits protein degradation more efficiently than EPA by regulating the PPAR γ /NF- κ B pathway in C2C12 myotubes.

5-allyl-7-gen-difluoromethoxychrysin enhances TRAIL-induced apoptosis in human lung carcinoma A549 cells.

BACKGROUND: 5-allyl-7-gen-difluoromethoxychrysin (AFMC) is a novel synthetic analogue of chrysin that has been reported to inhibit proliferation in various cancer cell lines. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent. METHODS: The cytotoxicity of A549 and WI-38 cells were determined using colorimetry. Apoptosis was detected by flow cytometry (FCM) after propidium iodide (PI) fluorescence staining and agarose gel electrophoresis. Caspase activities were evaluated using enzyme-linked immunosorbent assay (ELISA).The expressions of DR4 and DR5 were analyzed using FCM and western blot. RESULTS: Subtoxic concentrations of AFMC sensitize human non-small cell lung cancer (NSCLC) A549 cells to TRAIL-mediated apoptosis. Combined treatment of A549 cells with AFMC and TRAIL significantly activated caspase-3, -8 and -9. The caspase-3 inhibitor zDEVD-fmk and the caspase-8 inhibitor zIETD-fmk blocked the apoptosis of A549 cells induced by co-treatment with AFMC and TRAIL. In addition, we found that treatment of A549 cells with AFMC significantly induced the expression of death receptor 5 (DR5). AFMC-mediated sensitization of A549 cells to TRAIL was efficiently reduced by administration of a blocking antibody or small interfering RNAs against DR5. AFMC also caused increase of the Sub-G1 cells by TRAIL treatment and increased the expression levels of DR5 in other NSCLC H460 and H157 cell lines. In contrast, AFMC-mediated induction of DR5 expression was not observed in human embryo lung WI-38 cells, and AFMC did not sensitize WI-38 cells to TRAIL-induced apoptosis. CONCLUSIONS: AFMC synergistically enhances TRAIL-mediated apoptosis in NSCLC cells through up-regulating DR5 expression.

[Relevance of vasoactive intestinal peptide and total bronchial mucin in rat lung.].

Vasoactive intestinal peptide (VIP) is a neuropeptide with potent bronchodilator, immunomodulator, and anti-inflammatory properties, and thus has biological properties capable of counteracting all major features of the asthmatic response. However, the effect of VIP on bronchial mucin secretion remains unclear. In order to observe the influence of VIP on bronchial mucin, the present study was designed to observe the correlation between VIP and total bronchial mucin changes under different time of ozone stress in rat lung. Sixty-four Sprague-Dawley rats were used in the experiment. Under different time of ozone stress, VIP content in lung homogenate was analyzed by radioimmunoassay, and changes in total bronchial mucin in the lung were analyzed by calculating the goblet cell hyperplasia ratio and the epithelial cell mucus occupying ratio from the periodic acid-Schiff reaction (PAS) staining. The results showed that, at early stage of respiratory tract injury, VIP did not change significantly, while the total bronchial mucin secretion increased; with the development of damage, the secretion of VIP increased by compensation, followed by a decrease in total bronchial mucin; with further injury, the numbers of pulmonary endocrine VIP positive nerve fibers and endocrine cells decreased, but bronchial mucin volume gradually increased. It is concluded that the secretion of VIP is negatively correlated with the secretion of bronchial mucin during the development of inflammation.

Wound repair and proliferation of bronchial epithelial cells regulated by CTNNAL1.

Adhesion molecules play vital roles in airway hyperresponsiveness (AHR) or airway inflammation. Our previous study indicated that adhesion molecule catenin alpha-like 1 (CTNNAL1) is relevant closely to asthma susceptibility, but its biological function or significance is still unclear. In the present study, we observed the temporal and spatial distribution of CTNNAL1 expression in mouse lung tissue with the OVA-sensitized asthma model and found that the level of CTNNAL1 mRNA showed a prominent negative correlation with pulmonary resistance (R(L)). To study the function of CTNNAL1 in airway, effects of CTNNAL1 on proliferation and wound repair activity of human bronchial epithelial cells (HBEC) was investigated with antisense oligonucleotide (ASO) technique. The results showed that: (1) CTNNAL1 ASO could decelerate the repairing velocity and proliferation of HBEC; (2) CTNNAL1 expression was increased on the edge cells of mechanic wounded area in culture; (3) extracellular matrix component fibronectin (Fn) obviously promoted wound repair activity and proliferation of HBEC, which could be blocked by CTNNAL1 ASO; (4) Western blot showed that Fn could promote FAK phosphorylation, which also be inhibited by CTNNAL1 ASO. In conclusion, the level of CTNNAL1 mRNA expression is highly correlated to airway resistance; CTNNAL1 may contribute to the wound repair and proliferation of HBEC. Furthermore, it may serve to Fn mediated cell-extracellular adhesion and its signal transduction.

[Effect of vasoactive intestinal peptide and epidermal growth factor on the adhesion of eosinophils to bronchial epithelial cells].

OBJECTIVE: To investigate the effect of intrapulmonary regulatory peptides on adhesion of eosinophils (EOS) to bronchial epithelial cells (BECs). METHODS: Two regulatory peptides, namely vasoactive intestinal peptide (VIP) and epidermal growth factor (EGF) were investigated. VIP and EGF were observed on the secretion of ILs and expression of intercellular adhesion molecule-1 (ICAM-1). RESULTS: VIP and EGF could decrease ILs secretion and ICAM-1 expression. CONCLUSION: VIP and EGF inhibited the adhesion of EOS to BEC in the inflammatory process to lighten the airway inflammation.

Regulatory peptides modulate adhesion of polymorphonuclear leukocytes to bronchial epithelial cells through regulation of interleukins, ICAM-1 and NF-kappaB/IkappaB.

A complex network of regulatory neuropeptides controls airway inflammation reaction, in which airway epithelial cells adhering to and activating leukocytes is a critical step. To study the effect of intrapulmonary regulatory peptides on adhesion of polymorphonuclear leukocytes (PMNs) to bronchial epithelial cells (BECs) and its mechanism, several regulatory peptides including vasoactive intestinal peptide (VIP), epidermal growth factor (EGF), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP), were investigated. The results demonstrated that VIP and EGF showed inhibitory effects both on the secretion of IL-1, IL-8 and the adhesion of PMNs to BECs, whereas ET-1 and CGRP had the opposite effect. Anti-intercellular adhesion molecule-1 (ICAM-1) antibody could block the adhesion of PMNs to ozone-stressed BECs. Using immunocytochemistry and reverse transcription-polymerase chain reaction (RT-PCR), it was shown that VIP and EGF down-regulated the expression of ICAM-1 in BECs, while ET-1 and CGRP up-regulated ICAM-1 expression. NF-kappaB inhibitor MG132 blocked ICAM-1 expression induced by ET-1 and CGRP. Furthermore, in electric mobility shift assay (EMSA), VIP and EGF restrained the binding activity of NF-kappaB to the NF-kappaB binding site within the ICAM-1 promoter in ozone-stressed BECs, while CGRP and ET-1 promoted this binding activity. IkappaB degradation was consistent with NF-kappaB activation. These observations indicate that VIP and EGF inhibit inflammation, while ET-1 and CGRP enhance the inflammation reaction.

Wound repair and proliferation of bronchial epithelial cells enhanced by bombesin receptor subtype 3 activation.

The present study was designed to investigate the role of bombesin receptor subtype 3 (BRS-3) in airway wound repair. The results showed that: (1) There was few expression of BRS-3 mRNA in the control group. In contrast, the expression of BRS-3 mRNA was gradually increased in the early 2 days, and peaked on the fourth day, and then decreased in the ozone-stressed AHR animal. BRS-3 mRNA was distributed in the ciliated columnar epithelium, monolayer columnar epithelium cells, scattered mesenchymal cells and Type II alveolar cells; (2) The wound repair and proliferation of bronchial epithelial cells (BECs) were accelerated in a concentration-dependent manner by BRS-3 activation with P3513, which could be inhibited by PKA inhibitor H89. The study demostrated that activation of BRS-3 may play an important role in wound repair of AHR.

Combination of telomerase antisense oligonucleotides simultaneously targeting hTR and hTERT produces synergism of inhibition of telomerase activity and growth in human colon cancer cell line.

AIM: To investigate synergism of inhibition of telomerase activity and proliferation of human colon cancer cells by combination of telomerase antisense oligonucleotides (ASODNs) simultaneously targeting human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) in vitro. METHODS: ASODN of hTR and ASODN of hTERT were transfected into human colon cancer SW480 cells by liposomal transfection reagents. Telomerase activity of SW480 cells was examined using telomeric repeat amplification protocol (TRAP)-enzyme-linked immunosorbent assay (PCR-ELISA). Proliferation activity of SW480 cells was tested by methyl thiazolyl tetrazolium assay. Apoptosis and cell cycle were analyzed by flow cytometry. RESULTS: The telomerase activity and cell survival rate in SW480 cells transfected with 0.2 mumol/L of ASODN of hTR or ASODN of hTERT for 24-72 h were significantly decreased in a time-dependent manner compared with those after treatment with sense oligonucleotides and untreated (telomerase activity: 24 h, 73%, 74% vs 99%, 98%; 48 h, 61%, 55% vs 98%, 99%; 72 h, 41%, 37% vs 99%, 97%; P<0.01; cell survival rate: 24 h, 88%, 86% vs 94%, 98%; 48 h, 49%, 47% vs 94%, 97%; 72 h, 44%, 42% vs 92%, 96%; P<0.01). Moreover, the telomerase activity and the cell survival rate in SW480 cells treated by the combination of telomerase anti-hTR and anti-hTERT were more significantly suppressed than single anti-hTR or anti-hTERT (telomerase activity: 24 h, 59% vs 73%, 74%; 48 h, 43% vs 61%, 55%; 72 h, 18% vs 41%, 37%; P<0.01; cell survival rate: 24 h, 64% vs 88%, 86%; 48 h, 37% vs 49%, 47%; 72 h, 25% vs 44%, 42%; P<0.01). Meanwhile, the apoptosis rates in the combination group were markedly increased compared with those in the single group (24 h, 18.0% vs 7.2%, 7.4%; 48 h, 23.0% vs 13.0%, 14.0%; 72 h, 28.6% vs 13.2%, 13.75; P<0.01). Cells in combination group were arrested at G(0)/G(1) phase. CONCLUSION: Telomerase anti-hRT and anti-hTERT suppress telomerase activity, and inhibit growth of human colon cancer cells probably via induction of apoptosis and retardation of cell cycle. Additionally, combined use of telomerase ASODNs targeting both hTR and hTERT yields synergistic action selective for human colon cancer.

[Inhibitory effect of alveolar macrophages on the proliferation of pulmonary fibroblasts].

The effect of alveolar macrophages (AM) harvested from Wistar rats by lung lavage on proliferation of human embryo pulmonary fibroblasts in culture was investigated. It was observed that supernatants of AM decreased the uptake of (3)H TdR by the pulmonary fibroblasts. The AM activated with opsonized zymosan (OPZ) showed a stronger inhibitory effect on fibroblast proliferation compared with inactivated AM. Following pretreatment with indomethacin, the inhibitory effect of AM was abolished and reversed to stimulatory effect on pulmonary fibroblast proliferation. The PGE content in AM supernatant was measured with radioimmunoassay. It was observed that the inhibitory effect of AM was highly correlated to prostaglandin (PGE) content in the supernatant of AM. The results suggest that AM has both inhibitory and stimulatory effects on the proliferation of pulmonary fibroblast; the inhibitory effect is primary under normal conditions. This inhibitory action is mainly due to PGE secreted from AM. It is, therefore, suggested that AM plays an important role in suppressing pulmonary fibrosis under normal conditions.