Development and validation of a clinical and ultrasound features-based nomogram for preoperative differentiation of renal urothelial carcinoma and central renal cell carcinoma.

PURPOSE: This study aimed to develop and validate an ultrasound (US)-based nomogram for the preoperative differentiation of renal urothelial carcinoma (rUC) from central renal cell carcinoma (c-RCC). METHODS: Clinical data and US images of 655 patients with 655 histologically confirmed malignant renal tumors (521 c-RCCs and 134 rUCs) were collected and divided into training (n = 455) and validation (n = 200) cohorts according to examination dates. Conventional US and contrast-enhanced US (CEUS) tumor features were analyzed to determine those that could discriminate rUC from c-RCC. Least absolute shrinkage and selection operator regression was applied to screen clinical and US features for the differentiation of rUC from c-RCC. Using multivariate logistic regression analysis, a diagnostic model of rUC was constructed and visualized as a nomogram. The diagnostic model's performance was assessed in the training and validation cohorts by calculating the area under the receiver operating characteristic curve (AUC) and calibration plot. Decision curve analysis (DCA) was used to assess the clinical usefulness of the US-based nomogram. RESULTS: Seven features of both clinical features and ultrasound imaging were selected to build the diagnostic model. The nomogram achieved favorable discrimination in the training (AUC = 0.996, 95% CI: 0.993-0.999) and validation (AUC = 0.995, 95% CI: 0.974, 1.000) cohorts, and good calibration (Brier scores: 0.019 and 0.016, respectively). DCA demonstrated the clinical usefulness of the US-based nomogram. CONCLUSION: A noninvasive clinical and US-based nomogram combining conventional US and CEUS features possesses good predictive value for differentiating rUC from c-RCC.

Low-Intensity Ultrasound Causes Direct Excitation of Auditory Cortical Neurons.

Cochlear implantation is the first-line treatment for severe and profound hearing loss in children and adults. However, deaf patients with cochlear malformations or with cochlear nerve deficiencies are ineligible for cochlear implants. Meanwhile, the limited spatial selectivity and high risk of invasive craniotomy restrict the wide application of auditory brainstem implants. A noninvasive alternative strategy for safe and effective neuronal stimulation is urgently needed to address this issue. Because of its advantage in neural modulation over electrical stimulation, low-intensity ultrasound (US) is considered a safe modality for eliciting neural activity in the central auditory system. Although the neural modulation ability of low-intensity US has been demonstrated in the human primary somatosensory cortex and primary visual cortex, whether low-intensity US can directly activate auditory cortical neurons is still a topic of debate. To clarify the direct effects on auditory neurons, in the present study, we employed low-intensity US to stimulate auditory cortical neurons in vitro. Our data show that both low-frequency (0.8 MHz) and high-frequency (>27 MHz) US stimulation can elicit the inward current and action potentials in cultured neurons. c-Fos staining results indicate that low-intensity US is efficient for stimulating most neurons. Our study suggests that low-intensity US can excite auditory cortical neurons directly, implying that US-induced neural modulation can be a potential approach for activating the auditory cortex of deaf patients.

Regulatory role of Golgi brefeldin A resistance factor-1 in amyloid precursor protein trafficking, cleavage and Aß formation.

ß-amyloid peptide (Aß) deposition derived from sequential cleavage of the amyloid precursor protein (APP) through the amyloidogenic pathway is an important characteristic feature of Alzheimer's disease (AD). During this process, cellular trafficking plays a crucial role. A large Sec7-domain containing ADP-ribosylation factor guanine nucleotide exchange factor (ARF-GEF), Golgi brefeldin A resistance factor 1 (GBF1) has been reported to initiate the ADP-ribosylation factor (Arf) activation cascade at trans-Golgi network, which plays a crucial function at the endoplasmic reticulum-Golgi interface. In this study, we investigated the role of GBF1 in APP transmembrane transport and Aß formation. Using APP/PS1 (presenilin 1) overexpressing transgenic mice, we demonstrate that GBF1 has upregulated the expression of APP, indicating a role for GBF1 in APP physiological process. Knocking down of GBF1 using small interfering has significantly increased the intracellular but not the surface expression of APP. In contrast, overexpression of wild-type (WT) and guanine nucleotide exchange factor (GEF) in the activated form but not the GEF deficient mutation induced continuous activation of GBF1, which subsequently increased the surface level of APP. Interestingly, inhibition of GBF1 by c(BFA) also impaired APP trafficking and induced endoplasmic reticulum (ER) stress in SH-SY5Y cells. Our results thus for identified the role of GBF1 in APP trafficking and cleavage, and provide evidence for GBF1 as a possible therapeutic target in AD.

Specific Influences of Early Acoustic Environments on Cochlear Hair Cells in Postnatal Mice.

The auditory function develops and matures after birth in many mammalian species. After hearing onset, environmental sounds exert profound and long-term effects on auditory functions. However, the effects of the acoustic environment on the functional development of the peripheral auditory system, especially the cochlear sensory hair cells, are still unclear. In the present study, we exposed mouse pups to frequency-enriched acoustic environments in postnatal days 0-14. The results indicated that the acoustic environment significantly decreased the threshold of the auditory brainstem response in a frequency-specific manner. Compared with controls, no difference was found in the number and alignment of inner and outer hair cells or in the length of hair bundles after acoustic overstimulation. The expression and function of prestin, the motor protein of outer hair cells (OHCs), were specifically increased in OHCs activated by acoustic stimulation at postnatal days 7-11. We analyzed the postnatal maturation of ribbon synapses in the hair cell areas. After acoustic stimulation, the number of ribbon synapses was closer to the mature stage than to the controls. Taken together, these data indicate that early acoustic exposure could promote the functional maturation of cochlear hair cells and the development of hearing.

SNX10 Plays a Critical Role in MMP9 Secretion via JNK-p38-ERK Signaling Pathway.

Matrix metalloproteinases (MMPs) plays a critical role in the degradation of extracellular matrix (ECM). Sorting nexin (SNX) 10 is a member of the SNX family, which functions in regulation of endosomal sorting and osteoclast activation, has been implicated to play an important role in the bone erosion of rheumatoid arthritis. In this study, we aimed to investigate the possible role of SNX10 on MMP9 secretion and the potential mechanism. By immunostaining and co-immunoprecipitation, we found that SNX10 was extensively co-localized with MMP9, indicating that SNX10 might participate in MMP9 trafficking. After knocking down SNX10 via siRNA, the secretion and activity of MMP9 was significantly reduced, but the amount of protein was increased. By contraries, over-expression of SNX10 could increase the secretion and activity levels. Deficiency of SNX10 impaired the differentiation and bone resorption function of osteoclast, with a low activity of MMP9 compared to WT one. In SNX10 knockout osteoclast, the phosphorylation levels of JNK, p38, and ERK were obviously down-regulated. Our results first identified the role of SNX10 in MMP9 trafficking and secretion, and provided an evidence for SNX10 as a possible therapeutic target for bone destructing disease. J. Cell. Biochem. 118: 4664-4671, 2017. © 2017 Wiley Periodicals, Inc.

Deficiency of sorting nexin 10 prevents bone erosion in collagen-induced mouse arthritis through promoting NFATc1 degradation.

OBJECTIVE: Periarticular and subchondral bone erosion in rheumatoid arthritis caused by osteoclast differentiation and activation is a critical index for diagnosis, therapy and monitoring of the disease. Sorting nexin (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting, has been implicated to play an important clinical role in malignant osteopetrosis. Here we studied the roles and precise mechanisms of SNX10 in the bone destruction of collagen-induced arthritis (CIA) mice. METHODS: The role of SNX10 in bone destruction was evaluated by a CIA mice model which was induced in male SNX10(-/-) mice and wild type littermates. The mechanism was explored in osteoclasts induced by receptor activator of nuclear factor κB ligand from bone marrow mononuclear cells of wild type and SNX10(-/-) mice. RESULTS: SNX10 knockout prevented bone loss and joint destruction in CIA mice with reduced serum levels of TNF-α, interleukin 1ß and anticollagen IgG 2α antibody. SNX10 deficiency did not block osteoclastogenesis, but significantly impaired osteoclast maturation and bone-resorption function by disturbing the formation of actin belt. The production of TRAP, CtsK and MMP9 in SNX10(-/-) osteoclasts was significantly inhibited, and partially restored by SNX10 overexpression. We further demonstrated that the degradation of NFATc1 was accelerated in SNX10(-/-) osteoclasts causing an inhibition of integrin ß3-Src-PYK2 signalling. CONCLUSIONS: Our study discloses a crucial role and novel mechanism for SNX10 in osteoclast function, and provides evidence for SNX10 as a promising novel therapeutic target for suppression of immune inflammation and bone erosion in rheumatoid arthritis.

Synchronized Progression of Prestin Expression and Auditory Brainstem Response during Postnatal Development in Rats.

Prestin is the motor protein expressed in the cochlear outer hair cells (OHCs) of mammalian inner ear. The electromotility of OHCs driven by prestin is responsible for the cochlear amplification which is required for normal hearing in adult animals. Postnatal expression of prestin and activity of OHCs may contribute to the maturation of hearing in rodents. However, the temporal and spatial expression of prestin in cochlea during the development is not well characterized. In the present study, we examined the expression and function of prestin from the OHCs in apical, middle, and basal turns of the cochleae of postnatal rats. Prestin first appeared at postnatal day 6 (P6) for basal turn, P7 in middle turn, and P9 for apical turn of cochlea. The expression level increased progressively over the next few days and by P14 reached the mature level for all three segments. By comparison with the time course of the development of auditory brainstem response for different frequencies, our data reveal that prestin expression synchronized with the hearing development. The present study suggests that the onset time of hearing may require the expression of prestin and is determined by the mature function of OHCs.

Histotype differentiation of hypo-echoic renal tumors on CEUS: usefulness of enhancement homogeneity and intensity.

PURPOSE: The purpose of this study is to evaluate qualitative and quantitative analysis of contrast-enhanced ultrasound (CEUS) in differential diagnoses of hypo-echoic renal tumor histotypes. METHODS: Our study cohort comprised 103 clear cell renal cell carcinomas (ccRCCs), 24 papillary renal cell carcinomas (pRCCs), 28 chromophobe renal cell carcinomas (cRCCs), and 34 angiomyolipomas (AMLs), hypo-echoic on ultrasound, and imaged between January 2011 and December 2013. Enhancement homogeneity and tumor-to-cortex intensity ratio (TOC ratio) were retrospectively analyzed. RESULTS: Overall, heterogeneous enhancement was more common in ccRCCs than AMLs, pRCCs, and cRCCs. TOC ratio showed the trend ccRCC > AML > pRCC = cRCC. Similar trends were seen in tumors <4 cm. Using heterogeneous enhancement or TOC ratio >107.5% to differentiate ccRCC from other histotypes, the sensitivity, specificity, positive and negative predictive values were 93.1%, 74.5%, 84.8%, and 87.5%, respectively. Tumors >4 cm exhibited considerable overlap in enhancement homogeneity among different histotypes. TOC ratios were similar between homo- and heterogeneously enhancing tumors for ccRCCs and for pRCCs and cRCCs, but higher in homogeneously enhancing than heterogeneously enhancing AMLs. In homo- and heterogeneously enhancing tumors, TOC ratios followed the trends ccRCCs > AMLs > pRCCs = cRCCs and ccRCCs > AMLs = pRCCs = cRCCs, respectively. With TOC ratio >105.81% and >72.37% to differentiate homo- and heterogeneously enhancing ccRCCs from other histotypes in tumors >4 cm with same enhancement homogeneity, the sensitivity, specificity, positive and negative predictive values were 70.0%, 85.7%, 70.0%, 85.7%, and 91.7%, 94.4%, 95.7%, 89.5%, respectively. CONCLUSION: CEUS homogeneity and TOC ratio are helpful in differential diagnosis of hypo-echoic renal tumor histotypes. Diameter and enhancement homogeneity should be considered when deciding the diagnostic TOC ratio cutoff.

Triphasic and epithelioid minimal fat renal angiomyolipoma and clear cell renal cell carcinoma: qualitative and quantitative CEUS characteristics and distinguishing features.

PURPOSE: To determine the contrast-enhanced ultrasonography (CEUS) characteristics of minimal fat renal angiomyolipoma (AML) (triphasic and epithelioid) and compare them to each other and to clear cell renal cell carcinoma (ccRCC) to explore their differential diagnostic clue. METHODS: Qualitative and quantitative CEUS analyses were retrospectively conducted for epithelioid renal AMLs (EAMLs) (n = 15), triphasic minimal fat AMLs (TAMLs) (n = 25), and ccRCCs (n = 113). Enhancement patterns and features with CEUS were qualitatively evaluated. As for the quantitative parameters, rise times (RT), time to peak (TTP), and tumor-to-cortex enhancement ratio (TOC ratio) were compared among these renal tumor histotypes. RESULTS: No significant differences were detected on conventional ultrasound in the three histotypes of renal tumor. On qualitative CEUS analysis, centripetal enhancement in cortical phase (73.3% in EAMLs, 84.0% in TAMLs vs. 18.6% in ccRCCs, p < 0.001 for both), homogeneous peak enhancement (100.0% in both EAMLs and TAMLs vs. 43.4% in ccRCCs, p < 0.001 for both), and iso-enhancement in parenchyma phase (53.3% in AMLs, 52.0% in TAMLs vs. 26.5% in ccRCCs, p = 0.034 and 0.013, respectively) were valuable traits for differentiating EAMLs and TAMLs from ccRCCs. Furthermore, with quantitative analysis, RT and TTP were much shorter in ccRCCs than those in EAMLs and TAMLs. However, all these qualitative and quantitative characteristics made no significant difference between EAMLs and TAMLs. In the differential diagnosis of EAMLs from TAMLs, pseudocapsule sign was valuable (40.0% in EAMLs vs. 0.0% in TAMLs, p < 0.001), and TOC ratio was much higher in EAMLs (166.01 ± 64.47%) than that in TAMLs (93.74 ± 46.56%)(p < 0.001), though they did make overlaps with ccRCCs. With either heterogeneous peak enhancement or the presence of pseudocapsule or TOC ratio >97.34% as the criteria to differentiate ccRCCs and EAMLs from TAMLs, the sensitivity and specificity were 80.0% and 87.5%, respectively. CONCLUSIONS: Qualitative and quantitative CEUS analyses are helpful in the differential diagnosis of ccRCCs, EAMLs, and TAMLs.

Dynamic enhancement pattern of intrahepatic cholangiocarcinoma on contrast-enhanced ultrasound: the correlation with cirrhosis and tumor size.

PURPOSE: To retrospectively evaluate the dynamic enhancement pattern of contrast-enhanced ultrasound (CEUS) in intrahepatic cholangiocarcinoma (ICC) of varying sizes and hepatic backgrounds. MATERIALS AND METHODS: CEUS was performed in 98 pathologically confirmed ICCs (n = 39 < 30 mm, n = 59 > 30 mm; n = 45 with cirrhosis and n = 53 with normal liver). The dynamic enhancement pattern of CEUS was retrospectively analyzed. RESULTS: In the arterial phase, heterogeneous hyper-enhancement was more frequent in ICCs with cirrhosis (21/45, 46.7% vs. 11/53, 20.8% in ICCs with normal liver, p = 0.009), while peripheral hyper-enhancement and hypo-enhancement were more common in ICCs with normal liver (14/53, 26.4%; 11/53, 20.8% vs. 2/45, 4.4%; 2/45, 4.4% in ICCs with cirrhosis, p = 0.005 and 0.033, respectively). There were no significant differences between portal and delayed phases. In ICCs < 30 mm, homogeneous hyper-enhancement was more frequently identified (27/39, 69.2% vs. 10/59, 16.9% in ICCs > 30 mm, p < 0.001), whereas in ICCs > 30 mm, heterogeneous, and peripheral hyper-enhancement were more commonly observed (26/59, 44.1% vs. 6/39, 15.4% in ICCs < 30 mm, p = 0.004, and 14/59, 23.7% vs. 2/39, 5.1% in ICCs < 30 mm, p = 0.023, respectively). The washout pattern in portal and delayed phases were not significantly different in ICCs with different sizes. 60.7% (17/28) ICCs < 30 mm and 85.2% (23/27) ICCs > 30 mm with cirrhosis, together with 66.7% (14/21) ICCs < 30 mm with normal liver displayed intense contrast agent uptake (homogeneous or heterogeneous hyper-enhancement) in arterial phase followed by washout in portal and delayed phase, which was much higher than that in ICCs > 30 mm with normal liver (34.4%, 11/32, p < 0.001, <0.001 and =0.027, respectively). CONCLUSION: The CEUS dynamic enhancement pattern of ICC varies with size and hepatic background. The enhancement pattern is indistinguishable from hepatocellular carcinoma on CEUS in most ICCs with cirrhosis and in most ICCs < 30 mm with normal liver.

[Solitary hypovascular hepatic nodules: MR characterization and differential diagnosis].

OBJECTIVE: The purpose of this study was to compare MRI findings of solitary hypovascular hepatic nodules, benign and malignant, to identify their MRI characteristics. METHODS: We retrospectively assessed solitary hypovascular hepatic nodules ≤ 3 cm in 135 patients, among them there were 55 malignant nodules [29 peripheral nodules of cholangiocarcinoma, PCC, and 26 hepatic metastases, HM] and 80 benign nodules [48 inflammatory myofibroblastic tumors, IMT, and 32 hepatic hemangioma, HG], proved by surgery, biopsy or follow-up imaging. Unenhanced and dynamic enhanced MRI findings of the 135 patients were analyzed retrospectively. Statistical analysis included Chi-square test or Fisher's exact test, and receiver operating characteristic (ROC) curve. RESULTS: There was significant difference (P < 0.05) between the malignant group and benign group in terms of location, margin, T2WI signal intensity, heterogeneity or homogeneity of the nodule, and type and degree of peritumoral and intratumoral enhancement. Area under the curve at the first film reading by three radiologists was 0.678 ± 0.047, 0.920 ± 0.022 at the second time, and there was a significant difference (Z = 5.22, P < 0.05) between them. CONCLUSIONS: Our data indicated that solitary hypovascular hepatic nodules show unenhanced and dynamic enhanced MRI features. Therefore, MR imaging combined with clinical and biochemical data does provide reliable information for a proper diagnosis of such hepatic lesions and differentiation of malignant from benign nodules.

BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein modulates ATP-binding cassette transporter A-1 trafficking and function.

OBJECTIVE: Cell-surface localization and intracellular trafficking are essential for the function of ATP-binding cassette transporter A-1 (ABCA1). However, regulation of these activities is still largely unknown. Brefeldin A, an uncompetitive inhibitor of brefeldin A-inhibited guanine nucleotide-exchange proteins (BIGs), disturbs the intracellular distribution of ABCA1, and thus inhibits cholesterol efflux. This study aimed to define the possible roles of BIGs in regulating ABCA1 trafficking and cholesterol efflux, and further to explore the potential mechanism. METHODS AND RESULTS: By vesicle immunoprecipitation, we found that BIG1 was associated with ABCA1 in vesicles preparation from rat liver. BIG1 depletion reduced surface ABCA1 on HepG2 cells, and inhibited by 60% cholesterol release. In contrast, BIG1 overexpression increased surface ABCA1 and cholesterol secretion. With partial restoration of BIG1 through overexpression in BIG1-depleted cells, surface ABCA1 was also restored. Biotinylation and glutathione cleavage revealed that BIG1 small interfering RNA dramatically decreased the internalization and recycling of ABCA1. This novel function of BIG1 was dependent on the guanine nucleotide-exchange activity and achieved through activation of ADP-ribosylation factor 1. CONCLUSIONS: BIG1, through its ability to activate ADP-ribosylation factor 1, regulates cell-surface levels and function of ABCA1, indicating a transcription-independent mechanism for controlling ABCA1 action.

DEP domain containing 1 as a biomarker for poor prognosis in lung adenocarcinoma.

Objective: The DEP domain-containing 1 (DEPDC1) gene is essential in the development and advancement of different types of cancer. This study is to examine the levels of DEPDC1 in lung adenocarcinoma (LUAD), and to determine its relationship with clinical results and immune response. The goal is to assess its potential as a biomarker and therapeutic target for LUAD. Methods: By comprehensively utilizing the Cancer Genome Atlas (TCGA), gene Expression Synthesis (GEO), UALCAN, cBioPortal, TISIDB databases and online platforms, we conducted a bioinformatics analysis to investigate DEPDC1 gene survival analysis, prognostic diagnosis, prognostic survival, immune cell infiltration, DNA methylation, and the correlation of genetic mutations in LUAD. The results were validated through cell assay and immunohistochemical staining. Results: DEPDC1 shows high levels of expression in the majority of tumors, with its expression being notably elevated in LUAD compablue to normal tissues. The expression of DEPDC1 varies based on the clinical characteristics of patients with LUAD. DEPDC1 expression affects the survival prognosis and prognostic model construction of LUAD patients. In addition, the presence of DEPDC1 is linked to immune infiltration. Various chemokines and chemokine receptors, immunoinhibitors and immune-stimulators in LUAD are significantly correlated with DEPDC1 methylation levels. Cell experiments confirmed through qPCR that the mRNA expression of DEPDC1 in LUAD was markedly elevated in comparison to the normal population, and immunohistochemistry showed positive DEPDC1 expression in LUAD pathological sections. Conclusion: Systematic analysis and experiments have verified that DEPDC1 serves as a biomarker for detecting early, prediction of survival, and evaluation of immune cell infiltration in LUAD.

Association between perceived overqualification, work engagement, job satisfaction among nurses: a cross-sectional study.

OBJECTIVES: This cross-sectional correlational study aimed to understand nurses' perceived overqualification and work engagement, explore their effects on job satisfaction and provide a theoretical basis for hospital management policies in a public comprehensive tertiary hospital in China. DESIGN: Cross-sectional correlational study. SETTING: The study was conducted in a public comprehensive tertiary hospital in China. The specific location is not disclosed. PARTICIPANTS: 584 nurses participated in the study, with a completion rate of 97.3%. The average age of participants was 34.8±6.7 years, with 96.4% being women. 67.8% held a bachelor's degree or higher, and 71.6% had over 5 years of work experience. PRIMARY AND SECONDARY OUTCOME MEASURES: The Scale of Perceived Overqualification was used to assess nurses' perceptions of their qualifications, demonstrating a high level of reliability with a Cronbach's alpha coefficient of 0.832. Utrecht Work Engagement Scale was used to assess nurses' work engagement, showing internal consistency coefficients (Cronbach's alpha) of 0.683 for the vigour dimension, 0.693 for the dedication dimension and 0.834 for the absorption dimension. Minnesota Satisfaction Questionnaire was used to evaluate nurses' job satisfaction, with internal consistency coefficients (Cronbach's alpha) of 0.765 for the intrinsic satisfaction scale and 0.734 for the extrinsic satisfaction scale. The primary outcome measures included perceived overqualification, work engagement and job satisfaction. RESULTS: The average scores for perceived overqualification, work engagement and job satisfaction were 26.38±3.44, 65.36±14.92 and 74.29±15.04, respectively. Perceived overqualification showed negative correlations with work engagement (r=-0.562, p<0.05) and job satisfaction (r=-0.674, p<0.05). However, work engagement was positively correlated with job satisfaction (r=0.519, p<0.05). Path analysis indicated that perceived overqualification had both a direct (ß=-0.06, p<0.001) and an indirect effect (ß=-0.35, p=0.015) on job satisfaction, with work engagement partially mediating this relationship. CONCLUSION: The perception of overqualification among nurses shows a significant correlation with both their work engagement and job satisfaction. This finding suggests that hospital administrators should pay attention to nurses' perceptions of their qualifications and take measures to enhance their job satisfaction. Furthermore, work engagement acts as a mediator between the perception of overqualification and job satisfaction, emphasising the importance of increasing work engagement. Overall, hospitals can improve nurses' work engagement and job satisfaction by providing career development opportunities, establishing feedback mechanisms and fostering work-life balance. Comprehensive management measures focusing on nurses' career development opportunities and levels of work engagement are necessary. Future research could expand the sample size, employ more diverse research designs and integrate qualitative research methods to further explore the factors influencing nurses' job satisfaction and happiness.

Engineering Photothermal Catalytic CO2 Nanoreactor for Osteomyelitis Treatment by In Situ CO Generation.

Photocatalytic carbon dioxide (CO2) reduction is an effective method for in vivo carbon monoxide (CO) generation for antibacterial use. However, the available strategies mainly focus on utilizing visible-light-responsive photocatalysts to achieve CO generation. The limited penetration capability of visible light hinders CO generation in deep-seated tissues. Herein, a photothermal CO2 catalyst (abbreviated as NNBCs) to achieve an efficient hyperthermic effect and in situ CO generation is rationally developed, to simultaneously suppress bacterial proliferation and relieve inflammatory responses. The NNBCs are modified with a special polyethylene glycol and further embellished by bicarbonate (BC) decoration via ferric ion-mediated coordination. Upon exposure to 1064 nm laser irradiation, the NNBCs facilitated efficient photothermal conversion and in situ CO generation through photothermal CO2 catalysis. Specifically, the photothermal effect accelerated the decomposition of BC to produce CO2 for photothermal catalytic CO production. Benefiting from the hyperthermic effect and in situ CO production, in vivo assessments using an osteomyelitis model confirmed that NNBCs can simultaneously inhibit bacterial proliferation and attenuate the photothermal effect-associated pro-inflammatory response. This study represents the first attempt to develop high-performance photothermal CO2 nanocatalysts to achieve in situ CO generation for the concurrent inhibition of bacterial growth and attenuation of inflammatory responses.

Cryptotanshinone inhibits human glioma cell proliferation by suppressing STAT3 signaling.

Malignant gliomas (MGs) are among the most aggressive types of cancers in the human brain. Frequent tumor recurrence caused by a lack of effective therapeutic approaches results in a poor prognosis. Signal transducer and activator of transcription 3 (STAT3), an oncogenic protein, is constitutively activated in MGs and predicts a poor clinical outcome. STAT3 therefore is considered to be a promising target for the treatment of MGs. Cryptotanshinone (CTS), the main bioactive compound from the root of Salvia miltiorrhiza Bunge, has been reported to have various pharmacological effects. However, little is known about its function in MG cells. In this study, we evaluated the effect of CTS on the proliferation of human glioma cell lines (T98G and U87). Our results revealed that CTS significantly suppresses glioma cell proliferation. The phosphorylation of STAT3 Tyr705, but not Ser727, was inhibited by CTS, and STAT3 nuclear translocation was attenuated. Overexpression of constitutively active mutant STAT3C reversed the inhibitory effect of CTS, while knockdown STAT3 showed a similar inhibitory effect as CTS treatment. Following the downregulation of STAT3-regulated proteins cyclinD1 and survivin, cell cycle progression significantly arrested in G1/G0 phase. These results indicate that CTS may be a potential antiproliferation agent for the treatment of MGs and that its mechanism may be related to the inhibition of STAT3 signaling.

14-3-3ζ Mediates GABAAR Activation by Interacting with BIG1.

Most fast synaptic inhibitions in the mammalian brain are mediated by GABAA receptors (GABAARs). An appropriate level of GABAAR expression at the cell surface is essential for neurodevelopment and the efficacy of GABAergic synaptic transmission. We previously reported that brefeldin A-inhibited GDP/GTP exchange factor 1 (BIG1), a binding partner of GABAARs, plays an important role in trafficking GABAARs to the cell surface. However, its regulatory mechanisms remain unknown. In the present study, we identified a new cellular protein, 14-3-3ζ, which can interact with the ß subunit of GABAARs and BIG1 both in vitro and in vivo and colocalizes in the soma, dendrites, and axons of hippocampal neurons. Overexpression of 14-3-3ζ-WT increased the surface expression of BIG1 in dendrites and axons, as well as the binding of BIG1 with GABAAR. Depleted 14-3-3ζ with efficacious siRNA attenuated the interaction between BIG1 and GABAARs and resulted in significant decreases in the surface expression levels of BIG1 and GABAAR. GABAAR agonist treatment increased the expression levels of BIG1 and 14-3-3ζ on the surface, indicating that 14-3-3ζ is involved in regulating BIG1-mediated GABAAR surface expression. Depletion of BIG1 or 14-3-3ζ significantly decreased GABAAR expression at the cell surface and suppressed the GABA-gated influx of chloride ions. These data indicate that the combination of 14-3-3ζ and BIG1 is required for GABAAR membrane expression. Our results provide a potential promising therapeutic target for neurological disorders involving GABAergic synaptic transmission.

Rosmarinic acid nanomedicine for rheumatoid arthritis therapy: Targeted RONS scavenging and macrophage repolarization.

The infiltration of inflammatory cells, especially macrophages, integrated with the production of reactive oxygen and nitrogen species (RONS) and the release of inflammatory cytokines play a crucial role in the pathogenesis of rheumatoid arthritis (RA). Synergistic combination of RONS scavenging and macrophage repolarization from pro-inflammatory M1 phenotype towards anti-inflammatory M2 phenotype, provides a promising strategy for efficient RA treatment. Herein, this study reported a unique self-assembly strategy to construct distinct rosmarinic acid nanoparticles (RNPs) for efficient RA treatment using the naturally occurring polyphenol-based compound, rosmarinic acid (RosA). The designed RNPs exhibited favorable capability in scavenging RONS and pro-inflammatory cytokines produced by macrophages. Attributing to the widened vascular endothelial-cell gap at inflammation sites, RNPs could target and accumulate at the inflammatory joints of collagen-induced arthritis (CIA) rats for guaranteeing therapeutic effect. In vivo investigation demonstrated that RNPs alleviated the symptoms of RA, including joint swelling, synovial hyperplasia, cartilage degradation, and bone erosion in CIA rats. Additionally, the designed RNPs promoted macrophage polarization from M1 phenotype towards M2 phenotype, resulting in the suppressed progression of RA. Therefore, this research represents the representative paradigm for RA therapy using antioxidative nanomedicine deriving from the natural polyphenol-based compound.

3D-CEUS tracking of injectable chemo-sonodynamic therapy-enabled mop-up of residual renal cell carcinoma after thermal ablation.

Thermal ablation (TA), as a minimally invasive therapeutic technique, has been extensively used to the treatment of solid tumors, such as renal cell carcinoma (RCC), which, unfortunately, still fails to overcome the high risk of local recurrence and distant metastasis since the incomplete ablation cannot be ignored due to various factors such as the indistinguishable tumor margins and limited ablation zone. Herein, we report the injectable thermosensitive hydrogel by confining curcumin (Cur)-loaded hollow mesoporous organosilica nanoparticles (Cur@HMON@gel) which can locate in tumor site more than half a month and mop up the residual RCC under ultrasound (US) irradiation after transforming from colloidal sol status to elastic gel matrix at physiological temperature. Based on the US-triggered accelerated diffusion of the model chemotherapy drug with multi-pharmacologic functions, the sustained and controlled release of Cur has been demonstrated in vitro. Significantly, US is employed as an external energy to trigger Cur, as a sonosensitizer also, to generate reactive oxygen species (ROS) for sonodynamic tumor therapy (SDT) in parallel. Tracking by the three-dimensional contrast-enhanced ultrasound (3D-CEUS) imaging, the typical decreased blood perfusions have been observed since the residual xenograft tumor after incomplete TA were effectively suppressed during the chemo-sonodynamic therapy process. The high in vivo biocompatibility and biodegradability of the multifunctional nanoplatform confined by thermogel provide the potential of their further clinical translation for the solid tumor eradication under the guidance and monitoring of 3D-CEUS.

PPARα activation inhibits endothelin-1-induced cardiomyocyte hypertrophy by prevention of NFATc4 binding to GATA-4.

Peroxisome proliferator-activated receptor alpha (PPARα) has been implicated in the pathogenesis of cardiac hypertrophy, although its mechanism of action remains largely unknown. To determine the effect of PPARα activation on endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy and explore its molecular mechanisms, we evaluated the interaction of PPARα with nuclear factor of activated T-cells c4 (NFATc4) in nuclei of cardiomyocytes from neonatal rats in primary culture. In ET-1-stimulated cardiomyocytes, data from electrophoretic mobility-shift assays (EMSA) and co-immunoprecipitation (co-IP) revealed that fenofibrate (Fen), a PPARα activator, in a concentration-dependent manner, enhanced the association of NFATc4 with PPARα and decreased its interaction with GATA-4, in promoter complexes involved in activation of the rat brain natriuretic peptide (rBNP) gene. Effects of PPARα overexpression were similar to those of its activation by Fen. PPARα depletion by small interfering RNA abolished inhibitory effects of Fen on NFATc4 binding to GATA-4 and the rBNP DNA. Quantitative RT-PCR and confocal microscopy confirmed inhibitory effects of PPARα activation on elevation of rBNP mRNA levels and ET-1-induced cardiomyocyte hypertrophy. Our results suggest that activated PPARα can compete with GATA-4 binding to NFATc4, thereby decreasing transactivation of NFATc4, and interfering with ET-1 induced cardiomyocyte hypertrophy.